Bcl‐X_L and MCL‐1 constitute pertinent targets in ovarian carcinoma and their concomitant inhibition is sufficient to induce apoptosis

Abstract

In ovarian carcinomas, recurrence and acquired chemoresistance are the first leading causes of therapeutic failure and are responsible for the poor overall survival rate. Cisplatin exposure of sensitive cells has been previously associated with a down-regulation of Bcl-x L expression and apoptosis, whereas recurrence was systematically observed when Bcl-x L expression was maintained. Bcl-x L down-regulation could thus constitute an interesting chemosensitizing strategy. We showed that a Bclx L targeted RNA interference strategy efficiently sensitized chemoresistant ovarian carcinoma cells to cisplatin, but some of them were still able to re-proliferate. Considering the possible cooperation between Bcl-x L and MCL-1, we investigated the possibility to avoid recurrence in vitro using a multi-targeted RNAi strategy directed against these two anti-apoptotic proteins. We showed that their concomitant inhibition lead to massive apoptosis in absence of cisplatin, this multi-targeted RNAi approach being much more efficient than conventional chemotherapy. We thus demonstrated that Bcl-x L and MCL-1 cooperate to constitute together a strong molecular ''bolt'', which elimination could be sufficient to allow chemoresistant ovarian carcinoma cells apoptosis. Moreover, we demonstrated that in presence of a low concentration of cisplatin, the concomitant down-regulation of Bcl-x L and MCL-1 allowed a complete annihilation of tumour cells population thus avoiding subsequent recurrence in vitro in cell lines highly refractory to any type of conventional chemotherapy. Therefore, Bcl-x L and MCL-1 targeted strategies could constitute an efficient therapeutic tool for the treatment of chemoresistant ovarian carcinoma, in association with conventional chemotherapy.Ovarian cancer is the leading cause of death from gynecological malignancies worldwide and the fifth most common cause of cancer death in women. 1 Early diagnosis is difficult owing to the asymptomatic character of this disease in early stages, and more than 70% of these cancers are diagnosed in an advanced stage (FIGO stages III or IV). Patients with advanced ovarian cancer are treated initially with optimal debulking surgery and standard chemotherapy (platinumdrugs usually associated to taxanes). 2 Despite an initial 70-80% response rate, most patients will relapse within 1-2 years and develop resistance to chemotherapy 3 and the overall 5-year survival is less than 30%. The identification of new drugs or novel therapeutic strategies able to (re)sensitize ovarian carcinoma cells to existing chemotherapy thus appear as a major challenge.Cisplatin, a DNA-damaging agent that forms DNA adducts, is commonly used for the treatment of advanced ovarian cancers. It is widely accepted that these adducts lead to a cell cycle arrest followed by the induction of apoptotic cell death. 4 However, it should be considered that in resistant cells, a strong protection against apoptosis exist when the DNA damages reach their maximum level, to allow the reparation of these injuries and the r...

Inhibition of STAT3 Signaling Pathway by Nitidine Chloride Suppressed the Angiogenesis and Growth of Human Gastric Cancer

“…Therefore, suppression of Bcl-2 and Bcl-xL expression may be a useful strategy to potentiate cancer apoptosis (49,50). Notably, we found that STAT3-dependent target genes including Bcl-2 and Bcl-xL were dose-dependently downregulated by nitidine chloride.…”

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“…Several studies have shown that the antiapoptotic proteins Bcl-x L and Mcl-1, as well as the proapoptotic protein Bim, are key elements for therapeutic intervention to kill ovarian cancer cells (5)(6)(7)(8)(9)(10). In this context, the objective of the current work was to evaluate whether AZD8055-induced mTOR inhibition and/or trametinib-induced MEK inhibition could disrupt the imbalance between Mcl-1 and its proapoptotic partners, including Bim, and thus sensitize platinumrefractory ovarian cancer cell lines to the potent Bcl-x L inhibitor ABT-737.…”

The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

“…11) increases sensitivity of ovarian cancer cell lines to these chemotherapeutic agents. It may therefore be concluded that concomitant inhibition of Bcl-x L with chemotherapy could be an attractive treatment strategy for this cancer type (10,11).…”