Abstract
BackgroundOvarian cancer is one of the major causes of death among females in worldwide. Cisplatin is a primary anti-cancer drug against ovarian cancer, but the recurrent tumors after treatment frequently show acquired chemoresistance. Extract of Scutellaria baicalensis (SbE) has been reported to have functional compounds including baicalin, which has anti-cancer effects. However, the anti-cancer effects of SbE in ovarian cancer and its underlying mechanisms are elusive.MethodsWe investigated that the effects of SbE and/or cisplatin on cell death in the cisplatin sensitive ovarian cancer cell line A2780 (CSC) and the counterpart cell line that has cisplatin resistance (CRC). Molecular mechanisms of the effects, focusing on apoptosis and autophagy, were examined.ResultsTreatment of cisplatin or SbE reduced cell viability significantly in CSC and too much lesser extent in CRC. Cisplatin-induced cell death in CSC was mediated by p53-induced apoptosis acompanied by expresson of damage-regulated autophagy modulator (DRAM). In CRC, decreased DRAM expression (p < 0.01) hindered p21-mediated cell death and contributed to cisplatin resistance. Treatment of SbE also induced cell death in CSC by p53-dependent apoptosis, not in CRC. Autophagy was not induced by neither cisplatin nor SbE. Intriguingly, the combinational treatment of SbE and cisplatin significantly decreased cell viability in CRC. The cell death was mediated by autophagy with increased expression of Atg5 and Atg12 (p < 0.05), rather than p53-dependent pathway with repressed expression of p21 (p < 0.001) through HDAC1 activation.ConclusionsThe combined treatment of SbE with cisplatin was effective in CRC, leading to cell death via Beclin1-independent autophagy, suggesting that SbE treatment in combination with cisplatin has a potential as a chemotherapeutic agent in cisplatin-resistant ovarian cancer.
Highlights
Ovarian cancer is one of the major causes of death among females in worldwide
Ovarian cancer cell models differently respond to cisplatin and cisplatin treatment induces p53-dependent apoptosis in Cisplatin sensitive human ovarian cancer cell line (CSC), not in CRC To investigate the mechanisms underlying cisplatin resistance, we used a pair of ovarian cancer cell lines; the cisplatin sensitive A2780 as CSC and its counterpart that acquires the resistance as CRC
Scutellaria baicalensis (SbE) induced cell death in ovarian cancer cells in a dosedependent manner, the efficiency was significantly lower in CRC, compared to CSC
Summary
Ovarian cancer is one of the major causes of death among females in worldwide. Cisplatin is a primary anti-cancer drug against ovarian cancer, but the recurrent tumors after treatment frequently show acquired chemoresistance. The resistance can be caused by multiple mechanisms, including inadequate cisplatin accumulation, cisplatin inactivation, enhanced DNA repair, and activation of survival signaling pathways [5]. Drug resistant cancer cells show uncontrolled cell proliferation and reduced cell death such as apoptosis and autophagy not responding to the treatment [10]. P53 triggers apoptosis through up-regulating target genes in many cell types including cancer cells [12]. DRAM gene is another target gene, which is an important component of p53-induced apoptosis and triggers autophagy [16]. Autophagy is an intracellular self degradative process that dismantles unnecessary or dysfunctional cytoplasmic components and organelles in the lysosome. Some of anti-cancer therapeutic agents promote autophagy-induced cell death [17]. The transfer to lysosome requires DRAM in its membrane [19]
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