Ginsenoside Rg3 as a Potential Treatment for Metastatic Triple-Negative Breast Cancer
Date
2021
Authors
Nakhjavani, Maryam
Editors
Advisors
Hardingham, Jennifer
Townsend, Amanda
Townsend, Amanda
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Thesis
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Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer for which no approved targeted therapy is available, and chemotherapy is the mainstay of the treatment for these patients. Administration of various chemotherapies can be limited by toxicities and the development of tumour resistance and the median overall survival of these patients is low. This research aimed at studying the efficacy of epimers of ginsenoside Rg3 (Rg3), 20(S)-Rg3 (SRg3) and 20(R)-Rg3 (RRg3), in inhibition of cancer growth and angiogenesis for the potential treatment of this disease. The preliminary molecular docking studies predicted that Rg3 interacted well with aquaporin 1 (AQP1), which plays important roles in cancer progression.
First, stereoselectivity of Rg3 epimers was shown in inhibition of proliferation, migration and invasion of TNBC cell lines and blocking AQP1 water channel. Due to this stereoselectivity, the combination of both epimers was optimised for inhibition of loop formation in endothelial cells, using response surface methodology (RSM). It was shown that this optimised combination, referred to as C3, significantly inhibited the proliferation and migration of human and murine endothelial cells. Rg3 epimers worked as allosteric modulators of vascular endothelial growth factor receptor 2 (VEGFR2). C3 decreased the expression of VEGF and significantly decreased the expression of AQP1 and the phosphorylation of proteins downstream of AKT signalling in hypoxic and normoxic conditions.
In TNBC monolayer cultures, C3 significantly decreased cell migration but did not inhibit cell proliferation. In TNBC mammospheres, C3 decreased mammosphere formation efficiency, with no significant reduction in cell viability. C3 decreased the expression of CD44 and the ratio of CD44/24. C3 also decreased the function of cells via affecting the proteins downstream of activation of the mammalian target of rapamycin (mTOR). In molecular docking, Rg3 epimers showed good binding scores with VEGFR2 and insulin growth factor-1 receptor amongst the tested tyrosine kinase receptors. Rg3 epimers also showed a good binding score with rapamycin-binding site of mTOR and activator of mTOR, Rheb. In a mouse model of metastatic TNBC, when an extrapolated dose of C3 (23 mg/kg SRg3 + 11 mg/kg RRg3) or an escalated dose (46 mg/kg SRg3 + 23 mg/kg RRg3) was injected into mice, a significant reduction in the primary tumour volume and decreased load of metastasis in the lungs was noticed. Furthermore, the number of affected axillary lymph nodes was significantly reduced.
Since Rg3 is prone to extensive metabolism in vivo, the efficacy of deglycosylated metabolites of Rg3 epimers was also studied. It was shown that these metabolites were inhibitors of cell proliferation in TNBC and endothelial cells. The mechanism for this action was induction of necroptosis/necrosis in TNBC cell lines and apoptosis in endothelial cells. Among the tested metabolites, 20(S)-ginsenoside Rh2 (S-Rh2) showed the best inhibition of loop formation, and allosteric modulatory action on VEGFR2. It was also predicted to be a good blocker of the AQP1 water channel. Altogether, the findings of this project show the possibilities of Rg3, as a potential inhibitor of mTOR signalling for the treatment of TNBC patients.
School/Discipline
School of Medicine
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2021
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