Research ProposalPDF Available


  • Fondazione Di Bella
  • Fondazione Giuseppe Di Bella - Onlus
  • Fondazione Giuseppe Di Bella
  • Fondazione Giuseppe Di Bella ONLUS


Despite all the new developments in cancer therapy, the life expectancy of patients with sarcoma remains short. Since it was established as a cancer therapy, the Di Bella Method (DBM) has been able to increase survival rate and life quality, without overt toxicity, in comparison to what is described in the literature for the treatment of sarcoma with the same immunohistochemical, histologic and clinical features. We therefore treated 37 patients with sarcoma using the DBM protocol. The DBM therapy consists of somatostatin and analogues (octreotide), all trans-retinoic acid (ATRA), β-Carotene, axerophthol dissolved in vitamin E, vitamin D, vitamin C, melatonin (MLT), proteoglycans, glycosaminoglycans, hydroxyurea, Sodium butyrate (Na-Bu). These molecules have antiproliferative, antiangiogenic, cytostatic, antioxidant, antimetastatic (differentiative) and immunomodulating properties. Moreover, the inclusion of ATRA, MLT and Na-Bu has increased the antitumoral properties of the therapy by extending them to cancer stem cells. Furthermore, the non-cytolytic and non-cytotoxic metronomic dosage of hydroxyurea has improved the outcome of DBM therapy by increasing anti-tumour capability. The results of this treatment revealed the effectiveness of the DBM. In conclusion, the multi-strategic objectives of the DBM are to inhibit proliferation-invasiveness and neoplastic angiogenesis, silence the survival system of cancer stem cells, enhance immunomodulatory and antioxidant activities, improve the vitality and efficiency of normal cells, and depress the efficiency and vitality of neoplastic ones.
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Giuseppe Di Bella*, Vittoria Borghetto, Ilaria Moscato and Elena Costanzo
Di Bella Foundation, Bologna, Italy.
Despite all the new developments in cancer therapy, the life
expectancy of patients with sarcoma remains short. Since it was
established as a cancer therapy, the Di Bella Method (DBM) has been
able to increase survival rate and life quality, without overt toxicity, in
comparison to what is described in the literature for the treatment of
sarcoma with the same immunohistochemical, histologic and clinical
features. We therefore treated 37 patients with sarcoma using the DBM
protocol. The DBM therapy consists of somatostatin and analogues
(octreotide), all trans-retinoic acid (ATRA), β-Carotene, axerophthol
dissolved in vitamin E, vitamin D, vitamin C, melatonin (MLT),
proteoglycans, glycosaminoglycans, hydroxyurea, Sodium butyrate (Na-Bu). These
molecules have antiproliferative, antiangiogenic, cytostatic, antioxidant, antimetastatic
(differentiative) and immunomodulating properties. Moreover, the inclusion of ATRA, MLT
and Na-Bu has increased the antitumoral properties of the therapy by extending them to
cancer stem cells. Furthermore, the non-cytolytic and non-cytotoxic metronomic dosage of
hydroxyurea has improved the outcome of DBM therapy by increasing anti-tumour
capability. The results of this treatment revealed the effectiveness of the DBM. In conclusion,
the multi-strategic objectives of the DBM are to inhibit proliferation-invasiveness and
neoplastic angiogenesis, silence the survival system of cancer stem cells, enhance
immunomodulatory and antioxidant activities, improve the vitality and efficiency of normal
cells, and depress the efficiency and vitality of neoplastic ones.
KEYWORDS: Sarcoma; Growth Factor; Somatostatin; Melatonin; Retinoic Acid;
Vitamin D; Vitamin E; Prolactin; Di Bella Method; D2 R agonists.
World Journal of Pharmaceutical Research
SJIF Impact Factor 8.084
Volume 11, Issue 7, 1219-1278. Case Study ISSN 2277 7105
*Corresponding Author
Giuseppe Di Bella
Di Bella Foundation,
Bologna, Italy.
Article Received on
21 April 2022,
Revised on 11 May 2022,
Accepted on 01 June 2022
DOI: 10.20959/wjpr20227-24424
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Sarcomas are a rare heterogeneous group of malignant tumours of mesenchymal origin,
which comprise 1% of all malignant neoplasms in adults and 12% of malignant paediatric
cancers. The histopathological spectrum of sarcomas is broad, presumably because the
mesenchymal embryonic cells from which they emerge have the ability to mature into
striated skeletal muscle, adipose tissue, fibrous tissue, bone and cartilage.[1]
They are mainly divided into bone sarcomas and soft tissue sarcomas. The first are less
common, with significant morphological heterogeneity and broad-spectrum biology[2], while
the more common second type includes at least 100 different histologic and molecular
subtypes, with variable clinical behaviour.[3] While part of this intratumoural heterogeneity
could be explained in terms of clonal genetic evolution, an essential part includes a
hierarchical relationship between sarcoma cells, governed by both genetic and epigenetic
influences. The notion of this functional hierarchy operating within each tumour implies the
existence of sarcoma stem cells. With progressive evidence, the literature is documenting, in
osteosarcomas, the narrow causal relationship between the significant increase in serum GH
rate during development and in prepubertal and pubertal ages, and its site of action, clearly
prevalent in the osteocartilaginous growth areas.[4]
Both soft tissue sarcomas and bone sarcomas are mainly treated with neoadjuvant
chemotherapy, surgical resection and adjuvant chemotherapy. Radiotherapy is used less often
and is generally applied when other treatments cannot achieve significant results.[1,2,3] There
is no unique treatment for individual subtypes of soft tissue sarcoma because of the broad
biological spectrum. Treatment varies depending on tumour immunohistochemistry;
chemotherapy is rarely a reliable treatment for the effective resolution of the disease.[1]
In bone sarcomas, where surgery is not followed by disease relapse, five-year survival for
localised disease is just over 70%, while in metastatic osteosarcomas and Ewing sarcomas it
is just over 20%.[3] In soft tissue sarcomas, 5-year post-diagnosis survival depends on the
aggressiveness of the disease and on the precocity of diagnosis, with survival rates of just
over 50%. In half of soft tissue sarcomas, the disease presents as or becomes metastatic. The
main site of metastasis is the lung. In metastatic disease, survival is generally approximately
12 months.[5]
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Our retrospective observational study showed that progress in sarcoma therapy can be
achieved with the DBM in terms of objective response, quality of life and survival. Patients
with sarcoma were treated with the following DBM treatment protocol (Tab.1):
Method of
4 mg
or preferably
(12 night hours
with infuser)
Octreotide LAR
10 mg
Retinoid solution
0.5 g
0.5 g
2 g
1000 g
Daily (3
Vitamin C
4 g
Daily (lunch and
Vitamin D3
30 drops = 1 ml
= 1 mg
Daily (3
Tetracosactide Acetate
0.25 mg
3 administrations
per week, every
other day, with
2.5 mg
½ tablet twice a
0.5 mg
½ tablet twice a
Chondroitin Sulfate
500 mg
3 times a day
500 mg
3 times a day
Ursodeoxycholic Acid
300-450 mg
100 mg
Sodium Butyrate
500 mg
2 times a day
500 mg
2 times a day
Calcium Carbonate
500 mg
2 times a day
Calcium Levofolinate
22 mg
Once a day, every
other day
Sucrosomial Iron
14 mg
Once a day, every
other day
250 mg
½ tablet twice a
200 mg
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Patients with Sarcoma treated with the DBM and evaluable for this study all have a medical history of diagnosis, tumour stage and grade, along
with treatments that were performed prior to treatment with DBM. (Tab. 2)
File no.
Date of
Surgical interventions
Endometrial Stromal
G 3
surgery in 1997
G 2
1999 - 2004 surgical
removal of lung
and pelvic metastases
G 4
1996 - bone resection
G 1
radical resection (347-
Synovial sarcoma
G 3
left thigh amputation
G 3
thigh (2003) lung
G 4
thigh 1997
G 3
surgery in 1997/99 -
relapsed in 2007 -
relapsed in 2009
G 3
1996 - 2001 (relapse)
G 2
primary tum. 08/07 -
pulm. lobectomy 03/08
Malignant fibrous
G 2
radical resection
G 3
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
at onset
spindle cell sarcoma
G 4
resection in 8/2008 -
arm amputated
11/2008 pulm.
nodules 3/2009
Metastatic embryonal
resection in 2009
1997 - 2005 (relapse,
Monophasic synovial
Ewing sarcoma
Surgery + RT + CT
G 1
Monophasic synovial
G 2
Surgery + CT
Surgery + CT
G 1
G 2
Surgery + RT
G 1
Desmoid tumour
G 1
surgery in 2011 2012
(bladder relapse) -
2013 (pelvis relapse)
G 3
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
G 1
Sternal osteosarcoma
Ewing sarcoma
surgery + CT in 2008
The summary diagram below summarises the patient's conditions when first seeing the physician prescribing the DBM, the stage, and result of
the DBM treatment in the patient. From this data, the increase in survival (quantified in years) can be seen compared to the percentages
published in the AIOM guidelines. (Tab. 3)
DBM - treatment period and RESULT
File no.
pulmonary metastases
Complete remission
Absence of
inoperable retroperitoneal
pulm. nodules -
cardiopathy caused by
in 2007 was
in remission
after surgery
Treated for 1
year - then
surgery again
bilateral pulmonary
Remission then
10 months
pulm. nodules Abdominal
Complete remission
Absence of
after surgery
Complete remission
Absence of
lung metastasis relapse
Complete remission
Absence of
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
lung metastasis
Complete remission
Absence of
after the first surgery
13 years
Complete remission
Absence of
after surgery
Complete remission
Absence of
108 months
cranial recurrence
because treatment was
6 months of life - 4 cm
Complete remission
Absence of
subclavicular axillary
lung metastases
17 months
abdominal mass/iliac
lymph nodes
abdominal relapse
(then stopped)
12 months
after surgery
Complete remission
Absence of
72 months
lung metastases
absence of disease
Absence of
after surgery
absence of disease
absence of
after surgery
absence of disease
Absence of
after surgery
6 months after surgery
partial remission
reduction of
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
after surgery
absence of disease
Absence of
after surgery
absence of disease
Absence of
absence of disease
absence of disease
Absence of
after surgery
absence of disease
Absence of
lymphadenopathies in
various body districts
after several relapses
incl. the liver
relapse of cranial Ewing's
ask for
after surgery
Stable (thymic
leiomyosarcoma, pelvic
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
The aetiology of sarcomas remains largely unknown; they are sporadic, idiopathic and related
to genetic defects and environmental factors.[6,5] Genetic defects leading to sarcoma
development are divided into simple karyotypic defects and complex karyotypic defects.[7]
Simple karyotypic defects consist of disease-specific chromosomal translocations that lead to
abnormal gene (and protein) function, which facilitates the development of sarcoma.
Sarcomas associated with simple karyotypic defects include Ewing's sarcoma, alveolar
rhabdomyosarcoma and synovial sarcoma. On the contrary, complex karyotypic defects, such
as complex chromosomal rearrangements, intervene on cell cycle genes causing genetic
instability. Sarcomas generated in this way tend to manifest in older patients and have a high
frequency of mutations in the signalling pathways of p53 and retinoblastoma.[7,8]
Leiomyosarcoma, liposarcoma, angiosarcoma and osteosarcoma are examples of such
There is no evidence regarding the effectiveness of a sarcoma screening programme because
of the different manner in which they present, their ubiquitous diffusion in the different
anatomical areas, and the lack of an effective mass diagnostic test.[5] A radiologic and
pathological diagnosis is recommended, while staging is through cytological examination,
cutting needle biopsy, incisional biopsy or excisional biopsy. The classification by stage
allows a prognostic evaluation.[5]
Survival at 5 years for stage I is approximately 90%, stage II 70%, stage III 50%, and stage
IV 10%.[5]
Sarcomas with complex karyotypic defects may be secondary to radiotherapy.[6,9,10,11,12] A
study in patients diagnosed with radiotherapy-induced sarcoma showed that they are unique
in their epidemiology and tumour characteristics. They have an unfavourable prognosis and
need new innovative strategies, because with conventional oncology the survival rate at 5
years is only 32%.[13] It is not by chance that a significant percentage of aggressive bone
sarcomas occurs in children and young people of prepubertal and pubertal age, because in
this population the positive GH peak and negative Melatonin peak coincide. Cells in the bone
growth zones have the highest expression of GH receptor.[14] An increase in the incidence of
sarcomas is also documented in taller than average subjects.[4] There is clear and increasing
confirmation of the primary role of GH increase in osteosarcomas, including the statistical
study by Lisa Mirabello et al., which documented that, compared to subjects with average
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
birth weight (2,665-4,045 g), individuals with high birth weight (≥4,046 g) had an increased
risk of osteosarcoma (OR 1.35, 95% CI 1.01-1.79). Taller-than-average individuals (51-89th
percentile) and very tall individuals (≥90th percentile) had an increased risk of osteosarcoma
(OR 1.35, 95% CI 1.18-1.54 and OR 2.60, 95% CI 2.19-3.07, respectively; Ptrend <
The significant decrease in melatonin after 3 to 5 years of age, with particularly low levels in
the age groups most affected by osteosarcomas, coinciding with a GH increase peak, is
widely documented.[16,17,18]
In various sarcomas, the increasing percentage of tumour stem cells compared with these
tumours’ different neoplastic phenotypes is most likely the main reason these tumours rapidly
acquire resistance to chemo-radiotherapy, become very aggressive and progress rapidly.
Uncontrolled proliferation phenomena and loss of differentiation, although to varying
degrees, are common denominators to all cancers.
Protein synthesis and cellular proliferation (normal and neoplastic) are closely dependent on
the interaction of Prolactin with the greatest growth inducer, GH[19;20;21;22;23], and on
mitogenic molecules, GH-dependent growth factors that are positively regulated by it, such as
EGF, FGF, HGF, IGF1, VEGF, PDGF[24,25,26,27,28], as well as gastrointestinal growth factors
such as VIP, CCK, G.[29]
The GH and PRL receptors are co-expressed on cell membranes and dimerise, amplifying the
transduction of proliferative signalling pathways.[30] Numerous studies indicate how these
pituitary hormones play a crucial role in the development and progression of human tumours.
Their receptor expression is ubiquitous[19,31,32,33] and particularly high in cancerous tissue,
with a dose-dependent relationship between GH-PRL receptor expression and tumour
induction and progression processes, detected histochemically and through
immunohistochemistry techniques, Western Blot, in situ hybridisation and qPCR techniques.
The documentation of much higher GHR concentrations in tumour tissues compared to
normal and peritumoural tissues confirms its powerful mitogenic role.[15,21,20,34,35]
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Fig. 1: Central function of GH.
This evidence explains the reason why the DBM uses somatostatin, analogues and prolactin
inhibitors to prevent proliferation and the remaining components of the Method to achieve a
differentiating, immunomodulating and anti-oxidising function. The DBM supports and
enhances vital reactions and anticancer homeostasis, helping them counteract the onset of
neoplasia and its progression.[36] The DBM pursues this objective through innovative
formulations and criteria for the use of MLT (complexed with adenosine and glycine), of
retinoids solubilised in Vitamin E, as well as Vitamins C, D3, and ECM components.
Inserting apolar components such as Beta-carotene and Vitamin E between the phospholipids
of a cell membrane stabilises it, preserving it from oxidative damage and free
Sarcomas, therefore, represent a large group of heterogeneous malignant diseases, with a
single common characteristic, i.e. mesenchymal origin. The heterogeneity of sarcomas is
manifested in tumour mass but also intratumourally, which implies the existence of sarcoma
stem cells that may derive from mesenchymal stem cells. Mesenchymal stem cells have, in
fact, been used to establish several crucial experimental models of sarcoma and to trace the
respective stem cell populations. Mesenchymal stem cells are heterogeneous and may
develop differently. The different origin of cells determines substantial heterogeneity in the
possible initiation of sarcoma. Genetic and epigenetic changes associated with
sarcomagenesis can produce sarcoma stem cells. In the case of paediatric sarcomas
characterised by discrete reciprocal translocations and essentially stable karyotypes, the
oncogenes activated by translocation could be crucial factors that confer stemness, mainly
modifying the transcriptome and interfering with normal epigenetic regulation. The most
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
studied examples of this process are myxoid/round cell liposarcoma, Ewing's sarcoma and
synovial sarcoma. In adult sarcomas, which typically have complex and unstable karyotypes,
stemness could be defined more operationally, as a reflection of the actual assembly of stem
factors genetically and epigenetically conditioned and/or induced by the microenvironment.
The molecular mechanisms of stemness could be significantly similar in different types of
sarcoma, such as the silencing of the pRb and p53 oncosuppressors, the activation of Sox-2 or
the inhibition of Wnt/β-catenin canonical signalling. In addition, there is a homology with
markers of stem cells of various carcinomas or leukaemias. Understanding the biology of
sarcoma stem cells can improve therapy.[45] Consistently with this strategy, without observing
toxicity at the administered doses, the doses of active DBM components such as MLT,
ATRA, vitamins D and C, Glucosamine, Somatostatin and Octreotide analogue have been
increased and molecules active on stem cells have been added, such as Disulfiram and
Acetazolamide, which will be rationally contextualised below.
In this study, 37 cases of sarcoma (of bone and soft tissue) treated with the Di Bella Method
(DBM) were analysed. The treatment significantly improved the survival and quality of life
in sarcoma patients compared to patients with sarcomas bearing similar
immunohistochemical, histologic and clinical characteristics (oncological statistics).
The multitherapy includes, to prevent proliferation, Somatostatin and the Octreotide
analogue, with D2R agonist prolactin inhibitors, whereas ATRA, Beta-Carotene,
Axerophthol, solubilised in vitamin E, in addition to vitamins D and C, water-soluble
Melatonin, Glucosamine and Chondroitin Sulphate were included for their differentiating,
cytostatic, immunomodulating and antimetastatic action. Hydroxyurea was used at low
metronomic doses to induce apoptosis.
Melatonin (N-acetyl-5-methoxytryptamine, MLT) has antioxidant, anti-aging and
immunomodulatory properties. It plays a significant role in blood composition, medullary
dynamics, in platelet formation, in the protection of vascular endothelium, in platelet
aggregation, in the regulation of leukocyte ratios and haemoglobin synthesis, in perfusion and
blood-tissue exchanges. The considerable and non-toxic apoptotic, oncostatic, anti-
angiogenic, differentiating and antiproliferative properties of this indole on all neoplastic
diseases, both solid and liquid, are also documented.[40,46,47,48,49,50,51,52,53,54,55,56,57,58,
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Thanks to its remarkable functional versatility, MLT can have a direct and indirect anti-
tumour effect in a factorial synergism with other
differentiating/antiproliferative/immunomodulating molecules of the DBM. The interaction
of MLT with the DBM molecules combats the multiple processes that characterise the
neoplastic phenotype, mutation, proliferation, progression and/or dissemination. All these
characteristics suggest the use of this molecule in cancer pathologies.[69,70,71,72] MLT also
plays a significant role in perfusion and blood-tissue exchanges, preventing tissue ischaemia,
acidosis and hypoxia of the neoplastic environment and the consequent overexpression of
oncogenic genes, including HIF-1α. The anti-cellular expansion effect is also achieved
through the reduction of intracellular reactive oxygen species and the increase of
Because there is now evidence of the correlation between the decline in melatonin levels, the
increase in GH and the incidence of juvenile osteosarcomas, melatonin has been studied for
its anti-osteosarcoma action, as a coadjuvant to conventional chemotherapy for osteosarcoma
to improve the prognosis of the disease, which in most cases is poor.[73] In addition to the
multiple and above-mentioned anticancer mechanisms of action of MLT, some of its
particular properties in osteosarcoma are emerging. This cancer occurs most frequently in
adolescents, with peak incidence between 11 and 15 years. The decline of MLT to minimal
levels in the same age groups, coupled with an increase in the level of GH (and related factors
such as IGF1, VEGF, EGF, FGF) and subsequent bone growth, explains the osteosarcoma
peak in these age groups. The most frequent initial site of sarcomas is the metaphysis of long
bones (distal femur and proximal tibia) whose cells have the highest expression of GH
receptors and therefore a high proliferative index. The relationship between the incidence of
osteosarcoma and the bone growth rate[74] is evident. The rationale for using melatonin and
somatostatin against sarcomas is therefore logical and scientifically documented.
Melatonin blocks the proliferation of osteosarcoma MG-63 cells by reducing the D1 and B1
cyclins, CDK4 and CDK1, blocking the cell cycle in the interphase, with an increase in the
cells in the G0/G1 phase. In carcinosarcoma cells, MLT administration resulted in a reduction
in Bcl-2 expression and a decrease in tumour volume.[75] In Ewing's sarcoma, melatonin
induces cell death in SK-N-MC cells by increasing the expression of the Fas receptor and the
respective FasL ligand through the caspase 8 pathway. Fas/FasL expression is controlled by
the activation of the NF-kB nuclear factor, increased by melatonin, in relation to the
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
intracellular redox state.[76] In leiomyosarcomas, MLT inhibits tumour growth by blocking
the absorption and metabolism of linoleic acid, which would lead to the production and
release of the 13-HODE mitogen, ERK1/2, MEK and Akt, as well as the suppression of
cAMP production in tumours.[77]
The differentiation of mesenchymal stem cells is regulated by the action of mechanical and
molecular signals coming from the extracellular environment. Melatonin can also be an
important regulator of the commitment and differentiation of cell precursors. Adipogenesis
and osteogenesis are known to be reciprocally related in the bone marrow. On human
mesenchymal stem cells, melatonin directly inhibits adipogenic differentiation towards the
adipocyte lineage and simultaneously promotes osteogenic differentiation by suppressing the
expression of the γ receptor (PPARγ) activated by the peroxisome proliferator and improving
the Runt-related transcription factor 2 (RUNX2). MLT improves differentiation of human
mesenchymal stem cells into osteoblasts via MT2 receptors and the mitogenic/kinase
signalling cascade regulated by the extracellular (MEK)/kinase signal regulated by the
extracellular signal (ERK).[18]
Melatonin, with its immunomodulating, myeloprotective, differentiating and antioxidant
properties, increases the anticancer effects of chemotherapy while reducing its toxicity.
Through the radioprotective and radiosensitising effect, it improves the therapeutic response
to radiation therapy by reducing radiotoxicity and therapeutic failures due largely to the
refractoriness of mesenchymal tumour cells of sarcoma to cytolytic and radiation therapies.
A significant therapeutic property of melatonin is the differentiation and reprogramming of
mesenchymal stem cells, multipotent progenitors, osteocytes, chondrocytes, myocytes and
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Fig. 2: Role of Melatonin.
Retinoids are a family of molecules that derive from the metabolism of vitamin A, or
retinol.[78] Their function is mediated by the respective receptors on the plasma membrane
and nuclear membrane which act on cell growth, differentiation, tissue homeostasis and
apoptosis via the caspase 9 pathway, with a major, documented effect in the prevention and
treatment of tumours.[75] Retinoids are the most powerful non-hormonal activators of solely
orderly, functional growth aimed at optimal biological balance, while, at the same time, with
differential toxicity, they inhibit aimless and disorderly neoplastic growth with their
antiproliferative and cytostatic effect. Together with Melatonin, retinoids are the only
biological molecules with differential toxicity, with a cytostatic and apoptotic effect on
cancer cells alone and not on healthy cells in which, on the contrary, survival and
functionality are increased. Retinoids can preserve and enhance the vitality and efficiency of
normal cells while at the same time inhibiting neoplastic ones, which have a tendency to
mutate. Retinoids intervene in two critical aspects of neoplastic biology: fast proliferation and
the resulting mutations, common denominators of all cancer types. They play a crucial role
both in the prevention and therapy of cancer, limiting the consequences induced by cancer
and conventional anticancer therapies.[23,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95]
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
Type of effect
Protective on cell membranes[36];
Directly antiproliferative (regardless of conversion to ATRA) on cancer cells, suppressing
their mobility (as measured by tetrazolium “MTT” assay), DNA synthesis (controlled
through the uptake of 3H-thymidine) and proliferation (measured by cell count).
Works by inducing redifferentiation in blasts and tumour cells[96];
Suppresses the transcription of oncogenic factor genes and promotes the antiproliferative
Has anti-angiogenic action[98];
Decreases the potential for neoplastic proliferation and plays an important role in cell
differentiation, apoptosis and adhesion[99,100];
Makes the neoplastic cells particularly sensitive to chemotherapeutic agents, also
inducing an increase in intercellular communication in the junction spaces[101];
Counteracts the hepatotoxic effect of chemotherapy.[102]
Causes the apoptosis of neoplastic cells through the activation of proteolytic cell
enzymes, the Caspases, and the degradation of the general transcription factor Sp-
Among the tocopherols, Alpha-Tocopherol has the highest biological activity. Commonly
called vitamin E, it has a high antioxidant and anti-free radical activity;
As a constituent of enzyme systems, vitamin E directly affects a key step in energy exchange
and life itself, the transport of electrons in the respiratory chain;
It inhibits the growth of various tumour cell lines[105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116,
117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130];
It enhances the anticancer action of various chemotherapy drugs such as Adriamycin,
cisplatin and tamoxifen[116, 120];
It protects bone marrow cells from the lethal effects of doxorubicin[107];
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
It enhances the anticancer effect of chemotherapeutic agents, protecting healthy cells
from toxic effects[117];
It has anti-angiogenic activity.[37,109,112,113,123]
It has been observed that, in people with sarcoma, the number of granulocytic MDSC cells is
higher than in healthy conditions, resulting in reduced T-cell efficiency. Retinoic acid has the
ability to regulate the differentiation of MDSC cells and, in combination with GD2-CAR T
cells, has greater antitumour power and better combats the immunosuppressive action
associated with MDSC cells in sarcoma.[131]
When human osteosarcoma cells are treated with ATRA, the expression of vitamin D3
receptors has been observed to be greater; in addition, synergistic treatment with ATRA and
calcitriol is associated with an increase in the efficacy of the antiproliferative effect on these
cell lines.[132]
Retinoic acid acts during the initial stages of osteosarcoma associated with macrophages,
inhibiting the polarisation of M2 TAMs and the activity of neoplastic cells.[133] It can
stimulate cell differentiation in osteosarcoma cells and thus negatively act on cell
proliferation and induce apoptosis; these properties have been observed not only in cases of
osteosarcoma, but also in Kaposi's sarcoma, neuroblastoma and breast cancer.[134] Studies on
Kaposi's sarcoma cell lines treated with retinoic acid have shown that it acts by negatively
regulating cell growth, reducing IL-6 and TNF-α levels and increasing the expression of the
RARα receptor for retinoic acid; increased cellular adhesion[135] has also been observed.
Treatment with retinoic acid, which acts through the increased release of lysosomal enzymes,
may be a potentially effective therapy against chondrosarcoma.[136] In dermatofibrosarcoma
protuberans, the RAR β retinoic acid receptor is implicated in the reduced aggressiveness of
neoplastic growth, in relation to the COX-2 cyclooxygenase, on which it has a negative
Vitamin E (Tocopherol) is fat soluble and present in eight isoforms, known for their action
against the formation of reactive oxygen and nitrogen species in neoplastic tissues following
alterations in the oxidative systems. Vitamin E also performs important inhibitory functions
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
in angiogenesis, in the NF-kB signalling pathway and on the HMG CoA reductase
In several tumours, including sarcoma, thymic involution has been observed, leading to the
death of thymocytes and thus a decrease in T-cell production, resulting in decreased immune
system efficiency.[139]
In a preclinical study in mice with fibrosarcoma, the mechanism of action of vitamin E was
evaluated in combination with cyclophosphamide, an alkylating agent used in various
anticancer therapies, both alone and in combination with other cytotoxic drugs. However, it
may cause hyperlipidaemia in patients, and so was administered in combination with α-
tocopherol that reduces hyperlipidaemia. The results showed that lipid metabolism returned
to normal levels in treated mice and hyperlipidaemia was significantly reduced compared to
the values observed in the untreated control groups.[140]
Vitamin E also reduces damage from oxidative stress, regulates osteocartilaginous
homeostasis and promotes tumour apoptosis both in vitro and in vivo.[141]
Vitamin D3 is synthesised in the skin, starting from vitamin D, following exposure to
ultraviolet rays. It can be introduced through dietary intake; low concentrations of vitamin D3
are associated with increased sensitivity to infections and tumours. The active biological form
of vitamin D3, i.e. calcitriol, and its analogues perform important anticancer functions
mediated by the nuclear receptor, VDR.[142]
In Kaposi's sarcoma associated with Herpes virus, calcitriol was observed, both in vitro and
in vivo, to negatively regulate the growth of endothelial cells that express the vGPCR
receptor, by lowering cyclin D1 and the activation of p27 and p21. Calcitriol lowers vGPCR-
induced NF-kB action and induces cell death through increased VDR expression. It also
reduces Akt and ERK 1/2, which are important in the carcinogenesis process, and acts in the
angiogenic process through the dose-dependent down regulation of VEGF and HIF-
factors.[143] Treatment of Kaposi's sarcoma with calcitriol also results in decreased production
of IL-6 and IL-8, two important growth factors in this cancer.[144]
A study conducted on seven human osteosarcoma cell lines showed that therapy with ATRA
and calcitriol inhibits cell proliferation and increases sensitivity to inducers of differentiation
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with greater efficacy compared to when the molecules are used alone. Additionally, ATRA
indirectly increases the expression of VDR, at mRNA and protein level, in cells with high
endogenous levels of RARα and low endogenous levels of VDR.[132]
By analysing the human osteosarcoma MG-63 cell line in vitro, a decrease in cell growth,
saturation density and [3H]-thymidine uptake was observed following the administration of
calcitriol; moreover, an increase in cell adhesion was observed in treated cells following an
increase in fibronectin.[145]
Metabolites of vitamin D3 also act on cell differentiation in osteosarcoma cells at the same
doses at which they inhibit growth, as well as inducing osteocalcin synthesis.[146] The
antiproliferative effect of calcitriol has been studied on several soft tissue sarcoma cell lines,
including rhabdomyosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma and synovial
sarcoma, in relation to VDR expression. Cell growth following calcitriol treatment is
inhibited more effectively in cells with a higher amount of VDR and vice versa. This study
showed the correlation between VDR expression and the effect of calcitriol on soft tissue
Pro-differentiation activity, achieved not only through interaction with the receptor, but
also through an extra-receptorial membrane-mediated mechanism[148];
Inhibition of angiogenesis, development and growth induced by VEGF (vascular
endothelial growth factor), in a dose-dependent manner; inhibition of the formation of
elongated endothelial cell networks in 3D collagen gels, promoting apoptosis[149];
Vitamin D3 activates a specific nuclear receptor, inhibiting proliferation, promoting
differentiation of various types of tumour cells and adhesion of cells migrating from the
basal membrane, due to the downregulation of alpha-6 and beta-4 integrins, laminin
receptors associated with the greatest cellular migration and invasiveness of prostatic
cancer cells in vivo[150];
Induction of the expression of mRNA for the BRCA1 protein, and transcriptional
activation by the BRCA1 promoter. The sensitivity to the antiproliferative effects of
Vitamin D3 is intimately linked to the ability to modulate the BRCA1 protein by means
of transcriptional activation of the factors induced by VDR[151];
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The activation of VDR, in addition to the antiproliferative effect, increases the expression
of the protein-binding insulin-like growth factor, IGF[152];
It induces the phenotypic maturation of tumour cells into functionally mature,
differentiated, physiologically normal cells, simultaneously inhibiting neoplastic cell
proliferation by enhancing the antiproliferative effect of Trans-retinoic acid[153];
It inhibits the invasion of the extracellular matrix and metastases by blocking the
degradation of the extracellular matrix barriers (ECM) by tumour cells through
It exerts, also through non-receptor mechanisms, a powerful antiproliferative and pro-
differentiating action[155];
It suppresses proliferation and migration in glioma cell lines expressing the human
vitamin D receptor.[158]
Ascorbic acid, or Vitamin C, has a great reducing activity, reacting directly with oxygen
singlets, hydroxides and superoxide radicals[159]; biologically, it acts as a hydrogen carrier in
intermediary metabolism, including cellular respiration processes. Due to its key role, it was
included in anticancer therapy.[160,161,162,163] The antioxidant capacity and the natural role in
immunity of Ascorbic acid are very relevant, in addition to its remarkable biological activity
on cellular trophism and support structures.[164,165] It is easy to guess that Vitamin C, jointly
with melatonin, concurs to regulate these exchanges, leading to optimal function of the
epithelium in terms of resistance and permeability to the transit of cancer cells, and therefore
of metastasis.
The functions of Vitamin C in the DBM are various. Among them, the most relevant are:
To prevent cellular damage induced by oxidative molecules, including free radicals[166];
It can have a preventive and therapeutic role in cancer[167];
It can inhibit the carcinogenic effects of mutagenic molecules[168,169];
It can preserve the integrity of connective tissue in terms of antiblastic function[167];
It can exert angiostatic activity on endothelial cell proliferation[170];
It can exert an antineoplastic activity through various mechanisms of action.[33,171]
It can have an antimetastatic activity through collagen synthesis[172,173], the inhibition of
hyaluronidase[174] and by decreasing the permeability of endothelial cells to neoplastic
cell populations[175];
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It can reduce the toxicity of chemotherapeutic agents such as Adriamycin[176,177];
It reduces the risk of glioma[178];
The use of intravenous Vitamin C is a safe support intervention, decreasing inflammation
and symptoms related to deficiency in antioxidants and the collateral effects of standard
antitumoural treatments[179,180];
It can induce the degradation of the hypoxic inducible factor HIF-1, essential for tumour
cell survival in hypoxic conditions.[165]
Vitamin C, or ascorbic acid, is a water-soluble antioxidant that reacts with superoxide,
hydroxyl radicals and oxygen singlets; in laboratory studies, ascorbic acid has been observed
to protect plasma lipids and low-density lipoproteins (LDL) from peroxidative damage and
degeneration associated with aging and diseases such as cancer. It is very important for the
synthesis of glycosaminoglycan, by proteoglycans, and for the synthesis of collagen.
Ascorbic acid acts on various cancers in humans; it captures free radicals and reactive oxygen
species and reduces nitrite, preventing oxidation effects and damage to DNA and cell
membranes caused by free radicals associated with the tumour.
Studies have shown that, together with vitamin C, several other dietary nutrients, such as
vitamin E, carotenoids and folic acid, participate in protective processes.[159]
Vitamin C, in mice treated with MCA, significantly reduced the onset of sarcoma compared
to the control groups, demonstrating the prophylactic effect of this component[181]; moreover,
at supraphysiological concentrations, it inhibits cell proliferation and promotes the
differentiation of osteoblasts.[182]
Cases of regression of sarcomas have been observed following continuous treatment with
high doses of vitamin C[183], and so has the inhibition of the angiogenesis process.[184]
At physiological doses, ascorbic acid negatively regulates the migration of carcinosarcoma
cells, thus inhibiting tumour metastasis.[185]
Somatostatin is a 14-amino-acid peptide, which has documented, evident and generalised
anticancer properties, as already stated in the publication by the Nobel Prize winner, Schally,
in 1998, “Impressive antineoplastic activity of somatostatin analogues has been demonstrated
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in many tumour models”. Professor Di Bella had already published in 1979[186] a study on the
anticancer effects of somatostatin in synergy with other components of his method, such as a
solution of retinoids in vitamin E, prolactin inhibitors and melatonin. In 1981[187] he
presented a report on more than a thousand cases of neoplasia favourably treated with
Regardless of the presence of SSTR receptors in tumour cells, SST’s mechanisms of action
mean it acts directly through inhibition of cell growth, inducing apoptosis and preventing
metastasis; indirectly, it acts by suppressing the production of growth and angiogenesis
The use of somatostatin and analogues, by negatively regulating GH and GH-dependent
growth factors, is a rational indication for its use in any cancer.[15,21,62,90,186,189,190,191,192,193] It is
evident that the PRL/GH/GF axis has a decisive influence on neoplastic development, hence
the rationale for the synergistic use against cancer of anti-prolactin D2R agonists with
biological antagonists of GH, such as Somatostatin and analogues, which extend their
negative regulation to highly mitogenic GH-related growth factors, such as IGF1 - 2[189,194],
EGF[195,196], FGF[197], VEGF[170,198,199], PDGF[200] and the related signalling pathways,
resulting in anti-proliferative, pro-apoptotic, differentiating and anti-angiogenic effects.[196]
This vision is slowly emerging through more and more basic research, although still rarely
applied to humans. In many tumours, not only in neuroendocrine ones, the expression of a
somatostatin receptor has been documented.[21,75,196,200,201,202,203,204,205,206,207,208,209,210,211,212,213,
214,215,216,217,218,219,220,221,222,223,224,225,226] Although absent in the cell membranes of some
tumors, SST receptors are almost always expressed in the peritumoural vessels.
GFRs mitogenically respond to IGF, and the suppressive effect of SST and analogues on
serum IGF1 levels is direct (by inhibiting the IGF gene) and indirect (by suppressing the GH
and therefore its induction of IGF1 in the liver). The antiproliferative effect of somatostatin
and its analogues in sarcomas, as in other malignancies, is therefore also achieved through
mechanisms involving the suppression of the IGF system.[227] Regression and long-term
survival with somatostatin of a patient with primary gliosarcoma, a rare malignancy with
short-term negative prognosis, confirms the efficacy and indication of Somatostatin.[19,20,21,22,
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Mitogenic GH molecules such as EGF, FGF (whose receptors are co-expressed on cell
membranes), IGF, VEGF[24,25,26,27,28] and growth factors produced by the gastrointestinal
system (VIP, CCK, G)[29], are all negatively regulated by Somatostatin and Octreotide. The
mitogenic effects of GH on somatic cells are triggered by the signal transduction of several
pathways including JAK-2/STAT, MAPK, PIK3. This evidence validates the rationality of
using, in oncotherapy, somatostatin/octreotide that act independently of the presence of SSTR
in neoplastic cells, given the evidence about them in the peritumoural vessels and the
aforementioned indirect anticancer mechanisms.
Somatostatin receptors have been identified on cells of bone and vascular/perivascular
tumours, indicating that these neoplasms are the target for SST therapy.[229] In preclinical
studies, somatostatin has been shown to inhibit the growth of Kaposi's sarcoma cells with
SST receptors. In an in vivo model, somatostatin effectively inhibits angiogenesis, while in
vitro it acts on both endothelial cells and monocytes, inhibiting growth and invasion. Its
administration in these neoplasm, should be maintained over time as SST acts primarily as an
Suppression induced by somatostatin and its analogues on corticotropin levels is important as
well, because chondrosarcoma cells are sensitive to these molecules.
In studies on human and rodent cancer xenografts, the TT-232 somatostatin analogue leads to
a decrease in tumour growth, although this is dependent on the sensitivity of the tumour to
somatostatin, with S-180 osteosarcoma growth slowing by 67-100%.[230] Octreotide is an
analogue of somatostatin with a longer half-life than the native peptide. In vitro and in vivo it
inhibits the growth of cells expressing the receptors with high affinity for somatostatin, but
also acts indirectly by reducing the concentration of GH andIGF-1.[231] It has also been
observed that octreotide has a strong VEGF-suppressing effect, resulting in an anti-
angiogenic effect.[232]
In a study in rats, following partial removal of the liver, the effect of octreotide on tumour
growth in regenerating hepatic cells was studied and it was observed that, following the
drug’s administration, the proliferation of fibrosarcoma and colon adenocarcinoma cells was
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Fig. 3: Role of Somatostatin.
The proteoglycans of chondroitin sulphate participate in the modulation of various cellular
functions, including adhesion and migration. The role of the chondroitin sulphate chain in
adhesion, chemotaxis and migration has been studied in fibrosarcoma cells. The cleavage of
CS chains associated with cells and the specific inhibition of endogenous CS production
severely compromised these fibrosarcoma cellular functions. This result shows that the
reduction of chondroitin sulphate proteoglycans, e.g. via the cleavage of CS chains, inhibits
cell motility, migration and adhesion in fibrosarcoma. CS chains increase cell motility
through the MAP kinase pathway.[234]
In oestrogen-mediated bone anabolism, chondroitin sulphate-E plays an essential role by
increasing the differentiation and maturation of osteoblasts. The control of chondroitin
sulphate-E expression in bone metabolism therefore has an important therapeutic potential to
improve the loss of bone mineralisation.[235]
In patients recovered from osteosarcoma, the risk of developing osteoporosis is higher,
particularly if there are three additional risk factors: being male, having a diagnosis of
osteosarcoma at a young age and having a low amount of lean mass.[236] Other elements that
may determine the onset of osteoporosis following cancer are chemotherapy, radiotherapy
and hormonal decompensation, which cause a loss of bone mineral density. In addition,
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patients with osteosarcoma may have reduced physical activity during therapy or after
surgery and this results in a decrease in muscle mass, vitamin D and bone mineral density.[237]
Osteoporosis associated with diabetes is a bone disease, which can impair bone
microstructure, reduce resistance and increase bone fragility and the risk of fracture. This
disorder is associated with oxidative stress (which causes a decrease in the proliferation and
differentiation of osteoblasts) and with the inflammatory process: in people with diabetes, the
level of pro-inflammatory cytokines is considerably higher than in healthy people, resulting
in increased oxidative stress, the proliferation of osteoclasts and the absorption of the bone
matrix, causing osteoporosis. In addition, a high expression of biochemical markers of bone
formation and resorption has been observed in mice with type 1 diabetes, indicating that the
bone element turnover is much greater in diabetes cases. The study of chondroitin sulphate
therapy in mice with type 1 diabetes had positive effects in the treatment against
osteoporosis, leading to the reduction of cytokines and inflammation, to the inhibition of
oxidative stress and bone metabolism while enhancing the repair of bone microstructures.
This therapy is also very safe, with adverse effects limited to modest and transient
gastrointestinal disorders such as nausea and vomiting.[238]
The anticancer properties of glucosamine are documented by scientific evidence that has
identified the anticancer mechanism of action in the inhibition of cancer stem cells (CSC),
which are the subpopulation of tumour cells responsible for maintaining the tumour and for
relapse, due to their very high ability to resist various anticancer treatments.[239,240]
Glucosamine induces autophagic cell death through stress stimulation of the endoplasmic
reticulum (ER) in human glioma cells. ER stress induced by glucosamine was manifested by
the induction of the expression of BiP, IRE1alpha and phospho-eIF2alpha. Glucosamine
treatment reduced cell viability by increasing the autophagic cell death of glioma cells. This
information provides new insights into the potential anticancer properties of glucosamine.[241]
According to some studies, glucosamine suppressed the proliferation of the DU145 human
prostate cancer cell line by inhibiting STAT3 signalling. In DU145 cells, glucosamine
reduced the N-glycosylation of gp130, decreased the binding of IL-6 to cells and altered the
phosphorylation of JAK2, SHP2 and STAT3. The glucosamine-mediated inhibition of N-
glycosylation was neither specific for proteins nor cells. The sensitivity of DU145, A2058
and PC-3 cells to glucosamine-induced inhibition of N-glycosylation is directly correlated
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with glucosamine cytotoxicity in these cells. Global inhibition of glucosamine-induced N-
protein glycosylation could therefore be the mechanism underlying its multiple biochemical
and cellular effects.[242]
Glucosamine may also be a promising candidate for the prevention and/or treatment of some
other diseases due to its antioxidant and anti-inflammatory activities. Most of its function is
exerted through the modulation of inflammatory responses, especially through the nuclear
factor κB (NF-κB) which can control the production of inflammatory cytokines and cell
The conjugation of D-glucosamine with the lipophilic fraction can facilitate its application in
the superficial modification of liposomes.[244]
Pohlig F. carried out a study in which glucosamine sulphate was found to have a pronounced
suppressive effect, in particular on MMP-3 and also on the levels of MMP-9 mRNA and
proteins in the osteosarcoma cell lines in vitro.[245,246,247]
Below is a wider literature review on the differentiating, cytostatic, immunomodulatory,
homeostatic properties of Retinoids, vitamins E, C, D, Proteoglycans:
- Di Bella G et al.,2015[75]
- Di Bella G., 2010
- “The Di Bella Method” Mattioli ED., 2005[40]
- “La scelta antitumore” Macro-Uno Edizioni, 2019.[47]
Bromocriptine and cabergoline are two alkaloids derived from the ergot fungus; they are used
in preventive and anticancer therapy because they suppress prolactin synthesis, reduce cell
growth and tumour size and inhibit angiogenesis. Numerous studies have shown the
effectiveness of anticancer therapies with bromocriptine, suggesting that the administration of
high doses leads to a reduction in cancer[248] and also plays an important role in
chemotherapy and in the phenomenon of multidrug resistance, in which cancer cells develop
resistance to several drugs with cytotoxic action. Studies have shown that it can convert a
tumour’s pharmacological resistance to a normal condition, restoring the anti-tumour effect
of drugs such as doxorubicin.[249]
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Cabergoline also has an antitumor effect by suppressing growth factors that promote tumour
growth and expansion.[250]
In one clinical case of angiosarcoma, the high concentration of prolactin, together with IL-6
and osteocalcin, was associated with rapid tumour progression.[251]
Tumours whose growth is sensitive to prolactin concentration also include Swarm
These two components are therefore important as they lead to a decrease in the levels of
prolactin, which is involved in the development and sensitivity of some tumour cells. They
act through two different mechanisms: bromocriptine stimulates apoptosis through the
ERK/EGR1 pathway, while cabergoline induces autophagia by inhibiting the AKT/mTOR
signalling pathway.[253]
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Ursodeoxycholic acid is a secondary bile acid that is particularly important in maintaining the
integrity of the intestinal barrier and in lipid metabolism. It increases the proportion of non-
toxic hydrophilic bile acids and decreases hydrophobic endogenous bile acids; it also
increases the hepatocellular excretion of bile acids, has cytoprotective, immunomodulatory
actions and inhibits apoptosis.[254] It is indicated to counteract the cholagogue and choleretic
inhibition effect of somatostatin and octreotide.
The use of Sodium Butyrate in patients with Sarcoma is contextualised epigenetically in the
relaxation of chromatin. According to the study performed by Singh, butyrate blocks the
generation of dendritic cells from bone marrow stem cells, without affecting the generation of
granulocytes. This effect depends on SLC5A8, the sodium-coupled monocarboxylate
transporter that transports butyrate into the cell and allows it to inhibit the deacetylases of
histone acetate, which is also a substrate for SLC5A8 but not an inhibitor of histone
deacetylases. It therefore does not affect the development of dendritic cells, indicating the
essential role of histone deacetylase inhibition in the process.[255]
In the study performed by Gupa N. et al., SLC5A8 is identified as an oncosuppressor gene in
colorectal cancer. The subsequent definition of the functional identity of SLC5A8 as a Na(+)-
coupled transporter for short-chain monocarboxylates provides a mechanism for the
transporter’s function as tumour suppressor. Butyrate, a substrate for the transporter, is an
inhibitor of histone deacetylase. This fatty acid is produced in the lumen of the colon by
bacterial fermentation of the dietary fibre. SLC5A8 mediates the concentration-based entry of
butyrate into the cell. Consequently, the transport function of SLC5A8 has the ability to
influence the acetylation status of histones.[256]
SLC5A8, therefore, is a candidate oncosuppressor gene that is silenced in colon cancer,
gastric cancer and possibly other cancers in humans. This gene encodes for a transporter
belonging to the family of the Na(+)/glucose (SLC5) co-transporter gene. The silencing of
the gene associated with cancer involves hypermethylation of the CpG islands present in
exon 1 of the gene. The protein encoded by the gene mediates the electrogenic Na(+)-coupled
transport of a variety of monocarboxylates, including short chain fatty acids, lactate and
nicotinate. It can also carry iodide. One of the short chain fatty acids serving as a substrate for
SLC5A8 is butyrate. This fatty acid is an inhibitor of histone deacetylases and is known to
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induce apoptosis in a variety of tumours. Since high concentrations of butyrate are produced
in the colon lumen, as previously mentioned, by the bacterial fermentation of dietary fibre,
we hypothesise that the ability of SLC5A8 to mediate the entry of this short-chain fatty acid
into the colon epithelial cells underlies the potential oncosuppressor function of this
Sodium butyrate affects the proliferation and differentiation of different cell types, including
osteoblasts. In the study performed by Perego S. et al., the effects of different doses of
butyrate on the differentiation and functionality of osteosarcoma cells in vitro and the
expression of a pro-inflammatory phenotype in a normal or inflammatory environment were
evaluated. SaOS-2 osteosarcoma cells were induced to differentiate and simultaneously
treated for 24 h, 48 h or 7 days with sodium butyrate 10-4, 5 × 10-4 or 10-3 M in the presence
or absence of tumour necrosis factor alpha (TNFα) 1 ng/mL, a pro-inflammatory
stimulus. Despite the mild effects on proliferation and alkaline phosphatase activity, butyrate
induced the dose- and time-dependent expression of a differentiated phenotype (RUNX2,
COL1A1 gene expression, and gene and protein expression of osteopontin). This was
associated with a partial inhibition of nuclear factor κB activation (NF-κB) and the induction
of histone deacetylase 1 expression. The net effect was the expression of an anti-
inflammatory phenotype and the increase in the ratio of osteoprotegerin and the receptor
activator of NF-κB ligand (RANK-L). In addition, butyrate, especially at the highest dose,
counteracted the effects of the pro-inflammatory stimulus of TNFα 1 ng/mL.[258]
Aldehyde dehydrogenases are a family of enzymes that oxidise aldehydes to carboxylic acids.
These enzymes are important in cellular homeostasis during oxidative stress for the
elimination of toxic by-products of aldehyde from various cellular processes. In
osteosarcoma, aldehyde dehydrogenase 1A1 has been described as a marker of cancer stem
cells. Its activity has been found to be related to metastatic potential and metastatic
phenotype.[259] Disulfiram is an ALDH inhibitor, produced for the clinical purpose of treating
alcoholism; it has recently also been considered a drug that can be used to suppress sarcoma
stem cells.
Sarcoma tumour cells spread by local invasion and distant metastases, which depend on the
extracellular matrix. The expression of matrix metalloproteinases (MMP) has been implicated
in the invasion and metastases of the tumour cells. Cho HJ performed a study on the effects
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of disulfiram on the suppression of tumour invasion, as well as its effects on MMP-2 and
MMP-9 activity in human osteosarcoma cells (U2OS). The anticancer effects of disulfiram
have been demonstrated in an invasion test (that uses U2OS cells) and its inhibitory activity
on type IV collagenase, which inhibits the expression of genes and proteins responsible for
cellular and non-cell mediated invasion on pathways. Disulfiram inhibited the expression of
MMP-2 and MMP-9 and regulated the invasion of human osteosarcoma cells, making it a
clinically usable drug for the inhibition of cancer invasion.[260]
Carbonic anhydrases (CAH), zinc metalloproteins, are enzymes that can have a clinical
relevance in cancer therapy, because their cell-surface specific isoform, Ca9, is almost
exclusively associated with cancers and is involved in tumorigenesis. Its competitive
inhibition mediated by Acetazolamide (AAZ) is part of the development of new therapies
against cancer. Based on this evidence, we added AAZ to the DBM.
Hypoxia is associated with malignant progression and poor outcome in several human
tumours, including soft tissue sarcoma. The study performed by Måseide K. suggested that
CA IX is a potential intrinsic marker of hypoxia and a predictor of unfavourable prognosis in
patients with large, high-grade, deep soft tissue sarcoma.[261] CA IX is often overexpressed in
human osteosarcoma (OS) but not in normal tissues, and its expression levels correlate with
prognosis. In the study performed by Perut F., the therapeutic potential of newly synthesised
CA IX sulphonamide inhibitors in OS was studied. CA IX expression levels were
significantly higher in OS than bone marrow stromal cells (BMSC) after drug administration.
Consequently, CA IX inhibitor 3 induced significant cytotoxicity on OS cells without
affecting the proliferation of BMSC. This activity increased in hypoxia and was mediated by
stopping the cell cycle and modulating the cytosolic and extracellular pH. In vivo, CA IX
inhibitor 3 reduced tumour growth, leading to significant necrosis.[262]
Patients treated with DBM, although experiencing rare and temporary modest toxicity, had a
clear improvement in survival, objective response and quality of life compared to patients
with sarcomas in the same stages, with the same histochemical characteristics, treated with
conventional oncology protocols.
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The rare cases in which the DBM was applied as first-line therapy, both neoadjuvant and
adjuvant, had the best responses.
In the progression of sarcomas, as in most tumours, the percentage of tumour stem cells,
compared to other components of the neoplastic population, increases until it is almost total
and is associated with chemo-radio-resistance and rapid progression. For this reason, we have
gradually increased the doses of molecules that in the scientific literature are documented to
negatively regulate CSCs, such as Melatonin, ATRA, Glucosamine, which improve the
differentiation and reprogramming of tumour stem cells by negatively regulating
proliferation, invasiveness and resistance. This objective was also achieved by modifying the
criteria and methods of administration of alkylating drugs, such as hydroxyurea. Unlike in
oncology protocols, their metronomic administration in the DBM allowed better control of
the proliferation and invasiveness of tumour cells in the absence of myelotoxicity, thanks to
the myeloprotective properties of 100 mg of daily water-soluble MLT and about 25 ml of
retinoid solution in vitamin E, divided into 3 daily administrations.[46,48,263] The
antiproliferative and antiangiogenic effect was increased by the regular combination of 4 mg
of 14-amino-acid SST administered with a 12 hour-adjusted timer (because of the short half-
life of SST, 3 minutes) and delivered between 19.00 and 20.00, with the intramuscular
administration of 20 mg slow-release octreotide every 20 days, enabling receptorial and
temporal saturation. An improvement in the therapeutic response was achieved by
administering SST 14 intravenously instead of subcutaneously, always in 12 hours, using the
timer. The DBM, unlike the oncological conception, shifts the therapeutic axis from cytolytic
toxic and immunodepressive mechanisms to fighting neoplastic proliferation by negatively
regulating the blood level of GH, which activates oncogenesis through multiple
mechanisms.[15, 264] Current oncological paradigms are beginning to admit that cancer may be
considered a pathological recapitulation of growth processes.
The concomitant administration of Na-Butyrate creates an epigenetic context of chromatin
relaxation, essential for the interaction with transcription factors of the Zinc Finger and
Homeodomain family, the RXR, VDR, RZR, ROR receptors, co-expressed on nuclear
membranes and involved in differentiation processes. The differentiating components of
DBM, such as the solution of retinoids in vitamin E, Vitamins C, D and MLT, therefore
counteract the mutagenic capacity of cancer cells based on a defence system, and it is this
survival programme that allows them to effectively and quickly repair DNA damage induced
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by chemo-radiotherapy. The first forms of life, prokaryotes, survived to the present day
because, as they evolved, they became equipped with a defence system based on a
programme of mutations, which allowed them to repair DNA damage caused by various
adverse events. The prokaryotes transmitted the survival programme to bacteria, which in
turn transferred it to somatic cells. Radman, a molecular biologist, has identified and studied
this programme of survival and defence transferred from prokaryotes to eukaryotes, and from
the latter to somatic cells. Because of its functions and survival purpose in emergency
conditions, he called it the "SOS programme", which somatic cells access to overcome
critical situations.[265] Israel L. confirmed that these defence mechanisms are activated by
tumour cells that implement the same procedure as germs, selecting and retaining for each
mutation a number of benefits much more quickly and efficiently than bacterial cells.[266]
Tumour cells in an acute stress situation implement DNA repair systems and express or
silence genes according to their needs, selecting and retaining for each mutation a series of
advantages much more quickly and efficiently than bacterial cells. Israel studied the SOS
system, identifying numerous gene homologies between neoplastic and bacterial cells. The
SOS system allows neoplastic populations to become progressively refractory to various
oncotherapeutic treatments through DNA repairs and genetic recombinations. In our body,
under stable conditions and biologically balanced, the SOS system is silenced and inactive,
blocked by a transcriptional repressor, the LEX-A protein. When the DNA of a somatic cell
is severely damaged, to access the SOS survival path and repair the DNA, the cell deactivates
the LEX-A transcriptional repressor using the REC-A positive regulator. The expression of
SOS thus initiates a series of mutations that repair but at the same time modify the DNA,
initiating the carcinogenesis process. The cell, thus mutated, begins a tumoural involution,
continuously selecting and retaining, with a progression predefined by the SOS programme, a
series of advantages, as confirmed by Lambert[267] and, more recently, other authors,
including Russo[268], who showed that various mechanisms against tumour cells, even beyond
chemo- and radiotherapy, such as monoclonal antibodies and inhibitors of ligand mitogenic
signalling pathways such as EGFR, VEGF, IGF1, FGF, etc., can very rapidly activate the
SOS system and an extremely large number of multiple survival mechanisms. The two
strategic objectives of DBM, not yet pursued by oncology, are proliferative-invasive,
neoplastic angiogenic inhibition using SST/Octreotide, DR2 agonist analogues, together with
fighting the mutagenic capacity of the neoplastic phenotype by silencing the SOS survival
system through the distinguishing components of the DBM, which, with their trophic,
immunomodulating and antioxidant activity, improve the vitality and efficiency of healthy
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cells while, simultaneously, reducing the efficiency, vitality and functionality of neoplastic
cells. The same molecules exert opposite effects on healthy and neoplastic cells. The
metronomic use of apoptotic, non-cytotoxic doses in a biological context unfavourable to the
viability, proliferation and migration of neoplastic cells, slowly but progressively causes their
extinction through apoptosis. In a tumour, the chemo-radiotherapy-resistant stem cells also
play a crucial role in maintaining tumour growth and the initiation of the metastatic process.
Chemotherapy and radiation therapy act on actively proliferating tumour cells, the “cancer
transit amplifying cells”. On the contrary, tumour stem cells proliferate slowly and are not
affected by chemo- and radio-therapy. For this reason, the current therapeutic strategies
cannot maintain long-term control of the tumour process.
Today, in the absence of valid therapeutic alternatives, sarcomas are characterised by
particularly high proliferative indices and metastatic potential, resulting in a high mortality
Three causes contribute to this dramatic therapeutic failure:
1. Total unresponsiveness to all cancer protocols of sarcoma populations consisting mainly
of tumour stem cells on which, in contrast, the efficacy of the DBM molecules discussed
here has been demonstrated.
2. Non-administration of Melatonin.
3. Failure to administer somatostatin, a physiological inhibitor of GH (and related growth
factors) and, therefore, of neoplastic proliferation and dissemination.
The DBM, by extending its activity to fight multiple vital reactions of the neoplastic biology,
shifts the therapeutic axis from a pure cytotoxic-cytolytic conception and the illusory and
utopistic eradication of all cancer cells, to the gradual physiological reconversion of the vital
functions deviated by the cancer, to the recovery of immuno-neuro endocrine homeostasis, to
the differentiation of tumour cells and reprogramming of tumour stem cells. No cytotoxic
chemotherapy treatment (or monotherapy) exists (or will ever exist) that can heal a solid
tumour. There is only a method, a rational and biological multitherapy, a complex of
synergistic and factorially interactive substances, individually equipped with non-toxic
antitumour activity, which sequentially or simultaneously act centripetally on the myriad
biological reactions of tumour life, gradually restoring to normality the vital reactions altered
by the cancer.
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
ATRA - All Trans Retinoic Acid
CCK Cholecystokinin
C.M. - GH-induced chemotaxis of Monocytes
CSC - Cancer Stem Cells
DBM - Di Bella Method
EGF - Epidermal Growth Factor
EGFR - Epidermal Growth Factor Receptor
FGF - Fibroblastic Growth Factor
GF - Growth Factor
GH - Growth Hormone
GHR - Growth Hormone Receptor
HDAT - Histone deacetylase
HGF - Hepatocyte Growth Factor
HIF-- Hypoxia-Inducible Oncogenic Factor 1-alpha
IGF1-2 - Insulin-like Growth Factor 1-2
IGFR - Insulin-like Growth Factor Receptor
IL8 - Interleukin 8
MRI - Magnetic Resonance Imaging
MLT - Melatonin
NGF - Nerve Growth Factor
NHL - Non-Hodgkin’s Lymphoma
eNOS - Endothelial Nitric Oxide Synthase
PDGF - Platelet-Derived Growth Factor
PET - Positron Emission Tomography
PG2 - Prostaglandin 2
PRL - Prolactin
PRLR - Prolactin Receptor
NMR - Nuclear Magnetic Resonance
SSN - National Health Service
SST - Somatostatin
SSTR - Somatostatin Receptor
TGF - Transforming Growth Factor
TRK - Tyrosine-kinase
Bella et al. World Journal of Pharmaceutical Research Vol 11, Issue 7, 2022. ISO 9001:2015 Certified Journal
VEGF - Vascular Endothelial Growth Factor
VIP - Vasoactive Intestinal Peptide
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Vitamin C is an antioxidant that may scavenge reactive oxygen species preventing DNA damage and other effects important in cancer transformation. Dietary vitamin C from natural sources is taken with other compounds affecting its bioavailability and biological effects. High pharmacological doses of vitamin C may induce prooxidant effects, detrimental for cancer cells. An oxidized form of vitamin C, dehydroascorbate, is transported through glucose transporters, and cancer cells switch from oxidative phosphorylation to glycolysis in energy production so an excess of vitamin C may limit glucose transport and ATP production resulting in energetic crisis and cell death. Vitamin C may change the metabolomic and epigenetic profiles of cancer cells, and activation of ten-eleven translocation (TET) proteins and downregulation of pluripotency factors by the vitamin may eradicate cancer stem cells. Metastasis, the main reason of cancer-related deaths, requires breakage of anatomical barriers containing collagen, whose synthesis is promoted by vitamin C. Vitamin C induces degradation of hypoxia-inducible factor, HIF-1, essential for the survival of tumor cells in hypoxic conditions. Dietary vitamin C may stimulate the immune system through activation of NK and T cells and monocytes. Pharmacological doses of vitamin C may inhibit cancer transformation in several pathways, but further studies are needed to address both mechanistic and clinical aspects of this effect.
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Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11-15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in bone growth and the peak age distribution of osteosarcoma during puberty, so melatonin has been utilized as an adjunct to chemotherapy to improve the quality of life and clinical outcomes. While a large amount of research has been conducted to understand the complex pleiotropic functions and the molecular and cellular actions elicited by melatonin in various types of cancers, a few review reports have focused on osteosarcoma. Herein, we summarized the anti-osteosarcoma effects of melatonin and its underlying molecular mechanisms to illustrate the known significance of melatonin in osteosarcoma and to address cellular signaling pathways of melatonin in vitro and in animal models. Even in the same kind of osteosarcoma, melatonin has been sparingly investigated to counteract tumor growth, apoptosis, and metastasis through different mechanisms, depending on different cell lines. We highlighted the underlying mechanism of anti-osteosarcoma properties evoked by melatonin, including antioxidant activity, anti-proliferation, induction of apoptosis, and the inhibition of invasion and metastasis. Moreover, we discussed the drug synergy effects of the role of melatonin involved and the method to fortify the anti-cancer effects on osteosarcoma. As a potential therapeutic agent, melatonin is safe for children and adolescents and is a promising candidate for an adjuvant by reinforcing the therapeutic effects and abolishing the unwanted consequences of chemotherapies.
Aims About a half of all cancer patients receive radiotherapy as part of their oncological treatment. Because of the carcinogenic effect of ionising radiation, there is a rare, but definite, risk of developing secondary malignancies, including sarcomas. The aim of this retrospective study was to describe the prevalence, patient and tumour characteristics, as well as prognosis and outcome, of patients with radiation-induced sarcomas (RIS) in a cohort of patients treated in the Sarcoma Centre at Aarhus University Hospital over a period of 34 years. Materials and methods All patients who fulfilled the criteria for RIS and were treated for RIS in the period 1979–2013 were included. Patient data were retrieved from the Aarhus Sarcoma Registry and the National Danish Sarcoma Database, crosschecked with the National Register of Pathology and validated using the patients' medical records. The primary end point was the effect of surgery and treatment intent on overall survival. Overall survival is reported using the Kaplan–Meier estimates and compared using the Log-rank test. Descriptive statistics are presented for patients, tumours and treatment characteristics. Results Of 2845 patients diagnosed with sarcoma between 1979 and 2013, 64 (2%) were diagnosed with RIS. The median interval from the original malignancy was 11 years. The most common histological type was undifferentiated pleomorphic sarcoma (33%). Curative treatment was intended for 45 patients. Fifty patients underwent surgery, of whom 80% had microscopically radical resection (R0). The 5-year overall survival for the whole cohort was 32%. Patients who underwent surgery had a significantly better overall survival compared with patients who were not treated with surgery. In the univariate Cox proportional hazard analyses, no metastases at diagnosis, surgery and R0 resection were favourable prognostics factors of survival. Conclusion This study showed that RIS patients are unique in their epidemiology and tumour characteristics. They have a poor prognosis and need special research investigating new intensive treatment strategies to improve the outcome.
Aldehyde dehydrogenases are a family of enzymes that oxidize aldehydes to carboxylic acids. These enzymes are important in cellular homeostasis during oxidative stress by the elimination of toxic aldehyde by-products from various cellular processes. In osteosarcoma, aldehyde dehydrogenase 1A1has been described as a cancer stem cell marker. Its activity has been found to correlate with metastatic potential and the metastatic phenotype. As such, a more complete understanding of aldehyde dehydrogenase in osteosarcoma will give us a deeper knowledge of its impact on osteosarcoma metastatic potential. Our hope is that this knowledge can be translated into novel antimetastatic therapeutic strategies and thus improve osteosarcoma prognoses.
Soft‐tissue sarcomas (STS) are rare tumors that account for 1% of all adult malignancies, with over 100 different histologic subtypes occurring predominately in the trunk, extremity, and retroperitoneum. This low incidence is further complicated by their variable presentation, behavior, and long‐term outcomes, which emphasize the importance of centralized care in specialized centers with a multidisciplinary team approach. In the last decade, there has been an effort to improve the quality of care for patients with STS based on anatomic site and histology, and multiple ongoing clinical trials are focusing on tailoring therapy to histologic subtype. This report summarizes the latest evidence guiding the histiotype‐specific management of extremity/truncal and retroperitoneal STS with regard to surgery, radiation, and chemotherapy.
Conjugation of D-glucosamine with lipophilic moiety can ease its application in surface modification of liposomes. Interestingly, although D-glucosamine is safe, studies have shed light on “toxic effect” of its conjugates on cancer cells and highlighted its application in targeting glioma. However, understanding the safety of such conjugates for local delivery to the brain is unavailable. Herein, after successful synthesis of D-glucosamine conjugate (GC), the toxicity of functionalized liposome was evaluated both in vitro and in vivo. The study revealed a significant effect on cytotoxicity and apoptosis in vitro as assessed on grade IV-resistant glioma cell lines, SF268, U87MG, using MTT assay and PI staining. Additionally, this effect was not observed on normal human erythrocytes in the hemolysis assay. Furthermore, we demonstrated that GC liposomes were non-toxic to the normal brain tissues of healthy Sprague-Dawley rats. Successful functionalization yielded liposome with uniform particle size, stability, and cellular uptake. With < 10% hemolysis, all the liposomal formulations demonstrated hemato-compatibility but led to high glioma cytotoxicity. The surface density of conjugate played an important role in tumor toxicity (0.5 < 1.0 ≤ 2.0% molar ratio). PI staining revealed that compared to control cell, functionalization led 26-fold increase in induction of apoptosis in glioma cells. Absence of histological and behavioral changes along with the absence of caspase-3 in brain tissue confirmed the suitability of the system for direct infusion in the brain. Thus, this study will aid the future development of clinically useful local chemotherapeutic without “add-in” side effects.