Abstract 4676: 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a novel paclitaxel chemosensitizer to inhibit growth in Taxol non-resistant and Taxol resistant cancers

Abstract

Abstract 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a single molecule isolated from a traditional Chinese Medicinal herb Marsdenia tenacissima (MT). Recently, our group has isolated a few single molecules from the MT herb, they have shown significant anti-tumor activity in vitro and MT2 has the highest potential among all. We have performed MTT viability assay and clonogenic assay to demonstrate that MT2-alone is non-cytotoxic, but the cytotoxicity of the paclitaxel+MT2 combination treatment was more significant than that of paclitaxel, a microtubule stabilizing chemotherapeutic agent. The underlying mechanism of such growth inhibition is contributed by the down-regulation of the pro-survival signaling and up-regulation of the apoptotic signaling such as an increase in cleaved caspase 3 and decrease in anti-apoptotic Bcl-2 proteins when cancer cells are co-treated with MT2+paclitaxel. More importantly, intraperitoneal administration of the combination treatment 5 times of MT2+paclitaxel (30mg/kg, 8mg/kg) has a more significant anti-tumor effect than the paclitaxel-alone (8mg/kg) or MT2-alone (30mg/kg) treatments using the wild-type hepatic HepG2 xenograft model in nude mice. Besides the wild-type HepG2 cancer cells, we have further demonstrated that MT2 is able to resensitize paclitaxel-resistant HepG2 cancer cells by inhibiting the activity of p-glycoprotein (Pgp), a key drug efflux transporter in chemotherapy resistance cancer cells. Also, the combination treatment has shown a significant anti-tumor effect in HepG2/DOX Pgp-overexpressed xenograft in nude mice. Taken together, MT2 is a novel chemosensitiser in combination use with paclitaxel to treat cancer. It enhances cancer apoptosis by suppressing the anti-apoptotic and survival signaling pathways in cancer cells. Citation Format: Ka Ming Cheng, Gui yun Wu, Kowk Kuen Cheung, Xiao-Ling Shen, Ying-Jie Hu, Ki Lui. 11α-O-2-methylbutanoyl-12β-O-tigloyl-tenacigenin B (MT2) is a novel paclitaxel chemosensitizer to inhibit growth in Taxol non-resistant and Taxol resistant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4676.