Abstract 4039: Riluzole synergizes with paclitaxel to induce apoptosis and inhibit cell growth in triple negative breast cancer

Abstract

Abstract Introduction: Systemic treatment for triple negative breast cancer (TNBC) includes paclitaxel, which works by inhibiting the breakdown of microtubules. We previously observed that riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, can inhibit TNBC proliferation, invasion, and colony formation. We now test whether riluzole can act synergistically with paclitaxel to inhibit TNBC growth and induce apoptosis in TNBC. Methods: After treatment of various TNBC cell lines with constant ratio concentrations of riluzole and paclitaxel we conducted cell proliferation transformation assays (MTT) to measure cell inhibition potential. Synergy or additivity was determined by the Chou-Talalay using Compusyn software. PARP cleavage normalized to GAPDH was also measured by Western blot to estimate apoptosis due to the riluzole-paclitaxel combination. In vivo synergy was studied using a xenograft study with MDA-MB-231, a human TNBC cell line sensitive to riluzole. Results: MTT results show that riluzole and paclitaxel work synergistically to inhibit cell proliferation in all TNBC cell lines tested, as determined by isobolograms and CI values <1. The strongest synergistic effect was observed in the cell lines SUM159, SUM149, and SUM229, where synergism occurred at Fa values as low as 0.5 (50% inhibition of cell proliferation). Measuring PARP cleavage, we demonstrated that the riluzole-paclitaxel drug combination induces greater apoptosis than does either drug alone. The significant impact of the drug combination was best demonstrated in cell lines SUM159, SUM149 and SUM229, but was observed in all cell lines tested. In the xenograft study, the highest non-toxic dose of paclitaxel (7.2 mg/kg) combined with riluzole resulted in 8/9 tumor-free mice, with a tumor growth inhibition ratio (T/C) of 0%, where <10% is considered highly therapeutic. This result was better than riluzole monotherapy (0/9 tumor-free and T/C = 99%) or paclitaxel monotherapy (4/8 tumor-free and T/C = 8%). Conclusions: Our results demonstrate that the addition of riluzole to paclitaxel results in at least additive and in many cases synergistic effects against TNBC. Our observations thus suggest that repurposing riluzole, which is an oral drug with an excellent safety profile, to add to paclitaxel to treat TNBC represents a potential strategy to improve the efficacy of adjuvant and neoadjuvant treatments for TNBC and/or reduce chemotherapy doses and toxicity in patients. Our data support the need to proceed to clinical trials to test this approach in patients. Citation Format: Miriam A. Bukhsh, Cecilia L. Speyer, Waris S. Jafry, Rachel E. Sexton, David Thomas, David Gorki. Riluzole synergizes with paclitaxel to induce apoptosis and inhibit cell growth in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4039. doi:10.1158/1538-7445.AM2017-4039