Classification: Antibiotics and Chemotherapeutics.
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
Article first published online: 10 DEC 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Volume 171, Issue 1, pages 122–133, January 2014
How to Cite
Tsai, A.-C., Pai, H.-C., Wang, C.-Y., Liou, J.-P., Teng, C.-M., Wang, J.-C. and Pan, S.-L. (2014), 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. British Journal of Pharmacology, 171: 122–133. doi: 10.1111/bph.12427
An-Chi Tsai, Hui-Chen Pai and Chih-Ya Wang contributed equally to this work.
- Issue published online: 10 DEC 2013
- Article first published online: 10 DEC 2013
- Accepted manuscript online: 30 SEP 2013 09:24AM EST
- Manuscript Accepted: 11 SEP 2013
- Manuscript Revised: 30 AUG 2013
- Manuscript Received: 15 MAY 2013
- National Science Council of Taiwan. Grant Number: NSC 99-2320-B-038-020-MY3
- Taipei Medical University. Grant Number: TMU101-AE1-B48
- mitosis arrest;
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).
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.
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.