scholarly journals The Molecular Pathogenesis of Haemangioma

2021 ◽  
Author(s):  
◽  
Anasuya Vishvanath
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Primary Tumour ◽  
Treatment Options ◽  
Janus Kinase ◽  
Stem Cell Population ◽  
Induced Apoptosis

<p>Haemangioma is a primary tumour of the microvasculature characterised by active angiogenesis and endothelial cell (EC)  proliferation followed by slow regression or involution whereby the newly formed blood vessels are gradually replaced by fibrofatty tissue. These developmental changes have been arbitrarily divided into the proliferative, involuting and involuted phases. The cellular and molecular events that initiate and regulate the proliferation and spontaneous involution of haemangioma remain poorly understood. This study examined the expression of a number of genes known to be associated with angiogenesis. These include members of the signal transducers and activators of transcription (STAT) protein family of transcription factors, STAT-3 and STAT-1, and the endothelial receptor tyrosine kinases, VEGFR-1 and VEGFR-2. While STAT-3, STAT-1 and VEGFR-1 expression was detected in all phases of haemangioma, VEGFR-2 expression was found to be abundant only during the proliferative phase and decreased with ongoing involution. In this study the cellular structures that form capillary-like outgrowths in an in vitro haemangioma explant model were characterised as haemangioma-derived mesenchymal stem cells (HaemDMSCs) while the cells obtained directly from dissociated proliferative haemangioma tissue were defined as haemangioma-derived endothelial progenitor cells (HaemDEPCs). This investigation showed that although the vascular endothelial growth factor (VEGF), a key growth factor for ECs, was able to maintain HaemDEPCs morphology and immunophenotype for a limited period, these cells eventually differentiated into HaemDMSCs, which subsequently differentiated into adipocytes. Furthermore, while VEGF induced significant capillary-like sprouting from tissue explants, both capillary-like sprouting and HaemDMSCs proliferation was inhibited by the addition of AG490, a Janus kinase (JAK) inhibitor which has also been shown to inhibit the STAT protein pathway. These findings indicate that the development and differentiation of a progenitor cell and a stem cell population underlies the aethiopathogenesis of haemangioma and that VEGF and STAT signalling is involved in the programmed life-cycle of haemangioma. The in vitro explant model for haemangioma offers an opportunity to study and identify novel treatment options for haemangioma. Interferon-alpha (IFN ) has been used to treat steroid-resistant haemangioma but is associated with serious side-affects. The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically induce apoptosis of cancer cells while sparing normal cells. As IFN has previously been shown to sensitise cells to TRAIL-induced apoptosis, this study examined the efficacy of low dose IFN in combination with TRAIL in the in vitro explant model and also in the purified HaemDMSCs. Results showed that combining IFN with TRAIL led to synergistic inhibition of capillary-like outgrowth. These results indicate that IFN in combination with TRAIL serves as a potential treatment option for haemangioma. In contrast, HaemDMSCs were protected from TRAIL-induced killing. These cells were found to express high levels of the decoy receptors, osteoprotegerin (OPG) and decoy receptor 2 (DcR2). Increased OPG expression was also detected in the extracellular matrix and in the conditioned medium of HaemDMSCs. From these findings, we postulate that the increased level of extracellular OPG by HaemDMSCs is a stress response induced by their in vitro expansion and that secreted OPG functions as a protective shield preventing TRAIL action. The empirical and unsatisfactory nature of the current therapies for haemangioma underscores the importance of a scientific approach to this common tumour. A better understanding of the molecular mechanisms that govern haemangioma is of both clinical and biological interest as it may provide vital information with therapeutic potential for haemangioma and also for other angiogenesis-dependent conditions.</p>

scholarly journals The Molecular Pathogenesis of Haemangioma

2021 ◽  
Author(s):  
◽  
Anasuya Vishvanath
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Primary Tumour ◽  
Treatment Options ◽  
Janus Kinase ◽  
Stem Cell Population ◽  
Induced Apoptosis

<p>Haemangioma is a primary tumour of the microvasculature characterised by active angiogenesis and endothelial cell (EC)  proliferation followed by slow regression or involution whereby the newly formed blood vessels are gradually replaced by fibrofatty tissue. These developmental changes have been arbitrarily divided into the proliferative, involuting and involuted phases. The cellular and molecular events that initiate and regulate the proliferation and spontaneous involution of haemangioma remain poorly understood. This study examined the expression of a number of genes known to be associated with angiogenesis. These include members of the signal transducers and activators of transcription (STAT) protein family of transcription factors, STAT-3 and STAT-1, and the endothelial receptor tyrosine kinases, VEGFR-1 and VEGFR-2. While STAT-3, STAT-1 and VEGFR-1 expression was detected in all phases of haemangioma, VEGFR-2 expression was found to be abundant only during the proliferative phase and decreased with ongoing involution. In this study the cellular structures that form capillary-like outgrowths in an in vitro haemangioma explant model were characterised as haemangioma-derived mesenchymal stem cells (HaemDMSCs) while the cells obtained directly from dissociated proliferative haemangioma tissue were defined as haemangioma-derived endothelial progenitor cells (HaemDEPCs). This investigation showed that although the vascular endothelial growth factor (VEGF), a key growth factor for ECs, was able to maintain HaemDEPCs morphology and immunophenotype for a limited period, these cells eventually differentiated into HaemDMSCs, which subsequently differentiated into adipocytes. Furthermore, while VEGF induced significant capillary-like sprouting from tissue explants, both capillary-like sprouting and HaemDMSCs proliferation was inhibited by the addition of AG490, a Janus kinase (JAK) inhibitor which has also been shown to inhibit the STAT protein pathway. These findings indicate that the development and differentiation of a progenitor cell and a stem cell population underlies the aethiopathogenesis of haemangioma and that VEGF and STAT signalling is involved in the programmed life-cycle of haemangioma. The in vitro explant model for haemangioma offers an opportunity to study and identify novel treatment options for haemangioma. Interferon-alpha (IFN ) has been used to treat steroid-resistant haemangioma but is associated with serious side-affects. The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically induce apoptosis of cancer cells while sparing normal cells. As IFN has previously been shown to sensitise cells to TRAIL-induced apoptosis, this study examined the efficacy of low dose IFN in combination with TRAIL in the in vitro explant model and also in the purified HaemDMSCs. Results showed that combining IFN with TRAIL led to synergistic inhibition of capillary-like outgrowth. These results indicate that IFN in combination with TRAIL serves as a potential treatment option for haemangioma. In contrast, HaemDMSCs were protected from TRAIL-induced killing. These cells were found to express high levels of the decoy receptors, osteoprotegerin (OPG) and decoy receptor 2 (DcR2). Increased OPG expression was also detected in the extracellular matrix and in the conditioned medium of HaemDMSCs. From these findings, we postulate that the increased level of extracellular OPG by HaemDMSCs is a stress response induced by their in vitro expansion and that secreted OPG functions as a protective shield preventing TRAIL action. The empirical and unsatisfactory nature of the current therapies for haemangioma underscores the importance of a scientific approach to this common tumour. A better understanding of the molecular mechanisms that govern haemangioma is of both clinical and biological interest as it may provide vital information with therapeutic potential for haemangioma and also for other angiogenesis-dependent conditions.</p>

scholarly journals Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms

2012 ◽  
Vol 19 (3) ◽  
pp. 423-434 ◽  
Author(s):  
Kathrin Zitzmann ◽  
George Vlotides ◽  
Stephan Brand ◽  
Harald Lahm ◽  
Gerald Spöttl ◽  
...  
Keyword(s):  
Cell Viability ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Akt Inhibitor ◽  
Antitumor Effects ◽  
Akt Isoforms ◽  
Induced Apoptosis

The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)–Akt–mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3α/β, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3α/β, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform-specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the pan-Akt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease.

VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 255-262 ◽  
Author(s):  
Aikebaier Maimaiti ◽  
Amier Aili ◽  
Hureshitanmu Kuerban ◽  
Xuejun Li
Keyword(s):  
Western Blot ◽  
Cell Viability ◽  
Gallic Acid ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Dependent Manner ◽  
Lung Carcinoma Cells ◽  
Induced Apoptosis ◽  
The Impact

Aims: Gallic acid (GA) is generally distributed in a variety of plants and foods, and possesses cell growth-inhibiting activities in cancer cell lines. In the present study, the impact of GA on cell viability, apoptosis induction and possible molecular mechanisms in cultured A549 lung carcinoma cells was investigated. Methods: In vitro experiments showed that treating A549 cells with various concentrations of GA inhibited cell viability and induced apoptosis in a dose-dependent manner. In order to understand the mechanism by which GA inhibits cell viability, comparative proteomic analysis was applied. The changed proteins were identified by Western blot and siRNA methods. Results: Two-dimensional electrophoresis revealed changes that occurred to the cells when treated with or without GA. Four up-regulated protein spots were clearly identified as malate dehydrogenase (MDH), voltagedependent, anion-selective channel protein 1(VDAC1), calreticulin (CRT) and brain acid soluble protein 1(BASP1). VDAC1 in A549 cells was reconfirmed by western blot. Transfection with VDAC1 siRNA significantly increased cell viability after the treatment of GA. Further investigation showed that GA down regulated PI3K/Akt signaling pathways. These data strongly suggest that up-regulation of VDAC1 by GA may play an important role in GA-induced, inhibitory effects on A549 cell viability.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

scholarly journals ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ørjan Samuelsen ◽  
Ove Alexander Høgmoen Åstrand ◽  
Christopher Fröhlich ◽  
Adam Heikal ◽  
Susann Skagseth ◽  
...  
Keyword(s):  
Active Site ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Carbapenem Resistance ◽  
Functional Space ◽  
Bactericidal Effect ◽  
Gram Negative ◽  
Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

scholarly journals Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin

2014 ◽  
Vol 25 (22) ◽  
pp. 3654-3671 ◽  
Author(s):  
Changsheng Lin ◽  
Jason Ear ◽  
Krishna Midde ◽  
Inmaculada Lopez-Sanchez ◽  
Nicolas Aznar ◽  
...  
Keyword(s):  
Growth Factor ◽  
G Proteins ◽  
Protein Interaction ◽  
Cross Talk ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Growth Factor Receptors ◽  
Structural Basis ◽  
Nucleotide Exchange ◽  
Protein Protein Interaction

A long-standing issue in the field of signal transduction is to understand the cross-talk between receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major and distinct signaling hubs that control eukaryotic cell behavior. Although stimulation of many RTKs leads to activation of trimeric G proteins, the molecular mechanisms behind this phenomenon remain elusive. We discovered a unifying mechanism that allows GIV/Girdin, a bona fide metastasis-related protein and a guanine-nucleotide exchange factor (GEF) for Gαi, to serve as a direct platform for multiple RTKs to activate Gαi proteins. Using a combination of homology modeling, protein–protein interaction, and kinase assays, we demonstrate that a stretch of ∼110 amino acids within GIV C-terminus displays structural plasticity that allows folding into a SH2-like domain in the presence of phosphotyrosine ligands. Using protein–protein interaction assays, we demonstrated that both SH2 and GEF domains of GIV are required for the formation of a ligand-activated ternary complex between GIV, Gαi, and growth factor receptors and for activation of Gαi after growth factor stimulation. Expression of a SH2-deficient GIV mutant (Arg 1745→Leu) that cannot bind RTKs impaired all previously demonstrated functions of GIV—Akt enhancement, actin remodeling, and cell migration. The mechanistic and structural insights gained here shed light on the long-standing questions surrounding RTK/G protein cross-talk, set a novel paradigm, and characterize a unique pharmacological target for uncoupling GIV-dependent signaling downstream of multiple oncogenic RTKs.

scholarly journals Isorhynchophylline Protects PC12 Cells Against Beta-Amyloid-Induced Apoptosis via PI3K/Akt Signaling Pathway

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yan-Fang Xian ◽  
Zhi-Xiu Lin ◽  
Qing-Qiu Mao ◽  
Jian-Nan Chen ◽  
Zi-Ren Su ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Neuroprotective Effect ◽  
Protective Action ◽  
Protective Effects ◽  
Phosphorylated Akt ◽  
Induced Apoptosis

The neurotoxicity of amyloid-β(Aβ) has been implicated as a critical cause of Alzheimer’s disease. Isorhynchophylline (IRN), an oxindole alkaloid isolated fromUncaria rhynchophylla,exerts neuroprotective effect againstAβ25–35-induced neurotoxicityin vitro. However, the exact mechanism for its neuroprotective effect is not well understood. The present study aimed to investigate the molecular mechanisms underlying the protective action of IRN againstAβ25–35-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. Pretreatment with IRN significantly increased the cell viability, inhibited the release of lactate dehydrogenase and the extent of DNA fragmentation inAβ25–35-treated cells. IRN treatment was able to enhance the protein levels of phosphorylated Akt (p-Akt) and glycogen synthase kinase-3β(p-GSK-3β). Lithium chloride blockedAβ25–35-induced cellular apoptosis in a similar manner as IRN, suggesting that GSK-3βinhibition was involved in neuroprotective action of IRN. Pretreatment with LY294002 completely abolished the protective effects of IRN. Furthermore, IRN reversedAβ25–35-induced attenuation in the level of phosphorylated cyclic AMP response element binding protein (p-CREB) and the effect of IRN could be blocked by the PI3K inhibitor. These experimental findings unambiguously suggested that the protective effect of IRN againstAβ25–35-induced apoptosis in PC12 cells was associated with the enhancement of p-CREB expression via PI3K/Akt/GSK-3βsignaling pathway.

TMOD-02. GENERATION OF A NOVEL MOUSE MODEL FOR BRAIN TUMORS OF THE DNA METHYLATION CLASS “GBM MYCN”

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi216
Author(s):  
Melanie Schoof ◽  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Sina Al-Kershi ◽  
Ulrich Schüller
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Tumor Development ◽  
Model Systems ◽  
Preclinical Research ◽  
Human Gbm

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.

scholarly journals Natural Compounds in Sex Hormone-Dependent Cancers: The Role of Triterpenes as Therapeutic Agents

2021 ◽  
Vol 11 ◽  
Author(s):  
Codruţa Şoica ◽  
Mirela Voicu ◽  
Roxana Ghiulai ◽  
Cristina Dehelean ◽  
Roxana Racoviceanu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Active Role ◽  
Structural Features ◽  
Sex Hormone ◽  
Ongoing Research ◽  
New Treatment ◽  
Highly Correlated

Sex hormone-dependent cancers currently contribute to the high number of cancer-related deaths worldwide. The study and elucidation of the molecular mechanisms underlying the progression of these tumors was a double-edged sword, leading to the expansion and development of new treatment options, with the cost of triggering more aggressive, therapy resistant relapses. The interaction of androgen, estrogen and progesterone hormones with specific receptors (AR, ER, PR) has emerged as a key player in the development and progression of breast, ovarian, prostate and endometrium cancers. Sex hormone-dependent cancers share a common and rather unique carcinogenesis mechanism involving the active role of endogenous and exogenous sex hormones to maintain high mitotic rates and increased cell proliferation thus increasing the probability of aberrant gene occurrence and accumulation highly correlated with abnormal cell division and the occurrence of malignant phenotypes. Cancer related hormone therapy has evolved, currently being associated with the blockade of other signaling pathways often associated with carcinogenesis and tumor progression in cancers, with promising results. However, despite the established developments, there are still several shortcomings to be addressed. Triterpenes are natural occurring secondary metabolites biosynthesized by various pathways starting from squalene cyclization. Due to their versatile therapeutic potential, including the extensively researched antiproliferative effect, these compounds are most definitely a cornerstone in the research and development of new natural/semisynthetic anticancer therapies. The present work thoroughly describes the ongoing research related to the antitumor activity of triterpenes in sex hormone-dependent cancers. Also, the current review highlights both the biological activity of various triterpenoid compounds and their featured mechanisms of action correlated with important chemical structural features.

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