Abstract 2086: Noscapine chemosensitization enhances docetaxel anticancer activity and tumor stroma disruption against triple negative breast cancer

Abstract

Abstract Purpose: The use of Noscapine (Nos) as a chemosensitizer followed by docetaxel (DTX) treatment therapy could be a novel approach for the treatment for breast cancer and possibly reduce the adverse side effects associated with DTX based chemotherapy. The goal of this study was to examine the chemo-sensitizing effect of Nos to DTX and also tumor stromal disruption effect of Nos in mice bearing xenograft TNBC tumors. Methods: Effect of Nos chemosensitization on DTX cytotoxicity was evaluated in MDA-MB-231 cells by trypan blue dye method. Apoptosis was measured by AnnexinV/FITC method using flow cytometer. Expression of different proteins like phospho-p38, pJNK, bcl-2, α-tubulin, Akt, pAkt, survivin was evaluated by immunoblot. Alpha-tubulin binding assay was done by fluorescent microscopy. In vivo antifibrotic efficacy of Nos and uptake of coumarin-6 loaded fluorescent liposomes was evaluated by picro-sirius red staining and fluorescent microscopy respectively in xenograft breast tumors. Results: MDA-MB-231 TNBC cells were exposed at sub-therapeutic dose of Nos (4 μM) which increased the cytotoxicity of DTX by 3.0-fold. Flow-cytometric analysis showed significant increase (30 percent) of late apoptotic cells in Nos chemosensitized, DTX-treated MDA-MB-231 cells compared with DTX alone treatment. Further, chemosensitization of TNBC cells with Nos at different time intervals (6 h, 12 h and 24 h), the effect on stress transducer p38 stress activator protein kinase was significantly activated (p<0.01). Also, Nos (4 μM) chemosensitized cells followed by DTX treatment showed downregulation of bcl2 (2.3-fold), survivin (1.3-fold) and pAKT (1.9-fold) expression further illustrating the role of Nos in inducing apoptosis. Interestingly, at this dose of Nos (4 μM), there was no impact on alpha-tubulin. Also, in vivo studies with 100 mg/kg Nos given orally to MDA-MB-231 tumor bearing athymic nude mice revealed significant reduction in tumor collagen-1 levels in Nos treated group compared to control as determined by picro-sirius staining. In Nos treated tumors, uptake of coumarin-6 loaded fluorescent liposomes was 7-fold higher compared to controls suggesting antifibrotic role of Nos. Conclusion: In conclusion, chemosensitization with sub-therapeutic dose of oral noscapine could be a promising approach to increase anticancer activity of DTX and can further enhance uptake of liposomes suggesting that this approach may have potential in TNBC treatment. Citation Format: Ravi Doddapaneni, Ketan Patel, Nusrat Chowdhury, Mandip Sachdeva. Noscapine chemosensitization enhances docetaxel anticancer activity and tumor stroma disruption against triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2086.