Abstract 2934: Cucurbitacin D enhances the therapeutic efficacy of docetaxel via targeting cancer stem cells and miR-145

Abstract

Background: Docetaxel (DTX) is an FDA approved drug for the treatment of advanced prostate cancer (PrCa). However, chemo-resistance and toxicity limits its use in clinic. Accumulating evidence suggests that activation of cancer stem cells (CSCs) is one of the mechanisms leading to developing chemo-resistance Therefore, identification of new pharmacophores that can target CSCs may improve the therapeutic efficacy of docetaxel for the treatment of advanced PrCa. Cucurbitacin D is one of the potent analogues of cucurbitacin and has shown several health benefits including anti-cancer activity. Herein, we report that Cucurbitacin D augments the therapeutic efficacy of DTX via modulating CSCs and miR-145.

Methods: Prostate cancer stem cells (pCSCs) were used as a model system to investigate the effect of Cucurbitacin D alone or in combination with docetaxel. Effect of Cucurbitacin D was evaluated on cell growth by MTS and xCELLigence assays and apoptosis induction was evaluated by flow cytometry. Colony formation assay was performed to investigate the effect of Cucurbitacin D on clonogenic potential of pCSCs cells. Effect of Cucurbitacin D on key oncogenic molecules was analyzed by Western blot and qRT-PCR analyses. To investigate the therapeutic and chemo-sensitization effect of Cucurbitacin D, we performed xenograft study using pCSCs.

Results: Our results demonstrated that Cucurbitacin D potentiates the therapeutic effect of docetaxel in pCSCs. Cucurbitacin D treatment significantly inhibited growth and clonogenic potential. Moreover, Cucurbitacin D effectively sensitized the effect of docetaxel as analyzed by significant (P<0.01) decrease in colony forming and proliferative potential of pCSCs compared to docetaxel treatment alone. To understand the underlying molecular mechanism of Cucurbitacin targeting CSCs, we analyzed the effect of Cucurbitacin D on CSCs markers such as CD133, OCT4, SOX2 and miR-145 in pCSCs. Cucurbitacin D effectively inhibited the expression of CD133, OCT4, and SOX2 and induced the expression of miR-145 in pCSCs. Cucurbiatcin D administration (1 mg/kg body weight intra-tumoral three times for five consecutive weeks) inhibited pCSCs derived xenograft tumors in athymic nude mice. This effect was additive, when combined with docetaxel treatment.

Conclusion: Our findings suggest that cucurbitacin D is a novel agent and has great promise to improve the therapeutic efficacy of docetaxel. Thus, cucurbitacin could be a novel therapeutic modality for the treatment of advanced prostate cancer.

Citation Format: Mohammed Sikander, Shabnam Malik, Bilal Bin Hafeez, Hassan Mandil, Fathi T. Halaweish, Meena Jaggi, Subhash C. Chauhan. Cucurbitacin D enhances the therapeutic efficacy of docetaxel via targeting cancer stem cells and miR-145 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2934.