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Review
Magnolol andits semi‑synthetic derivatives: acomprehensive review
ofanti‑cancer mechanisms, pharmacokinetics, andfuture therapeutic
potential
AsmitaRayamajhi1· NishaGyawali1· DeepaKarki1· LuisE.Pérez‑Caltzontzin2· SheilaI.Peña‑Corona2·
HernánCortés3· AchyutAdhikari1· GerardoLeyva‑Gómez2· YadavUprety4· SolomonHabtemariam5·
LashynKiyekbayeva6· JavadShari‑Rad7,8,9
Received: 21 October 2024 / Accepted: 16 April 2025
© The Author(s) 2025 OPEN
Abstract
In recent years, magnolol (MG), a natural active compound of polyphenolic nature, has garnered signicant interest for
its anti-cancer eects. Numerous studies conducted on cell lines and animal models have indicated a positive impact
of administering drugs or semi-synthesized products derived from MG, including a decreased incidence of various can-
cers. This review aims to illustrate the underlying cellular and molecular basis of its actions. The article includes in-depth
explanations of phytochemistry, semi-synthetic derivatives, bioavailability, pharmacokinetics, preclinical research, anti-
tumor mechanisms, human clinical studies, toxicity, side eects, and safety. It also demonstrates that, in contrast to the
wealth of synthetic medications, MG is highly eective against bladder, colon, gastric, skin, liver, lung, gallbladder, and
prostate cancers. The ndings of this review indicate that MG is a promising candidate as an anti-tumor agent, and future
research should focus on developing new semi-synthetic derivative compounds with potential anti-tumor properties.
Keywords Natural polyphenolic compound· Magnolol· Cancer cell growth inhibition· Low water solubility· Magnolia
species· Semi-synthetic derivatives
Abbreviations
ABCD Administration Bioavailability Clearance and Distribution
ADP Adenosine diphosphate
Akt Protein kinase B
BT47 Human breast cancerous cell
CDK Cyclin-dependent kinase
* Achyut Adhikari, achyutraj05@gmail.com; * Gerardo Leyva-Gómez, leyva@quimica.unam.mx; * Javad Shari-Rad, javad.sharirad@
gmail.com; Asmita Rayamajhi, rayamajhiasmita9@gmail.com; Nisha Gyawali, gyawalinishu111@gmail.com; Deepa Karki, realdeepakarki@
gmail.com; Luis E. Pérez-Caltzontzin, LEPCQFB@outlook.com; Sheila I. Peña-Corona, sheila.irais.pc@gmail.com; Hernán Cortés, hcortes_c@
hotmail.com; Yadav Uprety, yadavuprety@gmail.com; Solomon Habtemariam, s.habtemariam@herbalanalysis.co.uk; Lashyn Kiyekbayeva,
Lashynk@mail.ru | 1Central Department ofChemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal. 2Departamento de Farmacia,
Facultad de Química, Universidad Nacional Autónoma de México, CiudaddeMéxico04510, México. 3Laboratorio de Medicina Genómica,
Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, CiudaddeMexico, México. 4Central
Department ofBotany, Tribhuvan University, Kirtipur, Kathmandu, Nepal. 5Pharmacognosy Research & Herbal Analysis Services UK, Central
Avenue, Chatham-Maritime, KentME44 TB, UK. 6Department ofPharmaceutical Technology, Pharmaceutical School, Asfendiyarov Kazakh
National Medical University, Almaty, Kazakhstan. 7Universidad Espíritu Santo, Samborondón, Iran. 8Centro de Estudios Tecnológicos y
Universitarios del Golfo, Veracruz, Mexico. 9Department ofMedicine, College ofMedicine, Korea University, Seoul02841, RepublicofKorea.
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DNA Deoxyribonucleic acid
ERK Extracellular signal-regulated kinase
HER2 Human epidermal growth factor receptor 2
HIF 1α Hypoxia-inducible factor 1alpha
HL60 Human promyelocytic leukemia cells
lbMPS Lecithin-based-mixed-polymeric micelle
IC50 Inhibition concentration
IGF Insulin like growth factor
IGFBP Insulin-like growth factor binding protein
i.p. Intraperitoneal
IUPAC International Union of Pure and Applied Chemistry
LO2 Human fetal hepatocyte line
MAPK Mitogen-activated protein kinase
MBE Magnolia Bark Extract
MAPK Mitogen-Activated Protein Kinase/Extracellular signal-regulated kinases
MAPK/ERK Mitogen-activated protein kinases
MCF-7 Michigan Cancer Foundation-7
MCF-10 A Mammary epithelial cell line
MG Magnolol
mM Millimolar
µM Micromolar
MMP2 Matrix metalloproteinase 2
MMP-9 Matrix metalloproteinase-9
MOLT-4 Human acute lymphoblastic leukemia cell line
mTOR Mammalian target of rapamycin
mTORC1 MTOR complex 1
NA Not applicable
NaDOC Sodium deoxycholate
NSCLC Non-Small Cell Lung Cancer
NF-κB Nuclear factor-KappaB
NSCLC Non-small cell lung cancer
OC2 Organ of Corti 2 (cell number)
PC-3 Prostate Cancer cells
PI3 K Phosphoinositide 3-kinase
PIP3 Phosphatidylinositol (3,4,5)-triphosphate
SKVO3 Human ovarian cancer cell
VEGE Vascular endothelial growth factor
VSMCs Vascular smooth muscle cells
4E-BP1 4E binding protein 1
1 Introduction
Forecasts for cancer incidence and mortality indicate that by 2030, the annual number of cancer diagnoses will exceed
2 million [1], with projections ranging from 2.2 million to nearly 3 million cases by 2050 [2]. The rise in diagnosis rates
is expected to outpace population growth during this period [1]. In 2022, people born in the USA have approximately
a 40% (men) and a 38% (women) risk, respectively, of being diagnosed with cancer in their lifetime [3]. Therefore, the
expected increase in cancer diagnoses underscores the urgent need for enhanced prevention, early detection, and treat-
ment strategies to tackle this growing public health challenge.
Cancer is the uncontrolled growth of abnormal cells that can invade nearby and distant tissues and organs. It
involves changes in cellular or tissue structure and function. Genetic mutations are the predominant cause of the
growth of neoplastic cells, which tend to increase their reproductive lifespan. The most common cancers in men
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are prostate, lung/bronchus, colon/rectum, and urinary bladder; in women, they are breast, lung/bronchus, colon/
rectum, uterine corpus, and thyroid [4].
On the other hand, the two most common cancers in children are blood cancer and cancers of the brain and lymph
nodes [5]. Cancer can affect anyone at any age but is more likely to occur in older people, and the treatment depends
on the disease stage and type of cancer.
In this sense, Magnolol (MG) is a hydroxylated biphenyl compound derived from the bark (roots and branches) of
Magnolia species such as M. officinalis, M. obovata, and M. grandiflora [6]. Historically, the genus Magnolia represents
plants of the family Magnoliaceae, which commonly grow in the valleys and mountains of China, Japan, and Korea
[7, 8]. The two main bioactive compounds isolated from these plants are MG (5,5ʹ-diallyl-2,2ʹ-dihydroxybiphenyl)
and Honokiol (3,5ʹ-diallyl-4,2ʹ-dihydroxybiphenyl) (Fig.1) which are phenolic regioisomers [9]. MG is a nonpolar
compound with a white fine powder appearance and with a melting point of 102 °C. In the bark extracts of Magnolia
plants, the composition of MG ranges from 1 to 10%, while Honokiol comprises 1 to 5%. In both cases, variation in
composition generally depends on environmental and developmental conditions such as genetic origin, altitude,
temperature, and plant age [10]. In the last few decades, MG has demonstrated a broad spectrum of biological
activities against cancer, affecting various aspects of cancer cell biology, such as proliferation, cell cycle, apoptosis,
metastasis, angiogenesis, and signaling pathways, such as NF-κB (Nuclear factor-KappaB), MAPK (Mitogen-activated
protein kinase), and PI3 K/Akt/mTOR (Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) [11]. MG
inhibits cancer cell growth in bladder [12], breast [13], cholangiocarcinoma [14], colon [15], esophagus [16], fibro-
sarcoma [17], gallbladder [18], gastric [19], glioblastoma [20], leukemia [17], liver [21], lung [22], lymphoma [23],
melanoma [24], oral carcinoma [25], osteosarcoma [26], ovarian [26], pancreatic [27], prostate [28], renal [29], skin
[30], and thyroid [31] cancer. MG acts through multiple anti-tumor mechanisms such as inhibition of DNA synthesis,
induction of apoptosis in human liver and colon cancerous cells [32], suppression of gallbladder cancer cell growth
via p53 [18], and promotion of autophagy to cause cell death in lung cancer cells [33]. Thus, MG has emerged as a
promising anti-cancer drug; nevertheless, its low bioavailability and solubility limit its potential clinical application.
Therefore, developing a delivery system that can solve these limitations [34] is essential. MG also possesses a variety
of pharmacological effects, including anti-oxidant [35], anti-inflammatory, anti-bacterial [36], anti-thrombotic or anti-
platelet [37], anti-stress [38], anti-anxiety, anti-Alzheimer [39], Alzheimer, anti-stroke[40], hypoglycemic [41], smooth
muscle relaxant [42], weight control [43], anti-dyspeptic/prokinetic [44], anti-epileptic[45] and hepatoprotective
effects [46]. Therefore, this review provides a comprehensive overview of the impact of MG and its semi- synthetic
derivatives on the molecular targets and signaling pathways involved in cancer cell growth and metastasis, as well
as their toxicity, bioavailability, pharmacokinetics, and formulations of MG.
Fig. 1 Structures of magnolol, honokiol and magnolol-2-O-glucuronide
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2 Review methodology
We conducted a comprehensive review of the anti-cancer properties of MG based on published research investigating
its eects against various types of cancer. We searched Google Scholar, PubMed, and the American Chemical Society for
articles related to “Magnolol and (cancer or tumor or carcinoma)” from 1986 to 2024. We focused on studies that examined
the anti-cancer eects of MG and its semi-synthetic derivatives, as well as those exploring the anti-cancer mechanisms of
MG, its bioavailability, and pharmacokinetics. Additionally, we analyzed MG’s pharmacological investigations and clinical
studies, including only English-language publications.
2.1 Molecular docking
We performed molecular docking using Molegro Virtual Docker (MVD) 6.0 to determine if MG interacts with PI3 Kα
(PDB:4 TV3), PI3 Kγ (PDB:7 JWE), and GSK-3beta (PDB:5 K5 N), which are critical regulators of cellular functions in cancer
cells. Additionally, we accessed the Gedatolisib PubChem database (#44516953), which demonstrates potential activ-
ity in cancer cells targeting PI3 K and the PI3 K/mTOR signaling pathway. This database revealed a high anity for the
active sites of PI3 Kα, PI3 Kγ, and GSK-3beta. The docking parameters included a Moldock Score with a GRID resolution
of 0.30, the MolDock SE algorithm, a maximum of 1500 iterations, a maximum size of 50, a generation energy position
threshold of 100, and ve multiple poses; the working radius was set to 15. The docking was conducted in the active site.
The molecule was prepared by removing water molecules and cofactors from the PDB molecule. The structure used for
docking was MG, which was obtained from the PubChem database (#72300). The working coordinates were as follows:
for (PI3 K) α (x: − 15.87, y:, and z: 27.28), PI3 Kγ (x: 26.15, y: 2.94, and z: 20.12), and GSK-3beta (x: 1.13, y: 9.35, and z:26.27).
3 Sources andphytochemistry ofmagnolol
MG is a polyphenol belonging to the lignans structural group and was originally isolated from a plant used in Chinese and
Japanese medicine to treat various conditions, including anxiety, fever, headache, and neurosis [44]. It also reduces the
body’s temperature by inhibiting the release of 5-hydroxytryptamine in the rat hypothalamus [45]. The IUPAC name of
MG is 2-(2-hydroxy-5-prop-2-enylphenyl)−4-prop-2-enylphenol, and it is also known by other names such as 5,5ʹ-diallyl-
2,2ʹ-dihydroxybiphenyl, 2,2ʹ-bichavicol, and 5,5ʹ-diallyl-(1,1ʹ-biphenyl)−2,2ʹ-diol [3]. MG and honokiol are the main con-
stituents of the leaf and bark of dierent Magnolia species, such as M. ocinalis, M. dealbata, and M. obovate [37]. These
are stereoisomers, and their structures are presented in Fig.1. MG exhibited greater solubility in basic and lower solubility
at acidic pH values [46]. Its unique pharmacophore structure, which consists of two hydroxylated aromatic rings con-
nected by a single C–C bond representing the hydroxylated biphenyl structure, plays a signicant role in its biological
activity [47]. The structural characteristic enables interactions with numerous proteins [47]. MG alters its structure inside
the dierent organs, forming magnolol-2-O-glucuronide and MG sulfate, both of which possess enhanced pharmaco-
logical properties [48]. Notably, many phytochemicals isolated from natural sources, such as avonoids, alkaloids, poly-
phenols, diterpenoids, and sesquiterpenes, exhibit anti-cancer properties [49]. Additionally, MG has benecial activities
that include anti-cancer, antibiotic, antispasmodic, and antidepression eects [48], anti-inammatory antioxidants, and
tumor-suppressive properties [50]. Furthermore, MG can protect DNA from oxidation caused by 2,2′-Azobis (2-amidino-
propane) dihydrochloride and can eectively trap 1.8 and 2.5 radicals [51].
4 Semi‑synthetic derivatives
Structural modications of MG have led to the development of semi-synthetic derivatives with various structural variants
that provide new and improved pharmacological properties; some have shown approximately 10- to 100-fold greater
cytotoxicity than MG. For instance, an MG derivative, 3-(4-aminopiperidin-1-yl) methyl magnolol, exhibited an eight-
fold increase in potency against HCC827, H1975, and H460 cell lines. This nding suggests that it may be a promising
candidate for treating non-small cell lung cancer (NSCLC) [47]. The derivative (Fig.2, structure A) was synthesized by
adding halohydrocarbons and removing t-butyloxycarbonyl under acidic conditions. A Friedel–Crafts alkylation reaction
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is conducted on MG, involving the addition of a halohydrocarbon to MG. Friedel–Crafts alkylation is an electrophilic
substitution reaction where an alkyl group attaches to the benzene ring of MG. At this point, an intermediate product
can form with t-butyloxycarbonyl. The subsequent step entails removing the t-butyloxycarbonyl group under acidic
conditions, which releases the t-butyloxycarbonyl group and regenerates the functional group on the benzene ring.
The resulting compound is treated with potassium carbonate (K2CO3) and acetonitrile (MeCN). This step may relate to
neutralizing residual acids and purifying the product. Nitrogen (N2) indicates that the reaction occurs under an inert
atmosphere. The reaction proceeds at 95 °C for 3 to 12 h. The objective was to introduce another functional group to the
product or conduct a substitution reaction [47].
On the other hand, an MG derivative was produced using a Suzuki coupling reaction catalyzed by Pd (Fig.3, Com-
pound B). Alkylation with n-butyl lithium (nBuLi) and tribromomethoxymethane (Br(OMe)3) in tetrahydrofuran (THF):
In this step, a trisubstituted benzene (with a methoxy group (OMe) in position 1 and bromine (Br) in position 2) reacts
with nBuLi and Br(OMe)3 in THF at − 78 °C for 2h. The reaction involves Friedel- Crafts alkylation. nBuLi is a strong base
that deprotonates the benzene meta to the OMe group, after which Br(OMe)3 acts as an electrophile in the Friedel-Crafts
reaction. Suzuki coupling with Pd(PPh3)4 and Na2 CO3 in DME: in this stage, the product (which now has Br(OMe)3 instead
of bromine) reacts with palladium (Pd) as a catalyst (Pd(PPh3)4) and sodium carbonate (Na2 CO3) in diethyl ether dimethyl
(DME) at reux for 6h. This step involves a Suzuki coupling reaction, a cross-reaction between an organic compound
containing a benzene group and a compound containing a boron group (usually an aromatic molecule with a boron
group). Pd(PPh3)4 catalyzes the formation of a carbon–carbon bond between the two molecules. Substitution of OMe
for OH and addition of I in the meta position: In this stage, the product from the previous stage (which has two disubsti-
tuted benzenes attached) reacts with iodide (I2) in the presence of CAN and acetonitrile (CH3 CN) at room temperature
for 2h. Following that, a reaction with aluminum chloride (AlCl3) and dimethyl sulde (Me2S) is performed at room tem-
perature for 1h. These steps involve a nucleophilic aromatic substitution in which methoxy (OMe) groups are replaced
by hydroxyl (OH) groups on each disubstituted benzene, and an iodine atom is added at a meta position to the former
location of the OMe group. The presence of CAN and AlCl3 serves as deprotecting agents to facilitate the substitution
and addition of the iodine group. A panel of three human cancer cell lines, including PC-3 (prostate cancer cells), HL-60
(human promyelocytic leukemia cells), and MOLT-4 (human acute lymphoblastic leukemia cell line), was used to assess
Fig. 2 Semi-synthetic magnolol derivative. A Friedel–Crafts alkylation introduces a halohydrocarbon to MG, adding an alkyl group to the
benzene ring. The intermediate product undergoes deprotection in acidic conditions, and the compound is puried using potassium car-
bonate (K2CO3) and acetonitrile (MeCN). The reaction is conducted under nitrogen (N2) at 95 °C for 3–12 h to introduce a functional group or
perform a substitution
Fig. 3 Production of MG derivative via Pd-catalyzed Suzuki coupling. Alkylation with nBuLi and Br(OMe)3 in THF yields a trisubstituted ben-
zene. The product undergoes Suzuki coupling with Pd(PPh3)4 and Na2CO3 in DME at reux for 6h. The nal substitution replaces OMe with
OH and introduces iodine (I) at the meta position, using I2, CAN, acetonitrile, AlCl3, and Me2S at room temperature
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the compound’s invitro antiproliferative potential. Compound B with diiodo and butyl substitutions was tested against
these cell lines, revealing cytotoxicity with IC 50 values of 2, 2, and 10 µM, respectively [52].
Other derivatives were obtained when the naturally isolated MG was subjected to the Williamson ether synthesis reaction,
yielding new products (Fig.4, structures C and D). In this stage of the Williamson ether reaction, the compound from the previ-
ous step (which has two disubstituted benzenes linked by OH groups) is reacted with sodium carbonate (Na2CO3) and dimeth-
ylformamide (DMF). Na2CO3 acts as a base to deprotonate the OH group, forming O-Na+ (a sodium alkyloxide ion). This ion
then reacts with an alkyl halide (a compound with an alkyl group attached to a halogen atom, such as Cl, Br, or I) to replace
the sodium ion with an alkyloxy group (OR), leaving OR in place of O-Na+. This step in the synthesis is known as a Williamson
ether reaction. Here, a sodium alkyloxide ion is formed from the OH group in disubstituted benzene and reacts with an alkyl
halide to form an alkyloxy ether. This reaction produces two products: one with an OR group on the rst benzene and another
with an OR group on the second benzene, replacing the initial OH groups. The new products are MG derivatives with alkyloxy
groups instead of hydroxyl groups, potentially modifying their chemical properties and applications. The compounds produced
more eective invitro antiproliferative eects against MD-NB-231, SMMC-7721, MCF-7, and CNE-2Z human cancer cell lines
than MG. Derivative C was especially eective against MDA-MB-231 cells, with an IC50 value of 20.43 µM, and it also reduced
the migration and invasion of this cell line by lowering the protein levels of HIF-1α (Hypoxia-inducible factor 1 alpha), MMP-9
(Matrix metalloproteinase-9), and MMP-2 (Matrix metalloproteinase-2). The cytotoxicity of the compound increased by having
a para-F-substituted benzyl group instead of ortho or meta position [48]. Thus, replacing the phenolic hydroxyl group of MG
with a para-uorobenzyl group enhances cytotoxic potency.
Other semi-synthetic derivatives of MG were synthesized through an esterication reaction (Fig.5). The hydroxyl group (OH) of
MG reacts with n-propyl acid chloride (nPrCOCl) to form an ester bond. Potassium carbonate (K2CO3) acts as a base to neutralize
the hydrochloric acid (HCl) produced during the reaction. Acetone and room temperature (r.t.) are suitable solvents and reaction
conditions. The products of this reaction are the monoester and diester of MG, indicating that one or both OH groups of MG
have been converted into ester groups, depending on the specic conditions of the reaction. These esters are semisynthetic
derivatives of MG and may have applications in chemistry and pharmacology, as modifying functional groups in a molecule can
alter its properties and biological activities. The butyrate ester, combined with parental MG (OH group), demonstrated potent
antiproliferative activity and promising pharmacological action against hepatocellular carcinoma. MG’s mono and dibutyrate
derivatives showed signicant cytotoxic eects against HepG2 cells after 48 h. The study indicated that the dibutyrate product
elicited higher activity than MG at concentrations as low as 1µM [49].
A derivative produced by a Mannich reaction (Fig.6) exhibited cytotoxicity in cancer cells by inducing autophagy. The
compound was obtained by substituting hydrogen at the C-2 position of MG with a Mannich base. Initially, 4,5-trimeth-
oxybenzaldehyde reacts with morpholine to form a Mannich base. This Mannich base, which contains an amino group
(NH2), is then reacted with MG. The Mannich reaction is an organic process involving the condensation of a ketone or
aldehyde, a compound with a primary amino group (such as morpholine in this case), and a compound with an active
group like a methylene ion (-CH2-). This reaction is employed to form Mannich bases, which are reactive intermediates
that can be used to synthesize various chemicals. MG reacts with the produced Mannich base, resulting in the formation
of the semisynthetic MG derivative. The Mannich reaction can introduce specic functional groups into MG, potentially
modifying its chemical properties and applications. The exact nature of the MG derivative will depend on the structure
Fig. 4 MG derivatives were obtained through Williamson ether synthesis. The product from the previous reaction interacts with Na2CO3 and
DMF, resulting in a sodium alkyloxide ion. This ion subsequently reacts with an alkyl halide, replacing the OH group with an OR group and
leading to two products featuring alkyloxy groups instead of hydroxyl groups
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of the Mannich base and the reaction conditions applied. The derived compound (G) was tested alongside cisplatin
against human cancer cell lines, demonstrating promising antiproliferative eects against HeLa, T47D, and MCF-7 cancer
cell lines, with IC50 values of 1.71, 0.91, and 3.32 µM, respectively. The MG derivative (G) exhibited signicantly higher
cytotoxicity on the T47D cancer cell line, being 10.3 times more eective than MG [50].
Studies comparing the anti-cancer activities of MG derivatives are limited. Zhao etal. demonstrated that the MG
derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol exhibits superior activity compared to honokiol. Additionally,
the authors synthesized fty-one MG derivatives, with compound 30 showing the strongest antiproliferative eects on
H460, HCC827, and H1975 cell lines, with IC50 values ranging from 0.63 to 0.93 μM. The activity is approximately 10 to 100
times greater than C2 and MG, respectively [47]. In comparison, IC50 values for compound B tested against HL-60, PC-3,
and MOLT-4 cell lines were 2, 2, and 10 µM [52], while derivative C produced an IC50 of 20.43 µM against MDA-MB-231
cells [48], and compound G had IC50 values of 1.71, 0.91, and 3.32 µM for HeLa, T47D, and MCF-7 cells, respectively [50].
However, further research is necessary to identify the most eective derivative.
5 Mechanism ofanti‑tumor action ofmagnolol
MG exerts its anti-cancer eects through multiple mechanisms involving various signaling pathways (Figs.7 and 8). This
section discusses the mechanisms of action of MG as elucidated by other cancer models. We summarize evidence that MG
can induce cell cycle arrest and apoptosis, suppress cell growth and proliferation, and prevent angiogenesis. Additionally,
we explore the molecular pathways involved in MG’s anti-cancer actions, including PI3 K/Akt/mTOR, MAPK, and NF-κB
(Fig.8). Based on existing evidence, we can conclude that MG possesses multi-target anti-cancer activity, a trait attributed
to MG’s distinctive symmetrical bi-phenol structure, which makes it ideal for interacting with protein molecules [53].
Fig. 5 Semi-synthetic magnolol derivatives synthesized through esterication with n-propyl acid chloride (nPrCOCl) and K2CO3. This reac-
tion produces both monoester and diester derivatives
Fig. 6 Synthesis of a magnolol derivative via the Mannich reaction. The Mannich reaction involves the condensation of a ketone or alde-
hyde, a primary amino group (such as morpholine), and an active methylene group (–CH2–). This reaction produces a Mannich base that can
subsequently react with MG, resulting in a semisynthetic MG derivative that may modify its chemical properties and applications
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5.1 Suppression ofgrowth andproliferation
Cell proliferation is the process by which many diploid cells are produced from a single cell through growth and the cell
cycle, and it is regulated by both external and internal factors [54]. Proliferation is a critical characteristic of cancer, which
is marked by abnormal growth. While normal cell growth is tightly regulated, tumor cells lose this regulation during
tumor formation and metastasis, resulting in a lack of standard growth control [55]. Understanding this transition aids in
identifying how cancer begins and in improving treatment methods that do not harm normal cells [55]. MG can inhibit
the growth of cells in various cancer types, including those from the bladder [12], breast [56], cholangiocarcinoma [14],
esophageal [16], gastric [19], leukemia [17], liver [57], lung [22], lymphoma [23], melanoma [24], oral carcinoma [25],
pancreatic [27], and skin [30] cancers.
Fig. 7 The active site is similar to Gedalotisib (green) and Magnolol (red)
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5.2 Inhibition ofsignaling (PI3 K/Akt/mTOR/MAPK/NF‑kB)
The PI3 K/Akt/mTOR signaling pathway is often involved in the growth and survival of cancer cells [58]. This pathway
is activated when PI3 K converts phosphatidylinositol (3,4-bisphosphate) to phosphatidylinositol (3,4,5)-triphosphate
(PIP3), which leads to the phosphorylation of Akt and the mTOR complex 1 (mTORC1) [59, 60]. mTOR regulates the
production of many proteins that promote proliferation by phosphorylating p70S6 kinase (p70S6 K) and eukaryotic
translation initiation factor 4E binding protein 1 (4E-BP1) [61]. MG has decreased the phosphorylation of PI3 K, Akt,
mTOR, p70S6 K, and 4E-BP1 in various cancer types [11]. Therefore, MG can inhibit the PI3 K/Akt/mTOR signaling
pathway and reduce tumor cell growth; this MG-induced inactivation appears independent of cancer type. MG also
impacts the MAPK signaling pathway, another critical signal transduction pathway [62]. MG targets the three main
MAPK cascades: MAPK/ERK (Extracellular signal-regulated kinase), MAPK/C-Jun N-Terminal Kinase, and MAPK/p38
mitogen-activated protein kinase (p38). Finally, MG can also block the NF-κB signaling pathway by preventing the
phosphorylation of IκB and/or the p65 NF-κB subunit, essential for regulating tumor growth and metastasis [57].
Regarding molecular docking, our results indicate that Gelatoditosib interacts with the active site of PI3 Kα, bind-
ing to amino acids such as Val 851, Ser 774, and His 917, and with PI3 Kγ, interacting with Val 882, Asp 841, and Gly
966, as illustrated in Fig.7. Additionally, GSK3β is a crucial target due to its role in cancer, where it regulates multiple
proto-oncoproteins and acts as an intermediary in the epithelial-mesenchymal transition. Its deregulation contributes
to tumor cell survival, evasion of apoptosis, proliferation, invasion, maintenance of cancer stemness, and therapeutic
resistance. Within the active site of GSK3β, essential amino acids such as Val 135 and Asp 133 play a key role in inacti-
vating the site [63]. Other amino acids involved in this site include Arg 141, Glu 137, Thr 138, Val 70, Ala 83, Asp 133,
Fig. 8 Magnolol induces cell cycle arrest and apoptosis and suppresses cell growth and proliferation; it prevents angiogenesis. Magnolol
acts in molecular pathways involved with anti-cancer actions, such as PI3 K/Akt/mTOR, MAPK, and NF-κB
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Leu 188, and Tyr 134. When testing Gelatoditosib in the GSK3β active site, we found that it interacts specifically with
these amino acids, achieving a Moldock score of −142.925, which confirms its reported high specificity for receptors
involved in cancer.
Similarly, MG may interact with some of the same amino acids as Gelatoditosib, including Ile 932, Ser 774, and Asp 933
in PI3 Kα, and Asp 841, Asp 964, and Gly 966 in PI3 Kγ (Fig.7, Table1). These interactions may contribute to its anti-cancer
properties. Although its binding energy is weaker than that of Gelatoditosib, MG can still interact at the PI3 K action site.
In the case of GSK3β, MG forms hydrogen bonds with Val 135, Glu 137, Tyr 134, and Leu 188, suggesting that it interacts
with critical amino acids to inhibit GSK3β. Therefore, MG could exhibit anti-cancer activity by interacting with and form-
ing bonds at the action sites of PI3 K and GSK3β, as reported in the literature.
5.3 Arrest ofcell cycle
One mechanism by which MG exerts its anti-cancer eects is by arresting the cell cycle at dierent phases, depending
on the type of cancer cells. The cell cycle is a process that repeats from quiescence (G0 phase) to proliferation (G1, S, G2,
and M phases) and then back to the G0 phase [64]. Cell cycle progression is mainly controlled by the phosphorylation
of particular proteins by cyclin-dependent kinases (CDKs), their dephosphorylation by phosphatases, and specialized
proteolytic degradation by the ubiquitin–proteasome system [11, 64]. Any disruption or alteration of the cell cycle can
result in abnormal cell growth and proliferation, a hallmark of cancer. MG can stop the cell cycle in three phases: sub-G1
[65], G0/G1 [66], and G2/M MG [22]. While MG can reduce the number of cells in the G1 phase, it does not demonstrate
the potency to prevent cancer from spreading.
5.4 Induction ofapoptosis andinhibition ofangiogenesis
The natural mechanism for programmed cell death in a cell is apoptosis, which is crucial for maintaining homeostasis
and eliminating undesirable cells. This highly regulated process is triggered by DNA damage or uncontrolled growth
[67]. MG can simultaneously activate both the intrinsic and extrinsic pathways of apoptosis, which are characterized by
the loss of mitochondrial membrane potential and cleaved caspase-9 [20]. Circulating endothelial precursors, shed from
the vessel wall or mobilized from the bone marrow, can also contribute to tumor angiogenesis [68]. Additionally, MG can
inhibit blood supply to the cells by blocking angiogenesis.
5.5 Anti‑oxidant effects
MG modulates oxidative stress due to its high radical-scavenging activities [11, 69]. A study demonstrated that MG
reduces ONOO− and O2, trapping up to 2.5 radicals and protecting DNA from oxidation induced by the compound
2,2′-Azobis (2-amidinopropane) dihydrochloride (AAPH) [69]. Another study found that MG trapped four peroxyl radicals,
with a kinh of 6.1 × 104 M1 s1 in chlorobenzene and 6.0 × 103 M1 s1 in acetonitrile [35]. MG features a bisphenol core with
two allylic side chains, and its antioxidant activity is linked to hydroxyl and allyl groups, reinforcing its potential as a thera-
peutic agent [70]. In aristolochic acid (AA)-induced HK-2 cells, MG (10 μM) decreased oxidative stress and inhibited cell
proliferation by obstructing the cell cycle at the G1 phase and preventing G2/M arrest [71]. According to this information,
the main eect of MG as an anti-tumor agent is its capacity to protect DNA from oxidation by trapping various radicals.
6 Bioavailability andpharmacokinetics ofmagnolol
Bioavailability refers to the amount and percentage of a drug’s original dose that reaches the intended target site or the
body uids where the drug can access its targets [72, 73]. It is essential for pharmacokinetics, which studies how drugs
move through the body. ABCD summarizes pharmacokinetics as administration, bioavailability, clearance, and distribu-
tion [74]. MG is predominantly absorbed via a lipid-like route in the gastrointestinal system [51].
After oral treatment with 50 mg/kg of MG in rats, MG sulfates and glucuronides were detected in the blood, liver,
kidney, brain, lung, and heart. The liver showed the highest levels of MG and MG glucuronides among these organs
[75]. Magnolol-2-O-glucuronide, the primary metabolite of MG, was excreted in bile, while MG was eliminated
through the digestive tract following oral or intraperitoneal injection. The metabolic products excreted from oral MG
in rats included MG (< 90%) and free metabolites (6% glucuronic acid and sulfate) after 1day of oral administration
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Table 1 Comparative molecular docking analysis of Gedatolisib and Magnolol with PI3 Kα, PI3 Kγ, and GSK-3beta proteins
Molecules PI3 Kα PI3 Kγ GSK-3beta
Moldock Score Hidrogen
interactions Steric interactions Moldock Score Hidrogen
interactions Steric interactions Moldock Score Hidrogen
interactions Steric interactions
Gedatolisib − 105.839 Gln 859
Val 851
Ser 774
Ile 800, Asp 933
Ile 932, His 917
Ser 919
− 158.164 Asp 841
Val 882
Thr 887
Asp 837
Asp 964
Glu 880
Gly 966
− 142.925 – Asn 64, Gly 63, Phe 67, Val
135, Leu 188, Asp 133,
Ala 83
Leu 132, Asp 200, Gln 185
Cys 199, Lys 85
Val 70
Magnolol − 91.334 Lys 802
Asp 933 Ile 932, Trp 780
Met 772, Ser 774, Tyr 836
Asp 810, Tyr 836, Asp 806
Ile 848
− 87.849 Tyr 867
Asp 964
Asp 841
Asp 836
Gly 966
Leu 838
Ile 831
− 91.6004 Val 135
Glu 137 Tyr 134
Leu 188
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of MG [76]. The pharmacokinetics of MG were studied with intravenous injection (2 to 10 mg/kg) in rats. The absorp-
tion half-life, elimination half-life, maximum concentration, and time to reach maximum concentration were found
to be 0.63 h, 2.33 h, 0.16 µg/mL, and 1.12 h, respectively. This study indicated that the oral bioavailability of MG was
4.9%, suggesting poor water solubility and absorption in the gut [77].
Xie etal. indicated that sulfation is essential for magnolol metabolism. Their study identified the sulfated metabo-
lite of magnolol using UPLC-Q-TOF–MS and 1H-NMR. Magnolol metabolism was investigated in liver S9 fractions
from humans (HLS9), rats (RLS9), and mice (MLS9) [78]. The findings indicate that magnolol is metabolized into a
mono-sulfated form by SULTs, with SULT1B1 exhibiting the highest sulfation activity. In liver S9 fractions, the sulfa-
tion rates of magnolol were similar in HLS9 and RLS9 (0.96 and 0.99 µL/min/mg, respectively) but were lower in
MLS9 (0.30 µL/min/mg). Both magnolol and its sulfated metabolite significantly reduced the production of inflam-
matory mediators (IL-1β, IL-6, and TNF-α) in LPS-stimulated RAW264.7 cells. These results suggest that SULT1B1 is
the primary enzyme responsible for magnolol sulfation, and its sulfated metabolite possesses anti-inflammatory
effects [79].
Diverse pharmacokinetics studies indicate that various formulations can enhance MG’s bioavailability, including
nanoparticles, phospholipid complexes, zinc-based organometallic complexes, liposomes, and emulsions [80]. For
example, an invivo pharmacokinetics study revealed that the formulation of MG in solid dispersions, phospholipid
complexes, and solid lipid nanoparticles improved its bioavailability by 1.38, 2.12, and 3.45 times, respectively, com-
pared to MG suspension [80]. Another study in rabbits showed that MG bioavailability increased by 142.8% when
combined with PVP (polyvinylpyrrolidone K-30) in an amorphous melting solid dispersion [81]. Finally, a research
group demonstrated that lecithin-based mixed polymeric micelles enhance MG’s solubility and bioavailability [82].
The absolute bioavailability for MG after intravenous administration of the formulation was 3.4-fold higher than
that of the free compound. MG’s absolute and relative bioavailability for oral administration were 20.1% and 2.9-
fold higher, respectively. Therefore, the authors concluded that this formulation had better solubility with suitable
physical characteristics, leading to improved bioavailability of MG, which could facilitate its application as a thera-
peutic agent for treating human cancers. Furthermore, there is potential for research into improving formulations
using solid dispersions, phospholipid complexes, and microparticles to enhance bioavailability.
6.1 New formulations fortheadministration ofmagnolol
Magnolol exemplifies a typical case study of type IV molecules within the biopharmaceutical classification system,
characterized by low solubility and low absorption, resulting in very low bioavailability following oral administra-
tion. Traditionally, cancer therapies utilize vectorization systems with highly efficient administration routes, prefer-
ably parenteral, to optimize the administered dose. Drug carrier systems enhance the stability of the medication,
improve pharmacokinetic parameters, and consequently, increase bioavailability [83, 84]. However, this alone is
insufficient for cancer therapies; the targeting or specificity of the carrier system is also essential. Specificity is par-
tially achieved through the coupling of ligands on the surface with receptors that are overexpressed in the type
of cancer being addressed. Thus, the ligand-receptor attraction will direct the entire carrier system. Based on our
review of the literature, there remains limited information on the application of these technologies for MG, sug-
gesting a significant opportunity for exploring new projects to highlight the biological properties of MG.
We are still at an early stage in the study of MG that could revolutionize its more significant impact on the pos-
sible treatment of cancer.
Regarding the formulations discussed for MG in the previous section, the solid dispersion with PVP stands out.
It is a classic strategy for enhancing solubility in a straightforward and typically economical manner, [79] although
it does not provide specificity for cancer treatment. While various types of nanoparticles appear highly promis-
ing, their safety aspects are stringent and are generally suitable for high-potency drugs that require a low dose.
For natural products with low potency needing a high dose, the delivery system involving different nanoparticles
may be insufficient. However, additional concerns arise, as liposomes may significantly raise costs, and SLNs could
indicate lower stability. Conversely, there is limited information about the robust performance of niosomes in these
applications, and exosomes may prove to be a more suitable system for more specific active ingredients.
However, in regulatory terms, there is more experience in approving liposomes, which could facilitate their
manufacture and commercialization.
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7 Preclinical anti‑cancer studies
Preclinical studies are essential for cancer research because they provide initial evidence of the safety and ecacy of new
drugs before testing in humans. Moreover, they help identify the optimal dose, route, and schedule of administration,
as well as potential side eects, toxicity, molecular mechanisms of action and resistance, and interactions with other
drugs or biological factors. Additionally, preclinical studies can facilitate the design of clinical trials by oering rational
hypotheses, biomarkers, and endpoints for evaluating clinical outcomes. Therefore, these studies are crucial for advanc-
ing cancer research and improving cancer care. Since MG has attracted considerable attention for its potential against
various types of cancer, we review the latest advances in preclinical studies investigating MG’s anti-cancer properties and
mechanisms across dierent cancer models. By employing invitro (cell cultures or tissues) and invivo (animal models
or human tumor xenografts) methods, these studies have revealed various mechanisms of anti-cancer eects, such as
altering growth, proliferation, signaling, apoptosis, and angiogenesis.
7.1 In vitro studies
An invitro study on the anti-tumor activity of MG against SKOV3 human ovarian and BT474 human breast cancer cells
revealed a reduction in the overexpression of the HER2 gene by lowering PI3 K/Akt, along with inhibition of VEGF (vascular
endothelial growth factor), MMP2, and cyclin D1 at various concentrations (6.25, 12.5, 25, 50, 100, and 200 µM) [22]. MG
was also tested invitro at concentrations of 1, 5, 10, and 20 µM (IC50 = 5µM) against human NSCLC cells (NCI-1299) and
A549. Results indicated that MG blocked the cell cycle and disrupted the cellular microtubule structures by inhibiting
the Akt/mTOR pathway [85].
On the other hand, in human HCT116, SW480, and HEK293 cell lines, MG stimulated the Wnt/β-catenin signaling
pathway and β-catenin/T-cell factor-targeted downstream genes. This eect inhibited tumor cell growth and motility
at 12.5, 20, 25, 30, 50, and 75 µM [85]. Rasul etal. indicated that MG induced mitochondria-dependent apoptosis while
suppressing the PI3 K/Akt pathway. Apoptosis markers such as alterations in the Bax/Bcl-2 ratio, activation of caspase-3,
and the induction of autophagy were observed in human gastric adenocarcinoma SGC-7901 cells (at concentrations of
MG of 10, 30, 50, 100, 200, and 300 µM) [19]. In another study, human DU145 and PC3 prostate adenocarcinoma cells were
incubated with 40 and 80 µM of MG. The study revealed that the compound modulated the cell cycle by downregulating
CDK2, CDK4, and pRBp130 expression, followed by increased protein levels of pRBp107 [28].
Similarly, McKeown and Hurta etal. evaluated the invitro eect of 80 µM of MG on human PC3 and LNCaP cells. The
authors found that it reduced the expression of insulin-like growth factor-1 (IGF-1) as well as other related proteins: IGFBP-
5, IGFBP-3, IGFBP-4, and the IGF-1 receptor [86]. Additionally, MG inhibited the growth of human lung carcinoma A549
cells by increasing lactate dehydrogenase activity, which facilitated the activation of caspase-3, cleavage of poly-(ADP)-
ribose polymerases, and reduction of NF-κB/RelA levels [87]. Finally, a study involving a human breast cancer cell line
showed that MG, at concentrations of 10, 20, 30, 40, 50, and 60 µM, prevented the invasiveness of these cells by blocking
the NF-κB pathway and suppressing MMP-9 expression [13]. MG has been assessed alongside cisplatin to evaluate its
impact on the viability and maintenance of MKN-45 gastric cancer cells. The combined use of MG and cisplatin resulted
in a substantial decrease in cell viability and increased Bax expression. Consequently, MG exhibits a signicant anti-tumor
eect on MKN-45 cells. MG has the potential to help overcome cisplatin resistance when used in conjunction with it
in gastric cancer cells [88]. Another study also found that the administration of MG enhanced the eect of cisplatin in
reducing cell viability, self-renewal, and invasion activities in cancer stem cells [25]. The administration of MG is not only
associated with increased anti-cancer activity of drugs but has also been described as preventing sarcopenia induced
by cancer chemotherapy [89]. Consequently, MG shows great promise in boosting the anti-tumor eects of cisplatin.
7.2 In vivo studies
In one experiment, tumors were established in nude mice by injecting A549 cells after administering MG at a dosage of
25 mg/kg for 20 days. The compound was shown to reduce tumor sizes and weights compared to the untreated control
group [22]. The eects of MG were also studied in female ICR mice during 12-O-tetradecanoylphorbol-13-acetate (TPA)-
induced tumor promotion, where topical application of 1 and 5μM of MG for 20 weeks signicantly reduced the multiplic-
ity, incidence, and size of papillomas. Furthermore, the authors reported that MG abolished inammation associated with
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experimental tumorigenesis, such as the transcriptional activation of iNOS and COX-2 mRNA [90]. Additionally, SK-Hep1/
luc2 cells were subcutaneously injected into the right ank of each mouse, followed by gavage administration of 50 or
100 mg/kg of MG for 15 days. The administration of MG diminished the growth and progression of tumors, inducing
apoptosis through both extrinsic and intrinsic pathways [57]. According to a study by Li etal. [18], MG demonstrated
an eect in both invitro and invivo studies on the growth of human gallbladder carcinoma. The mechanisms involved
include inducing cell cycle arrest at G0/G1 and apoptosis, along with a signicant increase in activated caspase-3. The
invivo study, which utilized GBC-SD cells injected into the left axilla of BALB/c nude mice, showed that MG (5, 10, or 20
mg/kg, i.p. for 28 days) suppressed the growth of xenograft gallbladder cancer tumors in a dose-dependent manner
through the induction of apoptosis [18]. In another study, similar invitro and invivo eects of MG related to apoptosis
induction and increased cleavage of caspase-8 were observed in UVB-induced skin tumor development in SKH-1 mice.
This research involved pretreated mice administered 30 and 60 μg of MG before UVB treatments (30 mJ/cm2, 5days/
week). Consequently, tumor multiplicity was reduced by 27–55% [30].
In MDA-MB-231 and MCF-7 xenografted murine models, MG (40 mg/kg, i.p. injection) demonstrated an anti-tumor
eect, suggesting its potential in breast cancer therapy. MG did not aect body weight or induce visible toxicity in the
mice [13]. Another study evaluated the impact of co-treatment with MG and honokiol.
The results indicated that cotreatment inhibited tumor progression and induced apoptosis more eciently than
either honokiol or MG alone. Therefore, the authors suggest combining both compounds (MG with honokiol) may be
applied as an adjuvant therapy to improve treatment ecacy of glioblastoma (a malignant brain tumor-associated) [91].
According to the studies described above, a research opportunity exists to evaluate the synergistic eect of MG with
other compounds that have demonstrated anti-tumor properties, such as polyphenols [92, 93]. The combined treatment
of MG with gemcitabine and cisplatin or gemcitabine signicantly reduces body weight loss and skeletal muscle atrophy
compared to conventional chemotherapy in mice bearing bladder cancer [94].
Additionally, more studies are necessary to evaluate eective doses and side eects in animal models. Table1 sum-
marizes the evidence that MG can inhibit cancer cell proliferation and induce cell cycle arrest, autophagy, and apoptosis
(discussed in detail in “Preclinical anti-cancer studies” section). We also present some of the molecular pathways involved
in the anti-cancer actions of MG, such as PI3 K/Akt/mTOR, MAPK, and NF-κB. It is important to clarify that although pre-
clinical data are promising, human clinical studies are insucient to draw denitive conclusions (Table2).
8 Human clinical studies
Regarding human clinical studies, the search on clinicaltrials.gov, only exposes one Clinical Trial phase III, randomized,
double-blind, placebo-controlled, that reports using MG as part of a formulation (Papilocare® Gel) directed to cervical
mucosal repair. Specically, the study focused on the repair of cervical lesions caused by human papillomaviruses. The
gel is a mix of hyaluronic acid niosomes, magnolol, honokiol, carboxymethyl beta-glucan, alpha-oligoglycan, coriolus
versicolor, neem extract, centella asiatica and Aloe vera. The results of the clinical trial have not yet been disclosed.
9 Toxicity, side eects, andsafety
Toxicity is referred to the degree to which something is detrimental. Before humans use a new compound, it is essential
to test its toxicity and ensure that it is safe and eective. This can reveal potential hazards such as causing cancer, dam-
aging DNA, harming the immune system, or aecting reproduction and development. These hazards can lead to severe
outcomes for human health and well-being, such as tumors, malformations, sterility, and immune diseases. Thus, testing
toxicity is vital to drug development and is mandated by regulatory agencies worldwide. For example, MG, combined
with other herbal-medicinal derivative compounds, is a remedy for various disorders, including gastrointestinal anxiety,
allergies, and sleeping pills. However, pure combination at high doses has adverse side eects in humans [8].
Thus, MG was tested in an invivo study to see its toxicity as an isolated compound; human normal hepatocyte U937
and LO2 cells were used to examine toxicity at 10–100 µM concentrations in a dose-dependent manner. According to
the authors, concentrations less than 60 µM did not aect the cell survival of U937 cells, while at concentrations below
70 µM, the mortality rate of LO2 cells was less than 20% after 48 h [95]. In contrast, MG at a concentration of 40 µM
exhibited cytotoxic eects on VSMCs [96]. Conversely, MG reduced the viability of OC2 cells in a dose-dependent manner
(20–200 µM of MG for 24 h) [97]. Interestingly, a study tested MG’s ability to prevent UV-induced mutations in Salmonella
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Table 2 Preclinical anti-cancer studies of magnolol
Type of cancer Model Invitro using cell lines
Invivo using animal models Concentrations IC50/doses Mechanism signaling pathways Results References
Bladder cancer In vitro 5637 cells 60 µM (24 h) Downregulation of Cyclin D1/E/
B1, CDK2/4, p-Cdc25c, p-Cdc2,
upregulation of p27
Induction of cell cycle at G0/G1 (low
and high dose) [105]
Breast
Cancer In-vitro MCF-7 cell line 58.27 µM (24 h)
:53.39 µM (48 h)
49.56 µM
Upregulation of p21, p53, and
downregulation of Cyclin B1,
CDK1, Upregulation of Bax,
Cytochrome C, Cleaved PAR, and
downregulation of Bcl-2
Induction of cell cycle arrest and
apoptosis [56]
Colon cancer In-vitro COLO 205: HT29 COLO 205 3–10 µM (6 days) Upregulation of p21, and Down-
regulation of cyclin A/E Induction of cell cycle arrest at G0/
G1 [32]
Gastric cancer In vitro SGC- 7901 50–100 µM
(48 h) Generates apoptosis
Upregulation of cleaved caspase-3
and downregulation of Bcl-2 that
inhibit Akt signaling, upregula-
tion of p-PI3 K, p-Akt dependent
pathway
Induction of cell cycle arrest at sub-
G1 NS [19]
Prostate cancer In-vitro Du145; PC3 Du145: ~ 40 µM PC3: ~ 80 µM (24 h) Downregulation of the protein
Cyclin D1 Induction of cell cycle arrest at G0/
G1 [28]
Lung cancer In-vitro H460 80–100 µM (24 h): 60–80 µM (48 h) Inhibition of PTEN/Akt signaling
with upregulation in PTEN and
downregulation of P-Akt
Induction of autophagy [33]
Skin cancer In vivo TP-induced Carcinogenesis 1–5 µM, twice a week Downregulation of iNOS, p-p65,
p-IκBα, p-ERK, and p-Ak Inhibition of inammation, NF-κB
signaling, MAPL signaling, and PI3
K/Akt signaling
[90]
Gall bladder cancer In-vivo BC-SD In-vitro BC-SD, 5–20 mg/kg every day (GBC-SD:20.5)
(48 h), 14.9 µM (48 h) Downregulation of Cyclin D1, Cdc25
A, CDK2 protein levels upregulat-
ing by Bax, p53, p21 protein levels
and downregulation of Bl-2
Induction of cycle arrest at G0/G1
and apoptosis [18]
Liver cancer In-vivo SK-Hep1 P.o. 50–100 mg/kg every day for
fteen days Downregulation of XIAP, c-P, and
Mc1-1 and upregulation of
Caspase-3/9 NF-κB activity, p-p65,
p-MMP-9, and cyclin
Induction of apoptosis and inhibi-
tion of NF-κB signaling [57]
Lung carcinoma In-vivo male nude mice i.p. 25 mg/kg every other day for
twenty days Perturbing the microtubule polym-
erization Reduced the tumor sizes and weight [22]
Breast cancer In vivo MDA-MB-231 and MCF-7 i.p. 40 mg/kg four times a week for
four weeks Inhibiting MMP-9 through the NF-κB
pathway Suppresses tumor invasion [13]
Human glioblastomas In-vivo BALB/cAnN 20 mg/kg/day for 14 days Reduced p-p38 and p-JNK expres-
sion induced autophagy Induction of apoptosis [91]
Skin cancer In-vivo SKH-1 mice Magnolol pretreated groups 30, 60
μg, 5days/week for 25 weeks Enhancing apoptosis, causing cell
cycle arrest at G2/M phase Reduction of tumor multiplicity [30]
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typhimurium TA102. The authors measured relative mutagenic activities, reecting the mutation rate of treated cells
compared to the mutation rate of control cells multiplied by 100%. The results indicated that MG can eectively prevent
UV-induced mutagenesis at low doses (5 µg MG/plate), possibly by removing OH radicals [98]. Notably, while some invivo
studies indicated a slight toxic impact of MG, there is no reported genotoxicity or mutagenic eect [99] for concentrated
Magnolia bark extract (> 240 mg/kg) [100]. Similarly, a study involving 40 volunteers who consumed 11.9 mg of MG daily
as chewing gum for 30 days did not report any adverse side eects [101]. MG is considered safe in aquaculture due to its
potential inhibitory eects against parasitic protozoans (Ichthyophthirius multiliis) in goldsh [102]. Additionally, it pos-
sesses anti-aging, anti-inammatory, antioxidant, and anti-cancer properties, making it a relevant ingredient in cosmetic
products [103]. Therefore, MG appears safe for human administration at low and moderate doses.
Other natural compounds are promising for cancer therapy because they reduce the toxicity produced by synthetic
anti-cancer drugs (see for review [104]). However, studies with MG that compare other compounds’toxicity, side eects,
and safety are missing. Therefore, this is a research opportunity for researchers focused on the area.
10 Conclusion andprospects
MG is a natural polyphenolic compound that has demonstrated signicant anti-cancer eects through multiple mecha-
nisms, including inhibiting cell proliferation, the promotion of apoptosis, and the suppression of angiogenesis medi-
ated by key signaling pathways. While MG’s low bioavailability and solubility have limited its clinical application, vari-
ous formulation strategies, including nanoparticles and phospholipid complexes, have been developed to enhance its
pharmacokinetics, showing promising results. Regarding safety and toxicity, MG has been tested invitro and invivo on
dierent cancer cells and has been used in human clinical trials with no adverse side eects. Despite these advances,
a complete understanding of its molecular mechanisms is still lacking, and further research is needed to elucidate its
anti-cancer actions fully. This is crucial because despite its potent anti-cancer properties. Additionally, although MG has
shown low toxicity and is considered safe at lower doses, there is still a need for more comprehensive clinical trials to
conrm its ecacy and safety in human populations. Therefore, while MG holds considerable potential as an anti-cancer
agent, further studies are essential to overcome existing challenges, such as improving its bioavailability, detailing the
mechanisms in cancer cells that support evidence for antiproliferative activity, and expanding clinical data.
Acknowledgements Sheila I. Peña Corona would like to thank the Postdoctoral Program Scholarship of Consejo Nacional de Humanidades,
Ciencias y Tecnologías (CONAHCyT) assigned CVU:495850. Gerardo Leyva-Gomez acknowledges the nancial support from DGAPA-UNAM
for PAPIIT IN204722 and PAPIME PE205524. We appreciate the professional assistance of María de los Dolores Campos Echeverría, School of
Chemistry, UNAM.
Author contributions AR, NG, DK, LE.P–C, SI.P–C, HC, AA, GL-G, YU, SH, LK, JS-R made a signicant contribution to the work reported, whether
that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas that is, revising or criti-
cally reviewing the article; giving nal approval of the version to be published; agreeing on the journal to which the article has been submitted;
and conrming to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.
Funding Not applicable.
Data availability No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate Not applicable.
Consent for publication Not applicable.
Competing interests The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which
permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to
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do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party
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the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco
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