Abstract
Material and Methods: For in vitro experiments, cells were exposed to paclitaxel and/or TAS-119. Cell viability was determined by measuring cellular ATP concentration. For in vivo experiments, antitumor efficacy was assessed in subcutaneous HCC-1806-luc (triple negative breast cancer) and NCI-H460-luc (non-small cell lung cancer) xenograft models. The potential of taxane therapy with TAS-119 was evaluated in non-small cell lung cancer orthotopic models of H460-luc tumor in nude mice. To monitor tumor burden, in vivo bioluminescence imaging in individual mice was monitored weekly. Results: TAS-119 selectively inhibited phosphorylation of Aurora A without affecting the activity of Aurora B and Aurora C in NCI-H460 cells. TAS119 showed synergistic cell growth inhibition in combination with paclitaxel in NCI-H460 and HCC1806 cells. TAS-119 clearly enhanced antitumor efficacy of docetaxel in NCI-H460-luc and paclitaxel in HCC-1806-luc nude mice with sc tumors. In the lung orthotopic models, TAS-119 with docetaxel improved median survival, with significant benefit of the combination (155% ILS) over docetaxel alone (67% ILS). Conclusions: TAS-119 has a potential as an enhancer of taxane therapy in NSCLC and TNBC cells both in vitro and in vivo.
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