Sensitization of Carboplatinum- and Taxol-Resistant High-Grade Serous Ovarian Cancer Cells Carrying p53, BRCA1/2 Mutations by Emblica officinalis (Amla) via Multiple Targets

Abstract

Background: Ovarian cancer (OC), the most lethal gynecologic malignancy, is highly resistant to current treatment strategies. High-grade serous epithelial ovarian cancer (HGSOC) cells with increased somatic mutations and genomic instability and the resulting heterogeneous mutant phenotypes are highly resistant to therapy. Plant-derived natural products, including Amla (Emblica officinalis) extract (AE), have demonstrated potent anti-neoplastic properties. Recently we demonstrated that AE inhibits cell growth and the expression of angiogenic factors in OVCAR3 and SKOV3 OC cells in vitro as well as in xenografts in vivo. The goal of this study was to determine the anti-proliferative, anti-angiogenic and anti-metastatic effects of AE on carboplatinum-and taxol-resistant HGSOC cells carrying p53, BRCA1/2 mutations. Methods: Anti-proliferative and anti-metastatic effects of AE on recently characterized carboplatinum-and taxol-resistant HGSOC cells (TOV3041G, OV866(2), OV4453 and, OV4485) was determined using the MTT, migration, invasion and spheroid assays in vitro. To understand the mechanism of AE-induced changes in angiogenesis-related hypoxia-inducible factor 1α (HIF-1α) and insulin growth factor receptor 1 (IGF1R), and EMT-associated SNAIL1 and E-cadherin proteins were studied using immunostaining and Western blotting. In vivo effects of AE were determined using mouse xenograft tumor model of OC developed by subcutaneous injection of OV4485 cells that carry mutant p53 and BRCA1, most aggressive and resistant among HGSOC cell lines used in this study. Tumor growth was measured using morphometry. Immunostaining and Western blotting were used to determine changes in Ki67 (proliferation marker), CD31 (angiogenesis marker) as well as changes in HIF-1α, IGF1R, SNAIL1 and E-cadherin proteins. Results: AE significantly attenuated migration and invasiveness properties of all tested HGSOC cell phenotypes (P≤0.001), significantly reduced the expression of HIF-1α, IGF1R, and SNAIL1 and increased the expression of E-cadherin in all tested HGSOC cell lines (P=<0.05). Oral administration of AE for 4 weeks caused a significant regression of mouse xenograft tumor (>60%) that derived from OV4855 cells and decreased the expression of endothelial cell antigen-CD31, HIF-1α, IGF1R and SNAIL1 and increased the expression of E-cadherin in tumor tissues. Conclusions: AE sensitizes platinum-and taxol-resistant heterogenous HGSOC cells carrying mutations in p53, BRCA1/2 genes, and attenuates their malignant characteristics through targeting key signaling mechanisms of angiogenesis and metastasis. AE is a potential adjunct therapeutic agent for treating resistant, mutant, heterogenous OC.

Administration of Thymoquinone Offer a Protective Effect through the Apoptogenic and Antioxidant Pathway in Acute Liver Failure induced by Taxol

“…34 De et al also found that the apoptotic genes are expressed significantly after taxol administration. 35 In the current study, thymoquinone reduced apoptotic cell index and apoptotic gene expression to prevent cell death. Based on the obtained results, it can be indicated that thymoquinone owns positive antioxidant effects on molecular function and histological construction of liver cells.…”

Effect of Thymoquinone on Ovarian Carcinoma Cell Viability (OVCAR-3)

“…15 . The current standard treatment for advanced ovarian cancer is cytoreductive surgery and platinum/taxane-based chemotherapy [16][17][18] . The response rate to treatment is approximately 80-90%, but many often relapse and develop resistance to chemotherapy 14 .…”

Current advances on the phytochemical composition, pharmacologic effects, toxicology, and product development of Phyllanthi Fructus

“…The pre-clinical experiments of various cancer cell lines (A549 [lung], HepG2 [liver], HeLa [cervix], MDA-MB-231 [breast], SK-OV-3 [ovary] and SW620 [colorectal]) showed that the water extracts of PF (50–100 μg/ml) can induce apoptosis by activating caspase-8 and caspase-3/7 and upregulating Fas expression ( Ngamkitidechakul et al, 2010 ). PF extracts also sensitized refractory high-grade serous ovarian cancer (HGSOC) cells with high drug resistance by regulating key signalling molecules of angiogenesis and metastasis ( De et al, 2020 ).…”