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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

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

An-Chi Tsai, Hui-Chen Pai, Chih-Ya Wang, Jing-Ping Liou, Che-Ming Teng, Jing-Chi Wang, Shiow-Lin Pan

Br J Pharmacol. 2014 Jan;171(1):122-33.

PMID: 24116948

Abstract:

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 Western 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 Mcl-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1215208595	MPT0B014		1215208-59-5	Price

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