Abstract 1977: BAL27862: A unique microtubule-targeted drug that suppresses microtubule dynamics, severs microtubules, and overcomes Bcl-2- and tubulin subtype-related drug resistance

Abstract

Abstract Microtubule-targeted drugs (MTDs) are widely used to treat human malignancies such as ovarian and breast cancers. However, a major limitation of their efficacy is the development of resistance modulated by P-gp over-expression or modification of the microtubular target and/or the expression/function of apoptotic pathway proteins such as Bcl-2 [1]. BAL27862 is a novel, orally bioavailable synthetic MTD that triggers apoptosis in cancer cell lines. BAL27862 induces a G2/M arrest, destabilizing microtubules (MT) to produce a unique MT phenotype distinct from that observed with vinca alkaloids (e.g. vinblastine), colchicine and taxanes. Moreover, BAL27862 retains its anti-proliferative activity against multi-drug-resistant, P-gp over-expressing tumor cells [2]. To investigate the mechanism of action of BAL27862, we analyzed its effects on MT dynamics in living breast cancer cells (SKBr3 cells). As measurements were not possible using equipotent cytotoxic concentrations of the MT destabilizer vinblastine, it was compared to the MT stabilizer paclitaxel. BAL27862 suppressed MT dynamic instability, supressing MT catastrophes and growth rate and increasing the mean duration of pauses. In contrast, paclitaxel suppressed the MT shortening rate and did not affect the MT growth rate. At equipotent cytotoxic concentrations, the suppression of MT dynamics by BAL27862 was 2-fold lower than paclitaxel. Strikingly, BAL27862 displayed a unique MT severing activity. We then determined the anti-proliferative potency of BAL27862 in paclitaxel- and Vinca-alkaloid-resistant ovarian cancer cells (A2780-TC1 cells) in comparison to the chemosensitive parental line (A2780-wt cells). A2780-TC1 cell resistance is mediated by P-gp over-expression, Bcl-2 down-regulation and modifications in tubulin subtype composition [1]. Importantly, BAL27862 remained fully active against A2780-TC1 cells. Indeed, when comparing EC50, the resistance factors observed were 1.14 (NS) and 147 (p<0.01) for BAL27862 and paclitaxel, respectively. Furthermore, in the presence of verapamil (P-gp inhibitor), resistance factors were 1.17 (NS) and 11.43 (p<0.01) for BAL27862 and paclitaxel, respectively. These results confirm that BAL27862 overcomes P-gp overexpression-mediated resistance, and demonstrate that Bcl-2 status and modifications in tubulin composition do not necessarily affect its cytotoxicity. In conclusion, BAL27862 shares properties with other MTDs such as suppression of MT dynamics, but displays unique features such as MT severing. In ovarian tumor cells, activity appears independent of Bcl-2 and tubulin modifications. These features make BAL27862 a promising compound for clinical development. 1. Estève MA et al, Mol Cancer Ther, 2006 2. Lane H. et al, EORTC-NCI-AACR 2008, Abstract 444 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1977.