ArticlePDF Available

Abstract and Figures

Forskolin is mainly found in the root of a plant called Coleus forskohlii (Willd.) Briq., which has been used in the traditional medicine of Indian Ayurvedic and Southeast Asia since ancient times. Forskolin is responsible for the pharmacological activity of this species. Forskolin is a labdane diterpenoid with a wide biological effect. Several studies suggested a positive role of forskolin on heart complications, respiratory disorders, high blood pressure, obesity, and asthma. There are numerous clinical and pre-clinical studies representing the effect of forskolin on the above-mentioned disorders but more clinical studies need to be performed to support its efficacy.
Content may be subject to copyright.
applied
sciences
Review
The Therapeutic Potential of the Labdane
Diterpenoid Forskolin
Bahare Salehi 1, Mariola Staniak 2, Katarzyna Czopek 2, Anna St˛epie ´n 2, Kamal Dua 3,4,5,*,
Ridhima Wadhwa 6, Dinesh Kumar Chellappan 7, Oksana Sytar 8,9 , Marian Brestic 9,
Namrata Ganesh Bhat 10, Nanjangud Venkatesh Anil Kumar 10 , María del Mar Contreras 11,* ,
Farukh Sharopov 12, * , William C. Cho 13,* and Javad Sharifi-Rad 14, *
1
Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam 44340847, Iran;
bahar.salehi007@gmail.com
2
Institute of Soil Science and Plant Cultivation—State Research Institute, Czartoryskich Str. 8, 24-100 Puławy,
Poland; staniakm@iung.pulawy.pl (M.S.); kczopek@iung.pulawy.pl (K.C.); astepien@iung.pulawy.pl (A.S.)
3Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney,
Ultimo, NSW 2007, Australia
4Centre for Inflammation, Centenary Institute, University of Newcastle, Callaghan, NSW 2308, Australia
5Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) & School of
Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia
6Faculty of Life Science and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri,
New Delhi 110021, India; rw4565@gmail.com
7Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil,
Kuala Lumpur 57000, Malaysia; Dinesh_Kumar@imu.edu.my
8Department of Plant Biology Department, Taras Shevchenko National University of Kyiv,
Institute of Biology, Volodymyrska str., 64, Kyiv 01033, Ukraine; oksana.sytar@gmail.com
9Department of Plant Physiology, Slovak University of Agriculture, Nitra, A. Hlinku 2, 94976 Nitra, Slovak;
marian.brestic@uniag.sk
10 Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education,
Manipal 576104, India; namrata.gb07@gmail.com (N.G.B.); nv.anil@manipal.edu (N.V.A.K.)
11 Department of Chemical, Environmental and Materials Engineering, University of Jaén, 23071 Jaén, Spain
12 Department of Pharmaceutical Technology, Avicenna Tajik State Medical University,
Dushanbe 73400, Tajikistan
13 Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong, China
14 Zabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol 61615-585, Iran
*Correspondence: Kamal.Dua@uts.edu.au (K.D.); mmcontreras@ugr.es or mcgamez@ujaen.es (M.d.M.C.);
shfarukh@mail.ru (F.S.); williamcscho@gmail.com (W.C.C.); javad.sharifirad@gmail.com (J.S.-R.)
Received: 30 August 2019; Accepted: 26 September 2019; Published: 30 September 2019


Abstract:
Forskolin is mainly found in the root of a plant called Coleus forskohlii (Willd.) Briq., which
has been used in the traditional medicine of Indian Ayurvedic and Southeast Asia since ancient
times. Forskolin is responsible for the pharmacological activity of this species. Forskolin is a labdane
diterpenoid with a wide biological eect. Several studies suggested a positive role of forskolin on
heart complications, respiratory disorders, high blood pressure, obesity, and asthma. There are
numerous clinical and pre-clinical studies representing the eect of forskolin on the above-mentioned
disorders but more clinical studies need to be performed to support its ecacy.
Keywords: forskolin; plant secondary metabolites; Coleus forskohlii; cAMP pathway
Appl. Sci. 2019,9, 4089; doi:10.3390/app9194089 www.mdpi.com/journal/applsci
Appl. Sci. 2019,9, 4089 2 of 13
1. Introduction
The fortitude of traditional medicine depends on the knowledge of plant medicinal characteristics.
The major drivers of the pharmacological actions of medicinal plants are plant secondary
metabolites [1,2]
. Secondary metabolites are known as signal molecules for plant biosynthesis but also
play defense role against herbivores, and other plants and microbes [
3
5
]. Terpenes are a diverse and
big group of organic compounds, which are present in medicinal plants and may protect the plants
that produce them by deterring herbivores and by attracting predators and parasites of herbivores [
6
].
The treatment of health disorders and infections with herbal medicines engages active natural products,
mostly of low molecular weight, with great structural diversity such as terpenes and terpenoids [
7
,
8
].
Terpenes and terpenoids are the main components of the essential oils of many types of plants
and flowers. Their biosynthesis occurs within specific tissues or at specific stages of development in
plants [
9
]. Many terpenoids also possess pharmaceutical properties and are currently being used in
clinical practices. Nowadays, terpenoids intensively applied in traditional drugs are taxol (diterpene)
from Taxus baccata L. and artemisinin (sesquiterpene lactone) from Artemisia annua L. as malaria and
cancer medicines, respectively, and forskolin (Figure 1a) from Coleus forskohlii (Willd.) Briq. (also
known as Plectranthus forskohlii Willd.) (Lamiaceae) [
10
13
]. Forskolin is known to treat conditions
such as heart complications, respiratory disorders, and asthma [14,15].
Appl. Sci. 2019, 9, x FOR PEER REVIEW 2 of 13
1. Introduction
The fortitude of traditional medicine depends on the knowledge of plant medicinal
characteristics. The major drivers of the pharmacological actions of medicinal plants are plant
secondary metabolites [1,2]. Secondary metabolites are known as signal molecules for plant
biosynthesis but also play defense role against herbivores, and other plants and microbes [35].
Terpenes are a diverse and big group of organic compounds, which are present in medicinal plants
and may protect the plants that produce them by deterring herbivores and by attracting predators
and parasites of herbivores [6]. The treatment of health disorders and infections with herbal
medicines engages active natural products, mostly of low molecular weight, with great structural
diversity such as terpenes and terpenoids [7,8].
Terpenes and terpenoids are the main components of the essential oils of many types of plants
and flowers. Their biosynthesis occurs within specific tissues or at specific stages of development in
plants [9]. Many terpenoids also possess pharmaceutical properties and are currently being used in
clinical practices. Nowadays, terpenoids intensively applied in traditional drugs are taxol (diterpene)
from Taxus baccata L. and artemisinin (sesquiterpene lactone) from Artemisia annua L. as malaria and
cancer medicines, respectively, and forskolin (Figure 1a) from Coleus forskohlii (Willd.) Briq. (also
known as Plectranthus forskohlii Willd.) (Lamiaceae) [1013]. Forskolin is known to treat conditions
such as heart complications, respiratory disorders, and asthma [14,15].
Figure 1. The chemical structure of: (a) forskolin; (b) geranyl geranyl diphosphate; and (c) 13R-manoyl
oxide.
In particular, forskolin, which is exclusively found in the root of C. forskohlii, has been used in
traditional Indian Ayurvedic, under the name “Makandi” or “Mayani”, and Southeast Asian
medicine since ancient times [15]. In African countries, it is commonly known as a drug in diseases
of the digestive, urinary and respiratory tracts [16]. C. forskohlii is commonly found in Nepal, Burma,
Thailand, and India. It is also grown in many East African countries [1618]. India is a leading
exporter of C. forskohlii extracts and its products to various countries, mainly USA, Poland, South
Korea, Australia, Japan, Italy, Spain, South Africa, and Canada [19]. Chemically, the whole plant is
rich in alkaloids, but the most desirable part of the plant is the roots, because they contain the highest
concentrations of forskolin. In the extracts obtained from the C. forskohlii, the presence of α-amyrin,
(a) (b)
(c)
Figure 1.
The chemical structure of: (
a
) forskolin; (
b
) geranyl geranyl diphosphate; and (
c
) 13R-manoyl
oxide.
In particular, forskolin, which is exclusively found in the root of C. forskohlii, has been used in
traditional Indian Ayurvedic, under the name “Makandi” or “Mayani”, and Southeast Asian medicine
since ancient times [
15
]. In African countries, it is commonly known as a drug in diseases of the
digestive, urinary and respiratory tracts [
16
]. C. forskohlii is commonly found in Nepal, Burma, Thailand,
and India. It is also grown in many East African countries [
16
18
]. India is a leading exporter of
C. forskohlii extracts and its products to various countries, mainly USA, Poland, South Korea, Australia,
Japan, Italy, Spain, South Africa, and Canada [
19
]. Chemically, the whole plant is rich in alkaloids,
but the most desirable part of the plant is the roots, because they contain the highest concentrations
Appl. Sci. 2019,9, 4089 3 of 13
of forskolin. In the extracts obtained from the C. forskohlii, the presence of
α
-amyrin,
β
-sitosterol,
betulinic acid,
α
-cedrol, citronellal and
α
-cedren was also identified. Other diterpenoids such as
forskoditerpenoside A and B were also detected in the ethanolic extract from C. forskohlii, while in the
essential oil obtained from the roots of the plant were identified, among others: borneol,
α
-humulene,
1-octadecanol, 1-decanol, decanoic acid, 4-terpineol, 1,8-cineol,
α
- and
β
-pinene, camphene,
α
-cedrol,
α
-ylangene, and
γ
-terpinene [
15
,
16
,
18
]. However, the latter compounds have a weaker therapeutic
eect compared to forskolin. Hence, the research results show that forskolin is mainly responsible for
the pharmacological activity of herbal materials obtained from this species [20].
Forskolin, or coleonol, is a labdane diterpene synthesized in the plastid of plant cells. In the higher
plant, the non-mevalonic acid pathway takes place in plastids and synthesizes hemi-, mono-, sesqui-,
and diterpenes along with carotenoids and phytol tail of chlorophyll [
21
]. Forskolin is synthesized
by diterpene synthases via the substrate protonation at the 14,15-double bond of the initial precursor
geranyl geranyl diphosphate (Figure 1b) [
22
]. Forskolin contains some unique functional elements,
notably the tetrahydropyran-derived heterocyclic ring [23].
Forskolin is stored inside cells within the bark of the root in structures called oil bodies, which
are similar to oil drops. A technique called RNA sequencing was used to identify several genes that
are highly active in oil body’s cells and encoded five cytochrome P450s and two acetyltransferases
involved in a cascade of chemical reactions that convert a molecule called 13R-manoyl oxide (Figure 1c)
into forskolin [24].
The C. forskohlii plant, due to forskolin presence, is used for prevention of cancer metastases,
where the decreased level of activated cyclic adenosine monophosphate (cAMP) may play a main
role in the disease development [
25
]. This ability to directly activate the adenylate cyclase enzyme
resulting in elevated levels of the cAMP from adenosine-5
0
-triphosphate (ATP) is also related to other
pharmaceutical characteristics of forskolin [
26
]. In this context, the present review is focused on the
health-promoting eects of forskolin elucidated through modern research.
2. Pharmacological Activities of Forskolin
Forskolin is a naturally derived diterpenoid that can interact with the cAMP pathway.
This interaction
endows forskolin with significant therapeutic benefits against several metabolic
diseases, cancers and others. According to a number of clinical studies reported on clinicaltrials.gov,
the eects of forskolin have been studied in conditions such as asthma, cystic fibrosis, homozygous
F508DEL mutation, chronic obstructive pulmonary disease (COPD), metabolic syndrome, obesity and
glaucoma [
27
34
]. Notable clinical and preclinical studies, along with their pharmacological actions,
are discussed below. Moreover, a summary of the eects of forskolin is shown in Figure 2.
Appl. Sci. 2019, 9, x FOR PEER REVIEW 3 of 13
β-sitosterol, betulinic acid, α-cedrol, citronellal and α-cedren was also identified. Other diterpenoids
such as forskoditerpenoside A and B were also detected in the ethanolic extract from C. forskohlii,
while in the essential oil obtained from the roots of the plant were identified, among others: borneol,
α-humulene, 1-octadecanol, 1-decanol, decanoic acid, 4-terpineol, 1,8-cineol, α- and β-pinene,
camphene, α-cedrol, α-ylangene, and γ-terpinene [15,16,18]. However, the latter compounds have a
weaker therapeutic effect compared to forskolin. Hence, the research results show that forskolin is
mainly responsible for the pharmacological activity of herbal materials obtained from this species
[20].
Forskolin, or coleonol, is a labdane diterpene synthesized in the plastid of plant cells. In the
higher plant, the non-mevalonic acid pathway takes place in plastids and synthesizes hemi-, mono-,
sesqui-, and diterpenes along with carotenoids and phytol tail of chlorophyll [21]. Forskolin is
synthesized by diterpene synthases via the substrate protonation at the 14,15-double bond of the
initial precursor geranyl geranyl diphosphate (Figure 1b) [22]. Forskolin contains some unique
functional elements, notably the tetrahydropyran-derived heterocyclic ring [23].
Forskolin is stored inside cells within the bark of the root in structures called oil bodies, which
are similar to oil drops. A technique called RNA sequencing was used to identify several genes that
are highly active in oil body’s cells and encoded five cytochrome P450s and two acetyltransferases
involved in a cascade of chemical reactions that convert a molecule called 13R-manoyl oxide (Figure
1c) into forskolin [24].
The C. forskohlii plant, due to forskolin presence, is used for prevention of cancer metastases,
where the decreased level of activated cyclic adenosine monophosphate (cAMP) may play a main
role in the disease development [25]. This ability to directly activate the adenylate cyclase enzyme
resulting in elevated levels of the cAMP from adenosine-5-triphosphate (ATP) is also related to other
pharmaceutical characteristics of forskolin [26]. In this context, the present review is focused on the
health-promoting effects of forskolin elucidated through modern research.
2. Pharmacological Activities of Forskolin
Forskolin is a naturally derived diterpenoid that can interact with the cAMP pathway. This
interaction endows forskolin with significant therapeutic benefits against several metabolic diseases,
cancers and others. According to a number of clinical studies reported on clinicaltrials.gov, the effects
of forskolin have been studied in conditions such as asthma, cystic fibrosis, homozygous F508DEL
mutation, chronic obstructive pulmonary disease (COPD), metabolic syndrome, obesity and
glaucoma [2734]. Notable clinical and preclinical studies, along with their pharmacological actions,
are discussed below. Moreover, a summary of the effects of forskolin is shown in Figure 2.
Figure 2. Effects of forskolin in human health.
Cystic fibrosis
Preclinical
Clinical
cAMP affecting
chloride conductance
Obesity
cAMP and
hormone-sensitive
lipase
in hip and waist
circumference
body mass index
appetite and
weigh gain
cAMP levels in the
bronchial smooth
muscle with a
bronchodilator effect
production of IL-
13, IL-5, and IL-1β,
eotaxin and histamine
Preventing asthma
attacks
Asthma
Cardiovascular
diseases
end-diastolic
pressure
blood pressure
systematic
vascular resistance
Cancer
Modulating cAMP
signaling
tumor colonizatio n
cell growth
sensitivity to
cytotoxic drugs
Diabetes
cAMP resulting in
insulin release and
sensitivity
Glaucoma
intraocular
pressure
Liver fibrosis
fibrosis
oxidative stress
biomarkers and
inflammation,
Hedgehog signaling
markers mediated by
cAMP-dependent
PKA kinases
Figure 2. Eects of forskolin in human health.
Appl. Sci. 2019,9, 4089 4 of 13
2.1. Cystic Fibrosis
Cystic fibrosis is caused due to a mutation in the cystic fibrosis transmembrane conductance
regulator (CFTR) gene [
35
]. Two potential drug targets can be used to treat cystic fibrosis; namely,
potentiator VX-770 and corrector VX-809 linked to CFTR gene [
36
]. CRE sequence (TGACaTCA)
present in the promoter CFTR gene has thrown more light on the processes from cAMP regulation to
gene expression [
37
]. Around 45–50% of cystic fibrosis patients suer from a homozygous mutation
named, F508DEL [
36
]. In 1991, Drumm et al. reported that the association between CFTR and chloride
conductance is sensitive to forskolin (Figure 3), where the order of sensitivity occurs at a similar level as
the disease severity [
38
]. Several clinical studies are reported for cystic fibrosis, such as NCT03652090,
NCT03390985, NCT03894657 and NCT02807415, where forskolin is used to analyze drug sensitivity
and classification of cystic fibrosis [27,28,32,34].
Figure 3.
Potential modulation eect of forskolin based on [
36
]. ADP, adenosine diphosphate; ATP,
adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PKA, cAMP-dependent protein
kinase; CFTR, cystic fibrosis transmembrane conductance regulator; CFTR-P, phosphorylated CFTR.
2.2. Cardiovascular Diseases
Forskolin has a particularly beneficial eect on the cardiovascular system. It works via
vasorelaxation, causing relaxation of smooth muscles in the walls of blood vessels, which results
in increasing the overall volume of the circulatory system while maintaining the volume of blood.
Thanks to this, it improves the blood circulation process, the blood supply to internal organs and
increases the eciency of the myocardium. In 1983, Bristow et al. reported the pharmacological
eects of forskolin in cardiovascular diseases. They reported positive inotropic eects of forskolin
in membrane preparations derived from failing and normal functioning human left ventricles [
39
].
Several clinical and preclinical studies have been carried out, which provide sucient evidence for
the involvement of forskolin in cardiovascular diseases. In isolates of guinea pig hearts, an increase
in the forskolin dose resulted in amplified contractions. However, changes in the heart rate were
low. The simultaneous increase in the coronary flow and oxygen consumption represents additional
vasodilator eects of this drug on the coronary circulation [
40
]. A clinical study conducted by Kramer
et al., in 1987, reported that 15 patients with dilated cardiomyopathy were administered with forskolin
(10
µ
g/kg) for a duration of 10 min in the first course of administration. The data were then compared
with those data with dobutamine administration [
41
]. In the second course, 3
µ
g/kg/min forskolin
was administered for 10 min before and at the end of each infusion period where the heart rate was
maintained constant by atrial pacing [
41
]. The study concluded that forskolin can inhibit the decrease
of end-diastolic pressure in the left ventricle. Schlepper et al. suggested, in their study, that the eect
of forskolin lies in its ability to cause vasodilation. They further elaborated that the dose of forskolin
needs to be high to produce positive eects in cardiovascular diseases, in addition to the decrease in
the blood pressure and systematic vascular resistance observed [42].
Appl. Sci. 2019,9, 4089 5 of 13
2.3. Obesity
Obesity is a multifactorial condition, generally related to unhealthy lifestyle and metabolic diseases
such as diabetes, cardiac diseases, etc. Hormone-sensitive lipase (HSL) is known to be involved in
moving stored triglycerides and releasing fatty acids for metabolic consumption [
43
]. HSL is activated
by cAMP, which helps forskolin to increase the production of HSL. There are numerous clinical and
pre-clinical studies representing the eect of forskolin in promoting lean body mass and decreasing
body fat. Shivaprasad et al. showed that C. forskohlii extract halted increase in food intake and weight
gain on cafeteria diet-induced obesity in rats as well as inhibited the development of dyslipidemia [
44
].
Moreover, one of the significant studies was done by Loftus et al., where a group of 41 obese patients
were administered forskolin along with 250 mg of C. forskohlii extract for 12 weeks with assessments in
the 4th, 8th, and the 12th weeks [
45
]. No significant changes in the weight were observed in comparison
with the control group, but changes in hip and waist circumference were significant, suggesting a
decrease in fat mass and an increase in bone mass [
45
]. Godard et al., in 2005, reported a similar
result in a study conducted on 12 men, who were administered with the same dose of C. forskohlii.
They observed decreases in body fat percentage and fat mass, and increases lean body mass and serum
free testosterone in overweight and obese men [
43
]. Several other early studies suggested a positive
role of forskolin in body composition [
46
52
]. Henderson et al. (2005) demonstrated its eectiveness in
weight reduction in women [
51
]. The interest in the appetite suppressant properties of C. forskohlii
extract was also revealed in the clinical trial NCT02143349 [30].
2.4. Asthma, COPD, and Other Allergies
During asthmatic conditions, forskolin acts by increasing the cAMP levels in the bronchial smooth
muscle, which reduces bronchial reactivity and subsequent bronchodilator eect [
53
]. Notably, cAMP is
also known to be involved in Na
+
/K
+
regulation. In 1984, Hiramitsu et al. explained the role of
forskolin in tracheal muscles [
54
]. Forskolin also possesses an activity that inhibits the production
of interleukins (IL-13, IL-5, and IL-1
β
), eotaxin and histamine. It also acts as an anti-oxidant [
55
69
].
Gonz
á
lez-S
á
nchez et al. reported the findings obtained for forskolin in 20 patients administered with
the 10 mg oral forskolin (capsules) daily (for six months) resulting in positive control of asthma attacks.
Moreover, the values of forced expiratory volume in 1 s and forced expiratory flow were similar to
those using inhalations of the drug sodium cromoglycate [
70
]. In 2010, Hureta et al. reported about
a clinical study conducted on 30 patients with mild or moderately persistent adult asthma, where
forskolin was administered orally (10 mg) once a day on an empty stomach. The report suggests
that there was no significant dierence between the treatment with this compound and the drug
beclomethasone for any studied lung function parameter. The authors indicated that more studies
are necessary in this regard [
71
]. Furthermore, Bauer et al. [
72
] and Kaik et al. [
73
] reported that the
forskolin capsules (10.0 mg) facilitate bronchodilatation in asthma patients.
2.5. Cancer
Generally, cAMP signaling, through protein kinase A (PKA)-dependent and/or independent
pathway is crucial for cancer and it could provide an anti-tumor drug target [
74
]. Thus, forskolin has
raised interest. In 1983, Agarwal et al. reported a reduction of tumor colonization in the lungs by
70% in a mouse model after a dose of 82
µ
g/mouse [
75
]. Forskolin also provides a potential pathway
to inhibit colon cancer cell growth and survival [
76
]. Perrotti and Neviani reviewed that forskolin
activates protein phosphatase-2A (PP2A) and antagonize leukemogenesis in multiple solid tumors
(both
in vitro
and
in vivo
) [
77
]. Recent studies suggest that forskolin can increase the antitumoral
eects of some anticancer drugs [
74
,
78
,
79
]. In this regard, the treatment with forskolin increased the
sensitivity of Aromatase inhibitor-breast cancer cells to everolimus [
78
] and human triple negative
breast cancer cells to doxorubicine [
79
] through activating PP2A and a mechanism dependent on the
cAMP/PKA mediated extracellular-signal-regulated kinase (ERK) inhibition, respectively (Figure 3).
Appl. Sci. 2019,9, 4089 6 of 13
Moreover, reports from several other animal studies are available online [
74
]. However, clinical studies
need to be performed to support its ecacy as an anti-cancer drug, as well as its therapeutic potential
to increase the sensitivity to cytotoxic drugs.
2.6. Diabetes
Diabetes is a metabolic syndrome that is dependent on insulin level and insulin sensitivity.
The levels
of cAMP are elevated due to the administration of forskolin. This elevated cAMP levels
further activate two signaling pathways: PKA and guanine exchange by cAMP (Figure 3) [
80
].
This results in a glucose-mediated response to pancreatic beta cells and insulin release [
81
]. An
in vivo
study on rats also supported the evidence for forskolin, causing a decrease in serum glucose levels,
which decreased the severity of fasting hyperglycemia [
82
]. A clinical study on forskolin administration
(250 mg of standardized C. forskohlii extract to 10% forskolin for 12 weeks) in conjunction with a
hypocaloric diet in 41 patients revealed glucose-dependent insulin release (Figure 4) and insulin
sensitivity. This was related to a decreased abdominal fat mass as indicated by a reduction of waist
circumference [
45
]. Moreover, forskolin (50 mg/kg per week for 12 consecutive weeks) has also shown
an attenuation of retinal inflammation in diabetic mice by means of limiting glucose transport into
the retina. It downregulated glucose transporter 1 expression and decreased inflammatory factor
expression levels [83].
Appl. Sci. 2019, 9, x FOR PEER REVIEW 6 of 13
Moreover, reports from several other animal studies are available online [74]. However, clinical
studies need to be performed to support its efficacy as an anti-cancer drug, as well as its therapeutic
potential to increase the sensitivity to cytotoxic drugs.
2.6. Diabetes
Diabetes is a metabolic syndrome that is dependent on insulin level and insulin sensitivity. The
levels of cAMP are elevated due to the administration of forskolin. This elevated cAMP levels further
activate two signaling pathways: PKA and guanine exchange by cAMP (Figure 3) [80]. This results
in a glucose-mediated response to pancreatic beta cells and insulin release [81]. An in vivo study on
rats also supported the evidence for forskolin, causing a decrease in serum glucose levels, which
decreased the severity of fasting hyperglycemia [82]. A clinical study on forskolin administration (250
mg of standardized C. forskohlii extract to 10% forskolin for 12 weeks) in conjunction with a
hypocaloric diet in 41 patients revealed glucose-dependent insulin release (Figure 4) and insulin
sensitivity. This was related to a decreased abdominal fat mass as indicated by a reduction of waist
circumference [45]. Moreover, forskolin (50 mg/kg per week for 12 consecutive weeks) has also shown
an attenuation of retinal inflammation in diabetic mice by means of limiting glucose transport into
the retina. It downregulated glucose transporter 1 expression and decreased inflammatory factor
expression levels [83].
Figure 4. Reduction of fasting plasma insulin concentration by Coleus forskohlii extract. * Significant at
p < 0.05 (adapted from [45]).
2.7. Intraocular Pressure in Glaucoma
Intraocular pressure (IOP) plays a critical role in regulating the changes in aqueous humor
volume [84]. The rate of production and drainage of aqueous humor by ciliary epithelium must be
balanced, as a small change in the aqueous humor can influence intraocular pressure. Forskolin has
been studied for IOP in glaucoma due to aqueous flow regulation by adenylate cyclase receptor
complex in the epithelium. The potential to modify retinal nerve fibers layers have also been studied
in the clinical trial NCT01254006 [33]. Witte et al. reported a double blind intra-individual study of
forskolin eye drops (0.3%, 0.6%, and 1.0% suspension) in 18 healthy males (in groups of six). It was
observed that forskolin reduced IOP by 2328% and the concentration influenced the duration by 3
5 h [85]. Another double-blind, control, randomized, comparative and non-crossover study was
conducted with 90 trial subjects. Forty-five individuals were given 1% (w/v) forskolin, which was
efficient in reducing IOP in mild open-angle glaucoma [86]. Badian et al. reported that the forskolin-
eyedrops decreased IOP in healthy male subjects. Sensations in less degree were observed in subjects
for a brief period [87]. Majeed et al. recruited 90 adult male/female patients suffering from open-angle
glaucoma with IOP of more than 24 mm Hg. They observed that 1% forskolin eye drops reduced IOP
to less than 5.4 mm Hg [88].
Placebo group
Colueus forskohlii treated group
Insulin (mU/L)
Figure 4.
Reduction of fasting plasma insulin concentration by Coleus forskohlii extract. * Significant at
p<0.05 (adapted from [45]).
2.7. Intraocular Pressure in Glaucoma
Intraocular pressure (IOP) plays a critical role in regulating the changes in aqueous humor
volume [
84
]. The rate of production and drainage of aqueous humor by ciliary epithelium must be
balanced, as a small change in the aqueous humor can influence intraocular pressure. Forskolin has
been studied for IOP in glaucoma due to aqueous flow regulation by adenylate cyclase receptor complex
in the epithelium. The potential to modify retinal nerve fibers layers have also been studied in the
clinical trial NCT01254006 [
33
]. Witte et al. reported a double blind intra-individual study of forskolin
eye drops (0.3%, 0.6%, and 1.0% suspension) in 18 healthy males (in groups of six). It was observed
that forskolin reduced IOP by 23–28% and the concentration influenced the duration by 3–5 h [
85
].
Another double-blind, control, randomized, comparative and non-crossover study was conducted
with 90 trial subjects. Forty-five individuals were given 1% (w/v) forskolin, which was ecient in
reducing IOP in mild open-angle glaucoma [
86
]. Badian et al. reported that the forskolin-eyedrops
decreased IOP in healthy male subjects. Sensations in less degree were observed in subjects for a brief
period [
87
]. Majeed et al. recruited 90 adult male/female patients suering from open-angle glaucoma
Appl. Sci. 2019,9, 4089 7 of 13
with IOP of more than 24 mm Hg. They observed that 1% forskolin eye drops reduced IOP to less than
5.4 mm Hg [88].
2.8. Liver Fibrosis
Liver fibrosis has been associated with high rates of morbidity and mortality worldwide due to
limited therapeutics. New therapies have been under development to arrest or reverse fibrosis. Studies
focusing the anti-fibrotic eect of Hedgehog (Hh) pathway and forskolin were elucidated [
89
,
90
].
Calcium tetrachloride was used to induce hepatic fibrosis in male Sprague-Dawley rats until six
weeks. Induction of fibrosis was confirmed by a reduction in ALT, AST, TC and TG levels. Treatment
with forskolin improved all changes in the hepatocytes [
91
]. The role of forskolin was observed by
oxidative stress markers (GSH, GPx, and lipid peroxides), inflammatory markers (NF-
κ
B, TNF-
α
,
COX-2, IL-1
β
, and TGF-
β
1) and Hh signaling markers (Ptch-1, Smo, and Gli-2). This was confirmed by
α
-SMA expression, which indicates that forskolin reduces hepatic stellate cells (HSCs) expression and
further fibrogenesis. Co-treatment with forskolin significantly reduced oxidative stress biomarkers
and inflammation, which has been studied by mRNA expression of Hh signaling markers and
cAMP-dependent PKA kinases. Thus, this study proves that forskolin has an antifibrotic eect.
3. Other Eects
Forskolin has been reported to be a potent activator of adenylate cyclase in the thyroid gland
and as well, stimulating thyroid secretion [
92
,
93
]. Laurberg et al. compared the eects of 10
5
M
forskolin and 100
µ
units/mL thyroid stimulating hormone (TSH) over T
3
and T
4
secretion of perfused
dog thyroid lobes. An ethanol concentration of 0.2% was used in forskolin containing medium [
92
].
Forskolin elevated the cAMP levels within 5 min post forskolin infusion. A lag phase resulted from the
increase in cAMP levels. Thus, it activated cAMP generation to interact with the catalytic subunit of
adenylate cyclase [
94
]. Bersudsky et al. reported that forskolin helps in transient mood elevation or
stimulation in schizophrenic patients with negative symptoms [
95
]. Moreover, Doorn et al. reported
forskolin induces alkaline phosphatase and insulin-like growth factor-1, thereby increasing bone
formation by human mesenchymal stromal cells [96].
4. Bioavailability of Forskolin
The administration form of forskolin depends on the tissue target, but it is a poorly water-soluble
compound, which limits both its topical and its oral bioavailability. Despite this low bioavailability,
forskolin has shown to be more potent than natural and synthetic analogs [97].
Some studies have evaluated dierent forms of administration than suspension to improve
ocular bioavailability when administered to eyes. In this respect, Saettone et al. (2009) tested several
solubilization eye-compatible polymeric agents. Polyoxyethylene-polyoxypropylene block copolymer
(Pluronic
R
F-127) increased 40 times the drug solubility in water (up to 120 mg/100 mL). It also prolonged
the duration of the hypotensive eects of forskolin with respect to a 1.0% traditional suspension of this
compound in rabbits presenting increased IOP [
98
]. More recently, a formulation based on forskolin
nanocrystals stabilized by poloxamer 407 and Noveon AA-1 polycarbophil/poloxamer 407 gel was able
to reduce IOP in rabbits around 31% and lasted for 12 h, better than the eect produced by traditional
suspension (18%, up to 6 h) [
99
]. Proper vehicles, such as in situ gel forming systems, may also increase
the contact time of this compound on the cornea [
100
], while nanoencapsulation within polymeric
system provided sustained drug release and enhanced permeation profile with maximum depth
penetration [
101
]. Other potential vehicles are through the formation of forskolin nanoemulsions [
102
]
and cocrystals able to enhance the water solubility properties of forskolin [103].
Concerning oral bioavailability, recent studies suggest that forskolin could be absorbed in all
segments of the intestine with an eective permeability in the range of drugs with high intestinal
permeability, but it was a saturable transport process mediated by P-glycoprotein. The authors
estimated that, after oral administration in humans, the absorbed fraction of dissolved forskolin could
Appl. Sci. 2019,9, 4089 8 of 13
be close to 100% [
104
]. Moreover, forskolin can bind to human serum albumin, which could play a role
in the pharmacokinetics of this compound [105] and it could be the basis of nanoparticles [106].
5. Conclusions
Forskolin is a natural diterpenoid with a wide biological eect. The mechanism of action of
forskolin is based on the activation of the adenylyl cyclase enzyme, which results in the synthesis of
cAMP. Forskolin increases the level of intracellular cAMP, which is a transmitter of intracellular signals
that regulates and aects the activity of many enzymes in the cell [
83
,
84
]. This is particularly important
in disease entities with reduced levels of this transmitter, such as asthma, cardiovascular disorders
and obesity, among others. The Indian nettle C. forskohlii is the natural source of forskolin. Beneficial
eects of forskolin have been reported in preclinical and clinical studies on the treatment cystic
fibrosis, cardiovascular disease, obesity, allergies, asthma, COPD, diabetes, cancer, thyroid disorders,
IOP in
glaucoma, and liver fibrosis. Forskolin can interact with the cAMP pathway.
More clinical
and
pre-clinical studies need to be performed to support forskolin ecacy since both the plant extract and
forskolin exhibit low toxicity [75,107].
Author Contributions:
Conceptualization, B.S. and J.S.-R.; validation, investigation, resources, data reviewing,
and writing, all authors; and review and editing, J.S.-R., M.d.M.C., K.D., F.S., and W.C.C. All authors read and
approved the final manuscript.
Funding: This research received no external funding.
Acknowledgments:
M.d.M.C. acknowledges the postdoctoral grant funded by the “Acci
ó
n 6 del Plan de Apoyo a
la Investigación de la Universidad de Jaén, 2017–2019”.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Wink, M. Modes of action of herbal medicines and plant secondary metabolites. Medicines
2015
,2, 251–286.
[CrossRef]
2.
Karakaya, S.; Koca, M.; Sytar, O.; Dursunoglu, B.; Ozbek, H.; Duman, H.; Guvenalp, Z.; Kılıc, C.S. Antioxidant
and anticholinesterase potential of ferulago cassia with farther bio-guided isolation of active coumarin
constituents. S. Afr. J. Bot. 2019,121, 536–542. [CrossRef]
3. Seigler, D.S. Plant Secondary Metabolism; Kluwer Academic Publishers: Boston, MA, USA, 1995.
4.
Wink, M. Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective.
Phytochemistry 2003,64, 3–19. [CrossRef]
5.
Sytar, O.; Brestic, M.; Rai, M. Possible ways of fagopyrin biosynthesis and production in buckwheat plants.
Fitoterapia 2013,84, 72–79. [CrossRef]
6.
Pichersky, E.; Noel, J.P.; Dudareva, N. Biosynthesis of plant volatiles: Nature’s diversity and ingenuity.
Science 2006,311, 808–811. [CrossRef]
7.
Chen, F.; Tholl, D.; Bohlmann, J.; Pichersky, E. The family of terpene synthases in plants: A mid-size family
of genes for specialized metabolism that is highly diversified throughout the kingdom. Plant J.
2011
,66,
212–229. [CrossRef]
8.
Jansen, D.J.; Shenvi, R.A. Synthesis of medicinally relevant terpenes: Reducing the cost and time of drug
discovery. Future Med. Chem. 2014,6, 1127–1148. [CrossRef]
9.
Vranova, E.; Coman, D.; Gruissem, W. Structure and dynamics of the isoprenoid pathway network. Mol. Plant
2012,5, 318–333. [CrossRef]
10.
De Souza, N.J. Industrial development of traditional drugs: The forskolin example. A mini-review.
J. Ethnopharmacol. 1993,38, 177–180. [CrossRef]
11.
Croteau, R.; Ketchum, R.E.B.; Long, R.M.; Kaspera, R.; Wildung, M.R. Taxol biosynthesis and molecular
genetics. Phytochem. Rev. 2006,5, 75–97. [CrossRef]
12.
Pollier, J.; Moses, T.; Goossens, A. Combinatorial biosynthesis in plants: A (p)review on its potential and
future exploitation. Nat. Prod. Rep. 2011,28, 1897–1916. [CrossRef] [PubMed]
Appl. Sci. 2019,9, 4089 9 of 13
13.
Numonov, S.; Sharopov, F.; Salimov, A.; Sukhrobov, P.; Atolikshoeva, S.; Safarzoda, R.; Habasi, M.; Aisa, H.A.
Assessment of artemisinin contents in selected artemisia species from tajikistan (Central Asia). Medicines
2019,6, 23. [CrossRef] [PubMed]
14.
Vanisree, M.; Lee, C.; Lo, S.; Satish, M.; Lin, C.; Tsay, H.S. Studies on the production of some important
secondary metabolites from medicinal plants by plant tissue cultures. Bot. Bull. Acad. Sin. 2004,45, 1–22.
15.
Kanne, H.; Burte, N.P.; Prasanna, V.; Gujjula, R. Extraction and elemental analysis of coleus forskohlii extract.
Pharmacogn. Res. 2015,7, 237–241. [CrossRef] [PubMed]
16.
Kavitha, C.; Rajamani, K.; Vadivel, E. Coleus forskohlii: A comprehensive review on morphology,
phytochemistry and pharmacological aspects. J. Med. Plants Res. 2010,4, 278–285.
17.
Lakshmanan, G.M.; Manikandan, S. Review on pharmacological eects of Plectranthus forskohli (wild) briq.
Int. Lett. Nat. Sci. 2015,1, 1–9.
18.
Tamboli, E.T.; Chester, K.; Ahmad, S. Quality control aspects of herbs and botanicals in developing countries:
Coleus forskohlii briq a case study. J. Pharm. Bioallied Sci. 2015,7, 254–259.
19.
Bhowal, M.; Mehta, D.M. Coleus forskholii: Phytochemical and pharmacological profile. Int. J. Pharm. Sci. Res.
2017,8, 3599–3618.
20.
Wagh, V.D.; Patil, P.N.; Surana, S.J.; Wagh, K.V. Forskolin: Upcoming antiglaucoma molecule. J. Postgrad.
Med. 2012,58, 199–202. [CrossRef]
21.
Singh, B.; Sharma, R.A. Plant terpenes: Defense responses, phylogenetic analysis, regulation and clinical
applications. 3 Biotech 2015,5, 129–151. [CrossRef]
22.
Tholl, D. Terpene synthases and the regulation, diversity and biological roles of terpene metabolism.
Curr. Opin. Plant Biol. 2006,9, 297–304. [CrossRef] [PubMed]
23.
Elwia, S.K.; Elnoury, H.A.; Muhammad, M.H. Forskolin eect on foxo1 expression and relationship of foxo1
activation to oxidative stress: From molecular to therapeutic strategy. Biomarkers 2018,4, 11.
24.
Pateraki, I.; Andersen-Ranberg, J.; Jensen, N.B.; Wubshet, S.G.; Heskes, A.M.; Forman, V.; Hallstrom, B.;
Hamberger, B.; Motawia, M.S.; Olsen, C.E.; et al. Total biosynthesis of the cyclic amp booster forskolin from
coleus forskohlii. eLife 2017,6, e23001. [CrossRef] [PubMed]
25.
Reddy, C.S.; Desireddy, R.B.; Ciddi, V. A review on forskolin: A cyclic AMP modulator from tissue cultures
of Coleus forskohlii.Pharmacogn. Mag. 2005,1, 85–88.
26.
Doseyici, S.; Mehmetoglu, I.; Toker, A.; Yerlikaya, F.H.; Erbay, E. The eects of forskolin and rolipram
on camp, cgmp and free fatty acid levels in diet induced obesity. Biotech. Histochem.
2014
,89, 388–392.
[CrossRef]
27.
Gonska, T.; The Hospital for Sick Children. Canadian Observation Trial in cf Patients Undergoing
Treatment with Ivacaftor. 2013. Available online: https://ClinicalTrials.gov/show/NCT03390985 (accessed on
31 August 2019).
28. Institut National de la SantéEt de la Recherche Médicale; ABCF2. Primary Nasal Cell Culture as a Tool for
Personalized Therapy in Cystic Fibrosis. 2010. Available online: https://ClinicalTrials.gov/show/NCT03652090
(accessed on 31 August 2019).
29.
University of Lincoln; National Health Service, U.K. Association of Physical Activity Levels and Inflammatory
Markers Following Pulmonary Rehabilitation. 2018. Available online: https://ClinicalTrials.gov/show/
NCT03455153 (accessed on 31 August 2019).
30.
Olive Lifesciences Pvt Ltd. The Eect of Coleus forskohlii Extract on the Risk Factors of Metabolic Syndrome.
2014. Available online: https://ClinicalTrials.gov/show/NCT02143349 (accessed on 31 August 2019).
31.
Assistance Publique—H
ô
pitaux de Paris. Bronchial Trans-Epithelial Transport in Patients with Idiopathic
Multiple Dilations of the Bronchi. 2016. Available online: https://ClinicalTrials.gov/show/NCT02586883
(accessed on 31 August 2019).
32.
Assistance Publique—H
ô
pitaux de Paris. Validation of Respiratory Epithelial Functional Assessment to
Predict Clinical Ecacy of Orkambi
®
. 2019. Available online: https://ClinicalTrials.gov/show/NCT03894657
(accessed on 31 August 2019).
33.
University of Roma La Sapienza. Retinal Nerve Fibres Layers Thickness Study in Glaucomatous Patients.
Available online: https://ClinicalTrials.gov/show/NCT01254006 (accessed on 31 August 2019).
34.
Hannover Medical School; Heidelberg University; University of Giessen. ICM to Evaluate the Activation of
p.Phe508del-cftr by Lumacaftor in Combination with Ivacaftor. 2016. Available online: https://ClinicalTrials.
gov/show/NCT02807415 (accessed on 31 August 2019).
Appl. Sci. 2019,9, 4089 10 of 13
35.
De Boeck, K.; Amaral, M.D. Progress in therapies for cystic fibrosis. Lancet Respir. Med.
2016
,4, 662–674.
[CrossRef]
36.
Boj, S.F.; Vonk, A.M.; Statia, M.; Su, J.; Dekkers, J.F.; Vries, R.R.; Beekman, J.M.; Clevers, H. Forskolin-induced
swelling in intestinal organoids: An
in vitro
assay for assessing drug response in cystic fibrosis patients.
JoVE (J. Vis. Exp.) 2017,120, e55159. [CrossRef]
37.
Matthews, R.P.; McKnight, G.S. Characterization of the camp response element of the cystic fibrosis
transmembrane conductance regulator gene promoter. J. Biol. Chem. 1996,271, 31869–31877. [CrossRef]
38.
Drumm, M.L.; Wilkinson, D.J.; Smit, L.S.; Worrell, R.T.; Strong, T.V.; Frizzell, R.A.; Dawson, D.C.; Collins, F.S.
Chloride conductance expressed by delta f508 and other mutant cftrs in xenopus oocytes. Science
1991
,254,
1797–1799. [CrossRef]
39.
Bristow, M.; Strosberg, A.; Ginsburg, R. Forskolin Activation of Human Myocardial Adenylate-Cyclase, Circulation;
AMER HEART ASSOC: Dallas, TX, USA, 1983; p. 60.
40.
Linderer, E.; Metzger, H. The positive inotropic and smooth muscle relaxing eects of forskolin by direct
activation of adenylate cyclase. In Proceedings of the International Symposium on Forskolin: Its Chemical
Biological and Medical Potential, Bombay, India, 28–29 January 1985; pp. 83–101.
41.
Kramer, W.; Thormann, J.; Kindler, M.; Schlepper, M. Eects of forskolin on left ventricular function in
dilated cardiomyopathy. Arzneim.-Forsch. 1987,37, 364–367.
42.
Schlepper, M.; Thormann, J.; Mitrovic, V. Cardiovascular eects of forskolin and phosphodiesterase-iii
inhibitors. In Inotropic Stimulation and Myocardial Energetics; Springer: Berlin-Heidelberg, Germany, 1989;
pp. 197–212.
43.
Godard, M.P.; Johnson, B.A.; Richmond, S.R. Body composition and hormonal adaptations associated with
forskolin consumption in overweight and obese men. Obes. Res.
2005
,13, 1335–1343. [CrossRef] [PubMed]
44.
Shivaprasad, H.N.; Gopalakrishna, S.; Mariyanna, B.; Thekkoot, M.; Reddy, R.; Tippeswamy, B.S. Eect of
Coleus forskohlii extract on cafeteria diet-induced obesity in rats. Pharmacogn. Res. 2014,6, 42–45.
45.
Loftus, H.; Astell, K.; Mathai, M.; Su, X. Coleus forskohlii extract supplementation in conjunction with
a hypocaloric diet reduces the risk factors of metabolic syndrome in overweight and obese subjects:
A randomized controlled trial. Nutrients 2015,7, 9508–9522. [CrossRef]
46.
Häkkinen, K.; Kraemer, W.J.; Pakarinen, A.; Tripleltt-Mcbride, T.; McBride, J.M.; Häkkinen, A.; Alen, M.;
McGuigan, M.R.; Bronks, R.; Newton, R.U. Eects of heavy resistance/power training on maximal strength,
muscle morphology, and hormonal response patterns in 60-75-year-old men and women. Can. J. Appl. Physiol.
2002,27, 213–231. [CrossRef] [PubMed]
47.
Hibino, N.; Kawai, A.; Uchikawa, S.; Chikazawa, G.; Kurihara, T.; Kihara, S.; Uebe, K.; Aomi, S.; Nishida, H.;
Endo, M. Cardiovascular eects of colforsin daropate hydrochloride for acute heart failure after open heart
surgery. Kyobu Geka Jpn. J. Thorac. Surg. 2001,54, 1016–1019.
48.
Iranami, H.; Okamoto, K.; Kimoto, Y.; Maeda, H.; Kakutani, T.; Hatano, Y. Use of corfolsin dalopate following
cardiac surgery in a neonate. Anesthesiol. J. Am. Soc. Anesthesiol. 2002,97, 503–504. [CrossRef]
49.
Paulson, J.D.; Keller, D.W.; Wiest, W.G.; Warren, J.C. Free testosterone concentration in serum: Elevation is
the hallmark of hirsutism. Am. J. Obstet. Gynecol. 1977,128, 851–857. [CrossRef]
50.
Badmaev, V.; Majeed, M.; Conte, A.A.; Parker, J.E. Diterpene forskolin (coleus forskohlii benth.): A possible
new compound for reduction of body weight by increasing lean body mass. NutraCos 2002,1, 6–7.
51.
Henderson, S.; Magu, B.; Rasmussen, C.; Lancaster, S.; Kerksick, C.; Smith, P.; Melton, C.; Cowan, P.;
Greenwood, M.; Earnest, C. Eects of coleus forskohlii supplementation on body composition and
hematological profiles in mildly overweight women. J. Int. Soc. Sports Nutr. 2005,2, 54. [CrossRef]
52.
Tsuguyoshi, A. Clinical Report on Root Extract of Perilla Plant (Coleus Forskohlii) Forslean in Reducing Body Fat;
Asano Institute: Tokyo, Japan, 2004.
53.
Yousif, M.H.; Thulesius, O. Forskolin reverses tachyphylaxis to the bronchodilator eects of salbutamol:
An in-vitro study on isolated guinea-pig trachea. J. Pharm. Pharmacol. 1999,51, 181–186. [CrossRef]
54.
Hiramatsu, T.; Kume, H.; Kotliko, M.I.; Takagi, K. Role of calcium-activated potassium channels in the
relaxation of tracheal smooth muscles by forskolin. Clin. Exp. Pharmacol. Physiol.
1994
,21, 367–375.
[CrossRef] [PubMed]
55.
Eleno, N.; Gajate, E.; Macias, J.; Garay, R. Enhancement by reproterol of the ability of disodium cromoglycate
to stabilize rat mastocytes. Pulm. Pharmacol. Ther. 1999,12, 55–60. [CrossRef] [PubMed]
Appl. Sci. 2019,9, 4089 11 of 13
56.
Lindner, E.; Metzger, H. The action of forskolin on muscle cells is modified by hormones, calcium ions and
calcium antagonists. Arzneim. Forsch. 1983,33, 1436–1441.
57.
Seamon, K.; Daly, J. Forskolin: A unique diterpene activator of cyclic AMP-generating systems. J. Cycl.
Nucleotide Res. 1981,7, 201–224.
58.
De Souza, N.J.; Dohadwalla, A.N.; Reden, Ü. Forskolin: A labdane diterpenoid with antihypertensive,
positive inotropic, platelet aggregation inhibitory, and adenylate cyclase activating properties. Med. Res. Rev.
1983,3, 201–219. [CrossRef]
59.
Tsukawaki, M.; Suzuki, K.; Suzuki, R.; Takagi, K.; Satake, T. Relaxant eects of forskolin on guinea pig
tracheal smooth muscle. Lung 1987,165, 225–237. [CrossRef] [PubMed]
60.
Danahay, H.; Atherton, H.; Jones, G.; Bridges, R.J.; Poll, C.T. Interleukin-13 induces a hypersecretory ion
transport phenotype in human bronchial epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol.
2002
,282,
L226–L236. [CrossRef]
61.
Penn, R.B.; Panettieri Jr, R.A.; Benovic, J.L. Mechanisms of acute desensitization of the
β
2ar–adenylyl cyclase
pathway in human airway smooth muscle. Am. J. Respir. Cell Mol. Biol. 1998,19, 338–348. [CrossRef]
62.
Tanizawa, M.; Watanabe, T.; Kurne, H.; Yarnaki, K.; Miyamoto, K.; Takagi, K. Phosphodiesterase iv inhibitors
synergistically potentiate relaxation induced by forskolin in guinea-pig trachea. Clin. Exp. Pharmacol. Physiol.
1998,25, 114–119. [CrossRef]
63.
Hidi, R.; Timmermans, S.; Liu, E.; Schudt, C.; Dent, G.; Holgate, S.; Djukanovic, R. Phosphodiesterase and
cyclic adenosine monophosphate-dependent inhibition of t-lymphocyte chemotaxis. Eur. Respir. J.
2000
,15,
342–349. [CrossRef]
64.
Hallsworth, M.P.; Twort, C.H.; Lee, T.H.; Hirst, S.J. B2-adrenoceptor agonists inhibit release of
eosinophil-activating cytokines from human airway smooth muscle cells. Br. J. Pharmacol.
2001
,132,
729–741. [CrossRef] [PubMed]
65.
Pang, L.; KNOX, A.J. Regulation of tnf-
α
-induced eotaxin release from cultured human airway smooth
muscle cells by β2-agonists and corticosteroids. FASEB J. 2001,15, 261–269. [CrossRef] [PubMed]
66.
Staples, K.J.; Bergmann, M.; Tomita, K.; Houslay, M.D.; McPhee, I.; Barnes, P.J.; Giembycz, M.A.; Newton, R.
Adenosine 3
0
,5
0
-cyclic monophosphate (camp)-dependent inhibition of il-5 from human t lymphocytes is not
mediated by the camp-dependent protein kinase a. J. Immunol. 2001,167, 2074–2080. [CrossRef] [PubMed]
67.
Couve, A.; Thomas, P.; Calver, A.R.; Hirst, W.D.; Pangalos, M.N.; Walsh, F.S.; Smart, T.G.; Moss, S.J. Cyclic
amp–dependent protein kinase phosphorylation facilitates gaba b receptor–eector coupling. Nat. Neurosci.
2002,5, 415. [CrossRef]
68.
Aksoy, M.O.; Mardini, I.A.; Yang, Y.; Bin, W.; Zhou, S.; Kelsen, S.G. Glucocorticoid eects on the
β
-adrenergic
receptor–adenylyl cyclase system of human airway epithelium. J. Allergy Clin. Immunol.
2002
,109, 491–497.
[CrossRef] [PubMed]
69.
Yoshida, N.; Shimizu, Y.; Kitaichi, K.; Hiramatsu, K.; Takeuchi, M.; Ito, Y.; Kume, H.; Yamaki, K.; Suzuki, R.;
Shibata, E. Dierential eect of phosphodiesterase inhibitors on il-13 release from peripheral blood
mononuclear cells. Clin. Exp. Immunol. 2001,126, 384–389. [CrossRef] [PubMed]
70.
Gonzalez-Sanchez, R.; Trujillo, X.; Trujillo-Hernandez, B.; V
á
squez, C.; Huerta, M.; Elizalde, A. Forskolin
versus sodium cromoglycate for prevention of asthma attacks: A single-blinded clinical trial. J. Int. Med. Res.
2006,34, 200–207. [CrossRef] [PubMed]
71.
Huerta, M.; Urzua, Z.; Trujillo, X.; Gonzalez-Sanchez, R.; Trujillo-Hernandez, B. Forskolin compared with
beclomethasone for prevention of asthma attacks: A single-blind clinical trial. J. Int. Med. Res.
2010
,38,
661–668. [CrossRef]
72.
Bauer, K.; Dietersdorfer, F.; Sertl, K.; Kaik, B.; Kaik, G. Pharmacodynamic eects of inhaled dry powder
formulations of fenoterol and colforsin in asthma. Clin. Pharmacol. Ther. 1993,53, 76–83. [CrossRef]
73.
Kaik, G.; Witte, P.U. Protective eect of forskolin against acetylcholine provocation in healthy
volunteers—Comparison of two doses with fenoterol and placebo. Wien. Med. Wochenschr.
1986
,136,
637–641.
74.
Sapio, L.; Gallo, M.; Illiano, M.; Chiosi, E.; Naviglio, D.; Spina, A.; Naviglio, S. The natural camp elevating
compound forskolin in cancer therapy: Is it time? J. Cell. Physiol. 2017,232, 922–927. [CrossRef] [PubMed]
75.
Agarwal, K.C.; Parks, R.E., Jr. Forskolin: A potential antimetastatic agent. Int. J. Cancer
1983
,32, 801–804.
[CrossRef] [PubMed]
Appl. Sci. 2019,9, 4089 12 of 13
76.
McEwan, D.G.; Brunton, V.G.; Baillie, G.S.; Leslie, N.R.; Houslay, M.D.; Frame, M.C. Chemoresistant km12c
colon cancer cells are addicted to low cyclic amp levels in a phosphodiesterase 4–regulated compartment via
eects on phosphoinositide 3-kinase. Cancer Res. 2007,67, 5248–5257. [CrossRef] [PubMed]
77.
Perrotti, D.; Neviani, P. Protein phosphatase 2a (pp2a), a drugable tumor suppressor in ph1(+) leukemias.
Cancer Metastasis Rev. 2008,27, 159–168. [CrossRef] [PubMed]
78.
Hayashi, T.; Hikichi, M.; Yukitake, J.; Wakatsuki, T.; Nishio, E.; Utsumi, T.; Harada, N. Forskolin increases
the eect of everolimus on aromatase inhibitor-resistant breast cancer cells. Oncotarget
2018
,9, 23451–23461.
[CrossRef] [PubMed]
79.
Illiano, M.; Sapio, L.; Salzillo, A.; Capasso, L.; Caiafa, I.; Chiosi, E.; Spina, A.; Naviglio, S. Forskolin improves
sensitivity to doxorubicin of triple negative breast cancer cells via Protein Kinase A-mediated ERK1/2
inhibition. Biochem. Pharmacol. 2018,152, 104–113. [CrossRef] [PubMed]
80.
Holz, G.G. Epac: A new camp-binding protein in support of glucagon-like peptide-1 receptor-mediated
signal transduction in the pancreatic β-cell. Diabetes 2004,53, 5–13. [CrossRef]
81.
Ammon, H.; Müller, A. Eect of forskolin on islet cyclic amp, insulin secretion, blood glucose and intravenous
glucose tolerance in rats. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1984,326, 364–367. [CrossRef] [PubMed]
82.
R
í
os-Silva, M.; Trujillo, X.; Trujillo-Hern
á
ndez, B.; S
á
nchez-Pastor, E.; Urz
ú
a, Z.; Mancilla, E.; Huerta, M.
Eect of chronic administration of forskolin on glycemia and oxidative stress in rats with and without
experimental diabetes. Int. J. Med. Sci. 2014,11, 448–452. [CrossRef] [PubMed]
83.
You, Z.-P.; Xiong, B.; Zhang, Y.-L.; Shi, L.; Shi, K. Forskolin attenuates retinal inflammation in diabetic mice.
Mol. Med. Rep. 2018,17, 2321–2326. [CrossRef]
84.
Majeed, M.; Nagabhushanam, K.; Natarajan, S.; Vaidyanathan, P.; Karri, S.K. A double-blind, randomized
clinical trial to evaluate the ecacy and safety of forskolin eye drops 1% in the treatment of open angle
glaucoma – A comparative study. J Clin Trials. 2014,4, 1000184. [CrossRef]
85.
Witte, P. Proceedings of the International Symposium on Forskolin: Its Chemical Biological and Medical
Potential, Bombay, India, 28–29 January 1985; pp. 175–182.
86.
Majeed, M.; Nagabhushanam, K.; Natarajan, S.; Vaidyanathan, P.; Kumar, S. A double-blind, randomized
clinical trial to evaluate the ecacy and safety of forskolin eye drops 1% in the treatment of open angle
glaucoma–a comparative study. J. Clin. Trials 2014,4, 184. [CrossRef]
87.
Badian, M.; Dabrowski, J.; Grigoleit, H.G.; Lieb, W.; Lindner, E.; Rupp, W. Eect of forskolin-eyedrops on
the intraocular pressure of healthy male subjects. Klin. Mon. Augenheilkd.
1984
,185, 522–526. [CrossRef]
[PubMed]
88.
Majeed, M.; Nagabhushanam, K.; Natarajan, S.; Vaidyanathan, P.; Karri, S.K.; Jose, J.A. Ecacy and safety of
1% forskolin eye drops in open angle glaucoma—An open label study. Saudi J. Ophthalmol.
2015
,29, 197–200.
[CrossRef] [PubMed]
89.
Philips, G.M.; Chan, I.S.; Swiderska, M.; Schroder, V.T.; Guy, C.; Karaca, G.F.; Moylan, C.; Venkatraman, T.;
Feuerlein, S.; Syn, W.-K. Hedgehog signaling antagonist promotes regression of both liver fibrosis and
hepatocellular carcinoma in a murine model of primary liver cancer. PLoS ONE
2011
,6, e23943. [CrossRef]
[PubMed]
90.
Choi, S.S.; Omenetti, A.; Syn, W.-K.; Diehl, A.M. The role of hedgehog signaling in fibrogenic liver repair. Int.
J. Biochem. Cell Biol. 2011,43, 238–244. [CrossRef]
91.
El-Agroudy, N.N.; El-Naga, R.N.; El-Razeq, R.A.; El-Demerdash, E. Forskolin, a Hedgehog signalling
inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats. Br. J. Pharmacol.
2016
,173, 3248–3260.
[CrossRef]
92.
Laurberg, P. Forskolin stimulation of thyroid secretion of t4 and t3. FEBS Lett.
1984
,170, 273–276. [CrossRef]
93.
Seamon, K.B.; Daly, J.W. Forskolin: Its biological and chemical properties. Adv. Cycl. Nucleotide Protein
Phosphorylation Res. 1986,20, 1.
94.
Mastan, A.; Bharadwaj, R.; Kushwaha, R.K.; Babu, C.S.V. Functional fungal endophytes in Coleus forskohlii
regulate labdane diterpene biosynthesis for elevated forskolin accumulation in roots. Microb. Ecol.
2019
.
[CrossRef]
95.
Bersudsky, Y.; Kotler, M.; Shifrin, M.; Belmaker, R.H. A preliminary study of possible psychoactive eects
of intravenous forskolin in depressed and schizophrenic patients. J. Neural Transm.
1996
,103, 1463–1467.
[CrossRef] [PubMed]
Appl. Sci. 2019,9, 4089 13 of 13
96.
Doorn, J.; Siddappa, R.; Van Blitterswijk, C.A.; De Boer, J. Forskolin enhances
in vivo
bone formation by
human mesenchymal stromal cells. Tissue Eng. Part A 2012,18, 558–567. [CrossRef] [PubMed]
97. Bhat, S.V.; Dohadwalla, A.N.; Bajwa, B.S.; Dadkar, N.K.; Dornauer, H.; de Souza, N.J. The antihypertensive
and positive inotropic diterpene forskolin: Eects of structural modifications on its activity. J. Med. Chem.
1983,26, 486–492. [CrossRef] [PubMed]
98.
Saettone, M.F.; Burgalassi, S.; Giannaccini, B. Preparation and evaluation in rabbits of topical solutions
containing forskolin. J. Ocul. Pharmacol. Ther. 2009,5, 2. [CrossRef]
99.
Gupta, S.; Samanta, M.K.; Raichur, A.M. Dual-Drug Delivery System Based on In Situ Gel-Forming
nanosuspension of forskolin to enhance antiglaucoma ecacy. AAPS Pharmscitech
2010
,11, 322–335.
[CrossRef] [PubMed]
100.
Gupta, S.; Samanta, M.K. Design and evaluation of thermoreversible in situ gelling system of forskolin for
the treatment of glaucoma. J. Pharm. Dev. Technol. 2010,15, 386–393. [CrossRef]
101.
Ameeduzzafar, K.N.; Khanna, K.; Bhatnagar, A.; Ahmad, F.J.; Ali, A. Chitosan coated PLGA nanoparticles
amplify the ocular hypotensive eect of forskolin: Statistical design, characterization and
in vivo
studies.
Int. J. Biol. Macromol. 2018,116, 648–663.
102.
Miastkowska, M.; Sikora, E.; Laso´n, E.; Garcia-Celma, M.J.; Escribano-Ferrer, E.; Solans, C.; Llinas, M.
Nano-emulsions as vehicles for topical delivery of forskolin. Acta Biochim. Pol.
2017
,64, 713–718. [CrossRef]
103.
Patil, S.; Agarwal, P.; Rojatkar, S.; Mahadik, K. Electrosprayed forskolin cocrystals with enhanced aqueous
solubility. Anal. Chem. Lett. 2018,8, 321–330. [CrossRef]
104.
Liu, Z.-J.; Jiang, D.-B.; Tian, L.-L.; Yin, J.-J.; Huang, J.-M.; Weng, W.-Y. Intestinal permeability of forskolin by
in situ single pass perfusion in rats. Planta Med. 2012,78, 698–702. [CrossRef]
105.
Godugu, D.; Rupula, K.S.; Rao, B. Binding interactions of forskolin with human serum albumin: Insights
from in silico and spectroscopic studies. Curr. Chem. Biol. 2016,10, 127–134. [CrossRef]
106.
Nagati, V.; Nakkka, S.; Yeggoni, D.P.; Subramanyam, R. Forskolin-loaded human serum albumin nanoparticles
and its biological importance. J. Biomol. Struct. Dyn. 2019,5, 1–12. [CrossRef] [PubMed]
107.
Majeed, M.; Nagabhushanam, K.; Natarajan, S.; Bani, S.; Vaidyanathan, P.; Majeed, S.; Karri, S.K. Investigation
of acute, sub-acute, chronic oral toxicity and mutagenicity of coleus forskohlii briq. hydroethanolic extract,
standardized for 10% forskolin in experimental animals. Int. J. Pharm. Pharm. Res. 2015,5, 219–238.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... In keeping with previous studies, these findings attribute the pivotal role of local microenvironments and dynamic mechanical forces in maturing and directing ECs to a distinct sub-phenotype. Further arterial specification was achieved with forskolin, a labdane diterpenoid extracted from the Coleus barbatus plant, which has shown several cardioprotective effects in early clinical studies [36,37]. Kim and colleagues first demonstrated that ETV2 activates cyclic AMP (cAMP) and exchange proteins directly activated by cAMP (EPAC) [16]. ...
Article
Full-text available
Cardiovascular disease is a globally prevalent disease with far-reaching medical and socio-economic consequences. Although improvements in treatment pathways and revascularisation therapies have slowed disease progression, contemporary management fails to modulate the underlying atherosclerotic process and sustainably replace damaged arterial tissue. Direct cellular reprogramming is a rapidly evolving and innovative tissue regenerative approach that holds promise to restore functional vasculature and restore blood perfusion. The approach utilises cell plasticity to directly convert somatic cells to another cell fate without a pluripotent stage. In this narrative literature review, we comprehensively analyse and compare direct reprogramming protocols to generate endothelial cells, vascular smooth muscle cells and vascular progenitors. Specifically, we carefully examine the reprogramming factors, their molecular mechanisms, conversion efficacies and therapeutic benefits for each induced vascular cell. Attention is given to the application of these novel approaches with tissue engineered vascular grafts as a therapeutic and disease-modelling platform for cardiovascular diseases. We conclude with a discussion on the ethics of direct reprogramming, its current challenges, and future perspectives.
... In the current study, we used Forskolin (FSK), derived from Coleus forskohlii, to treat CNS diseases such as insomnia, depression and seizures. In addition to its antioxidant and anti-inflammatory properties, it also has spasmolytic, sedative, anti-convulsive and asthmatic effects [22]. FSK reduces mitochondrial dysfunction in cardiomyopathy, asthma, glaucoma, hypertension, hair loss, cancer and obesity [23]. ...
Article
Full-text available
Parkinson’s disease (PD) is characterised by dopaminergic neuronal loss in the brain area. PD is a complex disease that deteriorates patients’ motor and non-motor functions. In experimental animals, the neurotoxin 6-OHDA induces neuropathological, behavioural, neurochemical and mitochondrial abnormalities and the formation of free radicals, which is related to Parkinson-like symptoms after inter-striatal 6-OHDA injection. Pathological manifestations of PD disrupt the cAMP/ATP-mediated activity of the transcription factor CREB, resulting in Parkinson’s-like symptoms. Forskolin (FSK) is a direct AC/cAMP/CREB activator isolated from Coleus forskohlii with various neuroprotective properties. FSK has already been proven in our laboratory to directly activate the enzyme adenylcyclase (AC) and reverse the neurodegeneration associated with the progression of Autism, Multiple Sclerosis, ALS, and Huntington’s disease. Several behavioural paradigms were used to confirm the post-lesion effects, including the rotarod, open field, grip strength, narrow beam walk (NBW) and Morris water maze (MWM) tasks. Our results were supported by examining brain cellular, molecular, mitochondrial and histopathological alterations. The FSK treatment (15, 30 and 45 mg/kg, orally) was found to be effective in restoring behavioural and neurochemical defects in a 6-OHDA-induced experimental rat model of PD. As a result, the current study successfully contributes to the investigation of FSK’s neuroprotective role in PD prevention via the activation of the AC/cAMP/PKA-driven CREB pathway and the restoration of mitochondrial ETC-complex enzymes.
... Although maternal hyperoxia results in increased oxygenation in the human fetus [39], which could stimulate the cAMP/PKA pathway and hence promote salt reabsorption, the toxicity of oxygen, especially in preterms resulting from the generation of reactive oxygen species, precludes its clinical use. Therefore, direct activators of the cAMP/PKA cascade such as forskolin, which can be given orally and has already been used in human clinical studies [40][41][42][43][44], could be studied in models of transient Bartter syndrome. ...
Article
Full-text available
Mutations in MAGED2 cause transient Bartter syndrome characterized by severe renal salt wasting in fetuses and infants, which leads to massive polyhydramnios causing preterm labor, extreme prematurity and perinatal death. Notably, this condition resolves spontaneously in parallel with developmental increase in renal oxygenation. MAGED2 interacts with G-alphaS (Gαs). Given the role of Gαs in activating adenylyl cyclase at the plasma membrane and consequently generating cAMP to promote renal salt reabsorption via protein kinase A (PKA), we hypothesized that MAGED2 is required for this signaling pathway under hypoxic conditions such as in fetuses. Consistent with that, under both physical and chemical hypoxia, knockdown of MAGED2 in renal (HEK293) and cancer (HeLa) cell culture models caused internalization of Gαs, which was fully reversible upon reoxygenation. In contrast to Gαs, cell surface expression of the β2-adrenergic receptor , which is coupled to Gαs, was not affected by MAGED2 depletion, demonstrating specific regulation of Gαs by MAGED2. Importantly, the internalization of Gαs due to MAGED2 deficiency significantly reduced cAMP generation and PKA activity. Interestingly, the internalization of Gαs was blocked by preventing its endocytosis with dynasore. Given the role of E3 ubiquitin ligases, which can be regulated by MAGE-proteins, in regulating endocytosis, we assessed the potential role of MDM2-dependent ubiquitination in MAGED2 deficiency-induced internalization of Gαs under hypoxia. Remarkably, MDM2 depletion or its chemical inhibition fully abolished Gαs-endocytosis following MAGED2 knockdown. Moreover, endocytosis of Gαs was also blocked by mutation of ubiquitin acceptor sites in Gαs. Thus, we reveal that MAGED2 is essential for the cAMP/PKA pathway under hypoxia to specifically regulate Gαs endocytosis by blocking MDM2-dependent ubiqui-tination of Gαs. This may explain, at least in part, the transient nature of Bartter syndrome caused by MAGED2 mutations and opens new avenues for therapy in these patients.
... Altogether, we conclude that inducing CREB activation through the PKA but not Bmp signaling cascade might be beneficial as chemotherapy adjuvant in medulloblastoma. Forskolin seems to be a promising compound for this, especially since this drug has already been clinically tested as treatment for several human diseases including diabetes and liver fibrosis; and there is increasing interest in Forskolin as anti-cancer treatment 44,49 . ...
Article
Full-text available
While there has been significant progress in the molecular characterization of the childhood brain cancer medulloblastoma, the tumor proteome remains less explored. However, it is important to obtain a complete understanding of medulloblastoma protein biology, since interactions between proteins represent potential new drug targets. Using previously generated phosphoprotein signaling-profiles of a large cohort of primary medulloblastoma, we discovered that phosphorylation of transcription factor CREB strongly correlates with medulloblastoma survival and associates with a differentiation phenotype. We further found that during normal cerebellar development, phosphorylated CREB was selectively expressed in differentiating cerebellar granule neuron progenitor (CGNP) cells. In line, we observed increased differentiation in CGNPs treated with Forskolin, Bmp6 and Bmp12 (Gdf7), which induce CREB phosphorylation. Lastly, we demonstrated that inducing CREB activation via PKA-mediated CREB signaling, but not Bmp/MEK/ERK mediated signalling, enhances medulloblastoma cell sensitivity to chemotherapy.
... Clinical studies of the plant and its main constituents support these traditional uses, ascribing most of the pharmacological actions to forskolin (coleonol), a labdane diterpenoid found exclusively in the tuberous roots of C. forskohlii. Its unique direct adenylyl-cyclase activation properties in diverse tissues endows forskolin with significant proven therapeutic benefits against various ailments, such as cystic fibrosis, asthma, obesity, cardiovascular diseases, cancer, diabetes, glaucoma, and liver fibrosis [162,163]. ...
Article
Full-text available
Since ancient times, plant roots have been widely used in traditional medicine for treating various ailments and diseases due to their beneficial effects. A large number of studies have demonstrated that—besides their aromatic properties—their biological activity can often be attributed to volatile constituents. This review provides a comprehensive overview of investigations into the chemical composition of essential oils and volatile components obtained from selected aromatic roots, including Angelica archangelica, Armoracia rusticana, Carlina sp., Chrysopogon zizanioides, Coleus forskohlii, Inula helenium, Sassafras albidum, Saussurea costus, and Valeriana officinalis. Additionally, their most important associated biological impacts are reported, such as anticarcinogenic, antimicrobial, antioxidant, pesticidal, and other miscellaneous properties. Various literature and electronic databases—including PubMed, ScienceDirect, Springer, Scopus, Google Scholar, and Wiley—were screened and data was obtained accordingly. The results indicate the promising properties of root-essential oils and their potential as a source for natural biologically active products for flavor, pharmaceutical, agricultural, and fragrance industries. However, more research is required to further establish the mechanism of action mediating these bioactivities as well as essential oil standardization because the chemical composition often strongly varies depending on external factors.
... This compound is used commercially for the treatment of glaucoma, asthma, and several heart ailments. 92 The complex chemical structure of forskolin with a decalin core, a tetrahydropyran ring, five oxidation sites, and eight chiral centers, represents a challenge for classical organic chemical synthesis. Pateraki et al. 40 reported the functional characterization of four CfTPSs via in vitro and in planta assays. ...
Article
Diterpenoids, including more than 18,000 compounds, represent an important class of metabolites that encompass both phytohormones and some industrially relevant compounds. These molecules with complex, diverse structures and physiological activities, have high value in the pharmaceutical industry. Most medicinal diterpenoids are extracted from plants. Major advances in understanding the biosynthetic pathways of these active compounds are providing unprecedented opportunities for the industrial production of diterpenoids by metabolic engineering and synthetic biology. Here, we summarize recent developments in the field of diterpenoid biosynthesis from medicinal herbs. An overview of the pathways and known biosynthetic enzymes is presented. In particular, we look at the main findings from the past decade and review recent progress in the biosynthesis of different groups of ringed compounds. We also discuss diterpenoid production using synthetic biology and metabolic engineering strategies, and draw on new technologies and discoveries to bring together many components into a useful framework for diterpenoid production.
Chapter
Diterpene forskolin is the active constituent derived from the roots of Coleus forskohlii. It is endowed for its versatile pharmacological properties. Forskolin is the only plant-derived compound known to stimulate the enzyme adenylate cyclase and subsequently effecting cyclic AMP (cAMP) synthesis. Because of its broad range of activity in signal transduction reactions, the cAMP is known as the “second messenger.” In the current chapter, some of the pharmacological properties including antiobesity, antidiabetic, antithrombotic, antioxidant, anti-inflammatory activity, asthma, glaucoma, heart disorders, hypertension, and anticancer activity of C. forskohlii and forskolin are discussed in detail.Keywords Coleus forskohlii ForskolinAntiobesityAntidiabeticAntithromboticGlaucomaAsthmaHeart disordersAnticancer
Article
A new multianalytical methodology based on gas chromatography (GC) and liquid chromatography (LC) coupled to mass spectrometry (MS) has been proposed to evaluate frauds affecting the composition of Coleus forskohlii root supplements (FKS). After optimization and validation of chromatographic methods, 24 FKS were analyzed. Forskolin, their main bioactive component, was only found in 50 % of the FKS evaluated (in the 0.032-17.1% range), with 27% of these supplements showing concentrations of this bioactive lower than those declared in their labels. Application of this methodology also proved to be successful for the detection of frauds regarding the replacement of C. forskohlii by other vegetable sources (green tea, soy leaves and a plant of the Berberidaceae family) in 17% of supplements analyzed. A study on stability of forskolin under accelerated conditions allowed to rule out its degradation as responsible for the lack of this bioactive or other natural constituents in 25% of FKS evaluated. It can be concluded that the multianalytical methodology here developed is shown to be advantageous to address the wide diversity of frauds affecting these supplements.
Article
The modification of highly oxygenated forskolin as well as manoyl and epi-manoyl oxide, two less functionalized model substrates sharing the same polycyclic skeleton, via intermolecular carbon-centered radical addition to the vinyl moiety has been investigated. Highly regio- and reasonably stereoselective iodine atom transfer radical addition (ATRA) reactions were developed. Unprotected forskolin afforded an unexpected cyclic ether derivative. Protection of the 1,3-diol as an acetonide led the formation of the iodine ATRA product. Interestingly, by changing the mode of initiation of the radical process, in situ protection of the forskolin 1,3-diol moiety as a cyclic boronic ester took place during the iodine ATRA process without disruption of the radical chain process. This very mild radical-mediated in situ protection of 1,3-diol is expected to be of interest for a broad range of radical and non-radical transformations. Finally, by using our recently developed tert-butyl­catechol-mediated hydroalkylation procedure, highly efficient preparation of forskolin derivatives bearing an extra ester or sulfone group was achieved.
Article
Full-text available
In this study, forskolin-loaded human serum albumin nanoparticles (FR-HSANPs) were successfully prepared by incorporation and affinity-binding methods. FR-HSANPs were characterized by transmission electron microscope that most of them are circular in shape and size is around 340 nm. The drug loading was more than 88% and further sustained release profiles were observed as it is 77.5% in 24 h time. Additionally, the cytotoxicity results with HepG2 cells indicated that FR-HSANPs showed significantly higher cytotoxicity and lower cell viability as compared to free forskolin (FR). Furthermore, to understand the binding mechanism of human serum albumin (HSA) with forskolin resulted from fluorescence quenching as a static mechanism and the binding constant is 6.26 ± 0.1 × 10⁴ M⁻¹, indicating a strong binding affinity. Further, association and dissociation kinetics of forskolin–HSA was calculated from surface plasmon resonance spectroscopy and the binding constant found to be Kforskolin = 3.4 ± 0.24 × 10⁴ M⁻¹ and also fast dissociation was observed. Further, we used circular dichroism and molecular dynamics simulations to elucidate the possible structural changes including local conformational changes and rigidity of the residues of both HSA and HSA–forskolin complexes. Communicated by Ramaswamy H. Sarma
Article
Full-text available
Coleus forskohlii is a perennial medicinal shrub cultivated mainly for its forskolin content. The plant has been used since ancient times in ayurvedic traditional medicines for the treatment of hypertension, glaucoma, asthma, congestive heart failures, obesity, and cancer. Use of endophytic microorganisms presents a special interest for the development of value-added bioactive compounds through agriculture. Limited investigations have been undertaken on in planta enhancement of forskolin content using endophytic fungus in sustainable agriculture. Here we report specific roles of three fungal endophytes, Fusarium redolens (RF1), Phialemoniopsis cornearis (SF1), and Macrophomina pseudophaseolina (SF2), functionally acting as plant probiotic fungus, regulating secondary metabolite (forskolin) biosynthesis in C. forskohlii. The root endophyte, RF1, and shoot endophytes, SF1 and SF2, were found to enhance forskolin content by 52 to 88% in pot and 60 to 84% in field experiments as compared to uninoculated control plants. The three endophytes also enhanced total biomass owing to plant growth promoting properties. The expression of diterpene synthases (CfTPSs) like CfTPS1, CfTPS2, CfTPS3, and CfTPS4 were significantly upregulated in endophyte-treated C. forskohlii plants. Elevated expression of key diterpene synthases (CfTPS2) in the forskolin biosynthesis pathway, exclusively present in the root cork of C. forskohlii, was observed following SF2 endophyte treatment. Furthermore, endophyte treatments conferred a variety of antagonistic activity against nematode galls (80%) and plant pathogens like Fusarium oxysporum, Colletotricum gloeosporioides, and Sclerotium rolfsii. RF1 and SF1 fungal endophytes showed positive for IAA production; however, SF1 also indicated phosphate solubilization activity. Overall, the qualitative and quantitative improvement of in planta forskolin enhancement represents an area of high commercial interest, and hence, our work focused on novel insights for the application of three fungal endophytes for in planta enhancement of forskolin content for C. forskohlii cultivation by a sustainable approach.
Article
Full-text available
Ferulago species are utilized as flavor, sedative, tonic, aphrodisiac, peptic, immunostimulant, antibronchitis, vermicidal, carminative and for the curation of cancers and skin disorders in Middle Eastern region. The presented research reports anticholinesterase and antioxidant capacities of aerial parts, fruits, flowers, roots extracts and isolated coumarins of roots from of Ferulago cassia Boiss (peucedanol (1), suberosin (2), grandivitinol (3) and umbelliferone (4)). The TBA antioxidant activity results of some samples were strong when compared the references rutin, propyl gallate and chlorogenic acid. The highest phenolics level and DPPH antioxidant capacity were determined in fraction from root and fruit. Among different studied extract fractions, the CH 2 Cl 2 fractions, especially root and fruit, has been detected to indicate considerable acetylcholinesterase (AChE) (53.24%) and butyrylcholinesterase (BuChE) (96.56%) inhibition at 20 μg/mL, respectively. Peucedanol (76.22%) and suberosin (71.67%) indicated strong inhibition towards BuChE. The umbelliferone (61.09%) exhibitted strong inhibition towards AChE at 20 μg/mL. F. cassia can be used a potency for pharmaceutical products which have antioxidant and anticholinesterase activity.
Article
Full-text available
Background: Central Asia is the center of origin and diversification of the Artemisia genus. The genus Artemisia is known to possess a rich phytochemical diversity. Artemisinin is the shining example of a phytochemical isolated from Artemisia annua, which is widely used in the treatment of malaria. There is great interest in the discovery of alternative sources of artemisinin in other Artemisia species. Methods: The hexane extracts of Artemisia plants were prepared with ultrasound-assisted extraction procedures. Silica gel was used as an adsorbent for the purification of Artemisia annua extract. High-performance liquid chromatography with ultraviolet detection was performed for the quantification of underivatized artemisinin from hexane extracts of plants. Results: Artemisinin was found in seven Artemisia species collected from Tajikistan. Content of artemisinin ranged between 0.07% and 0.45% based on dry mass of Artemisia species samples. Conclusions: The artemisinin contents were observed in seven Artemisia species. A. vachanica was found to be a novel plant source of artemisinin. Purification of A. annua hexane extract using silica gel as adsorbent resulted in enrichment of artemisinin.
Article
Full-text available
Aromatase inhibitor (AI) resistance is a major obstacle in the treatment of estrogen receptor-positive breast cancer. Everolimus (EVE) ameliorates AI-resistant breast cancer and is therefore used in cancer treatment. However, some patients show resistance to EVE. Here, we used 30 clones of long-term estrogen-deprived (LTED) MCF-7 cells as a model of AI-resistant breast cancer. We examined changes in protein phosphatase type 2A (PP2A) and cancerous inhibitor of PP2A (CIP2A), a negative regulator of PP2A, in LTED cells treated with EVE. In LTED cells with high sensitivity to EVE, CIP2A expression decreased at low EVE concentrations; however, in LTED cells poorly sensitive to EVE, CIP2A and PP2A did not change upon exposure to EVE. Therefore, we hypothesized that there is a relation between expression of CIP2A and sensitivity to EVE. Knockdown of CIP2A increased the sensitivity to EVE in three clones poorly sensitive to EVE. Additionally, we found that treatment with FSK, which activates PP2A, increased the sensitivity of the cells to EVE. Our data point to CIP2A and PP2A as novel therapeutic targets for AI-resistant breast cancer.
Article
Forskolin, a diterpene phytomolecule has several pharmacological activities including cardiovascular and pulmonary disorders, antiglaucoma, antiobesity, reversal of multidrug resistance and anticancer activity. However, its utility as a potential drug molecule has been arrested due to low aqueous solubility and in turn bioavailability. Herein we report cocrystal synthesis of forskolin with nicotinamide, caffeine and ascorbic acid coformers for the first time using electrospray technology. Ethanolic solutions containing forskolin and coformer were electrosprayed to obtain the cocrystals. The prepared cocrystals were characterized using powder X-ray diffractometry, differential scanning calorimetry, fourier transform infrared spectroscopy, proton nuclear magnetic resonance, scanning electron microscopy, particle size analysis and saturation solubility studies. Electrospray lead to formation of needle shaped forskolin cocrystals as confirmed by PXRD, DSC, FTIR and proton NMR which showed two fold enhancement in water solubility of forskolin which in turn is believed to enhance its bioavailability. Thus to conclude, forskolin cocrystals were successfully prepared using electrospray technology.
Article
Purpose: Enhancing the ocular hypotensive effect of forskolin (FK) by means of biodegradable chitosan (CS) coated poly lactic-co-glycolic acid (PLGA) nanoparticles (NP's). Methods: One step emulsion-sonication process was employed for the formulation of CS-PLGA NP's with optimization being carried out by employing a four factor four level Box Behnken Design Expert. Physical and spectral characterization, drug release, permeation, confocal and ocular tolerance studies (ex-vivo & in vivo) were performed. Corneal retention was assessed by gamma scintigraphic analysis and dexamethasone induced glaucamotous rabbit's intraocular pressure (IOP) was measured by means of Schiotz tonometer. Results and discussion: Particle size was optimized as 201.56 ± 10.92 nm with PDI 0.178 ± 0.05 and zeta potential value of 10.1 ± 3.49 mV. EE and DL were calculated to be 72.32 ± 1.12% & 28.39 ± 1.67 respectively. Spectral characterization confirmed the purity and encapsulation of the drug within polymeric system. A sustained drug release and permeation was observed exhibiting fluorescence intensity at a depth of 94.9 μm. Ocular tolerance studies explicated it safe use. Scintigraphy studies indicated longer retention of CS-PLGA NP's in comparison to aqueous suspension while increased effectiveness after single instillation in reducing the intraocular pressure was observed. Conclusion: CS-PLGA-NP's could be successfully formulated and are an excellent vehicle for FK in ocular delivery.
Article
Triple negative breast cancer (TNBC) is an invasive, metastatic, highly aggressive tumor. Cytotoxic chemotherapy represents the current treatment for TNBC. However, relapse and chemo-resistance are very frequent. Therefore, new therapeutic approaches that are able to increase the sensitivity to cytotoxic drugs are needed. Forskolin, a natural cAMP elevating agent, has been used for several centuries in medicine and its safeness has also been demonstrated in modern studies. Recently, forskolin is emerging as a possible novel molecule for cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of MDA-MB-231and MDA-MB-468TNBC cells to doxorubicin through MTT assay, flow cytometry-based assays (cell-cycle progression and cell death), cell number counting and immunoblotting experiments. We demonstrate that forskolin strongly enhances doxorubicin-induced antiproliferative effects by cell death induction. Similar effects are observed with IBMX and isoproterenol cAMP elevating agents and 8-Br-cAMP analog, but not by using 8-pCPT-2'-O-Me-cAMP Epacactivator. It is important to note that the forskolin-induced potentiation of sensitivity to doxorubicin is accompanied by a strong inhibition of ERK1/2 phosphorylation, is mimicked by ERK inhibitor PD98059 and is prevented by pre-treatment with Protein Kinase A (PKA) and adenylate cyclase inhibitors. Altogether, our data indicate that forskolin sensitizes TNBC cells to doxorubicin via a mechanism depending on the cAMP/PKA-mediated ERK inhibition. Our findings sustain the evidence of anticancer activity mediated by forskolin and encourage the design of future in-vivo/clinical studies in order to explore forskolin as a doxorubicin sensitizer for possible use in TNBC patients.
Article
Two O/W forskolin-loaded nano-emulsions (0.075% wt.) based on medium chain triglycerides (MCT) and stabilized by a nonionic surfactant (Polysorbate 80 or Polysorbate 40) were studied as forskolin delivery systems. The nano-emulsions were prepared by the PIC method. The mean droplet size of the nano-emulsions with Polysorbate 80 and Polysorbate 40 with oil/surfactant (O/S) ratios of 20/80 and 80% water concentration, measured by Dynamic Light Scattering (DLS), was of 118 nm and 111 nm, respectively. Stability of the formulations, as assessed by light backscattering for 24 h, showed that both nano-emulsions were stable at 25ºC. Studies of forskolin in vitro skin permeation from the nano-emulsions and from a triglyceride solution were carried out at 32ºC, using Franz-type diffusion cells. A mixture of PBS/ethanol (60/40 v/v) was used as a receptor solution. The highest flux and permeability coefficient was obtained for the system stabilized with Polysorbate 80 (6.91±0.75 µg·cm-2·h-1 and 9.21·10-3±1.00·10-3 cm·h-1, respectively) but no significant differences were observed with the flux and permeability coefficient value of forskolin dissolved in oil. The obtained results showed that the nano-emulsions developed in this study could be used as effective carriers for topical administration of forskolin.