In vitro and in vivo anti‐tumour effects of MPT0B014 , a novel derivative aroylquinoline, and in combination with erlotinib in human non‐small‐cell lung cancer cells

Background and Purpose The purpose of the current study was to assess a novel anti‐cancer drug, MPT0B014 , which is not a substrate for the P‐glycoprotein (P‐gp) transporter, alone and in combination with erlotinib, against human non‐small cell lung cancer ( NSCLC ). Experimental Approach Cytotoxicity in human NSCLC cell lines was assessed by sulforhodamine B and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays. Cell cycle phase distributions were estimated with FACScan flow cytometry. Protein expression was detected by W estern blotting analysis. Efflux of rhodamine 123 or calcein‐acetoxymethylester was used to study the P ‐gp profile. The A549 xenograft model in mice was used to assess in vivo anti‐tumour activity. Key Results MPT0B014 showed potent anti‐proliferative activity against A549 , H1299 and H226 cells. It induced G2/M arrest with down‐regulation of Cdc ( Tyr15 ) and Cdc25C , and up‐regulation of cyclin B1 , phospho‐ Cdc2 ( Thr161 ) and Aurora A/B . P ‐gp‐overexpressing National Cancer Institute/Adriamycin‐Resistant cells were also sensitive to B014 . B014 ‐induced loss of M cl‐1 was accompanied by activation of caspases‐3, ‐7, ‐8 and ‐9, and initiation of apoptosis. B014 in combination with erlotinib caused significant tumour inhibition in vitro and in vivo . Conclusions and Implications MPT0B014 exerted cytotoxicity against human NSCLC cell lines with little susceptibility to P ‐gp. Combined with the EGF receptor inhibitor, erlotinib, MPT0B014 exerted significant growth inhibition of A549 cells both in vitro and in vivo . B014 could be useful as an anti‐cancer agent.