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A Novel Combinatorial Strategy Using Seliciclib® and Belinostat® for Eradication of Non-Small Cell Lung Cancer via Apoptosis Induction and BID Activation. (Cancer Lett, Jun 2016)

Ong PS1, Wang L2, Chia DM1, Seah JY1, Kong LR3, Thuya WL3, Chinnathambi A4, Lau JA3, Wong AL5, Yong WP5, Yang D6, Ho PC1, Sethi G7, Goh BC8

1Department of Pharmacy, National University of Singapore, Singapore.
2Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, National University of Singapore, Singapore.
3Cancer Science Institute of Singapore, National University of Singapore, Singapore.
4Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
5Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Hematology & Oncology, National University Health System, Singapore.
6Department of Biological Science, National University of Singapore, Singapore.
7Department of Pharmacology, National University of Singapore, Singapore. Electronic address: gautam_sethi@nuhs.edu.sg.
8Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, National University of Singapore, Singapore; Department of Hematology & Oncology, National University Health System, Singapore. Electronic address: phcgbc@nus.edu.sg.

Abstract:

With conventional anticancer agents for non-small cell lung cancer (NSCLC) reaching therapeutic ceiling, the novel combination using histone deacetylase inhibitor, PXD101 (Belinostat®), and CDK inhibitor, CYC202 (Seliciclib®), was investigated as an alternative anticancer strategy. At clinically achievable concentration of CYC202 (15 µM), combination therapy resulted in significant reduction in cell proliferation (IC50 = 3.67 ± 0.80 µM, p < 0.05) compared with PXD101 alone (IC50 = 6.56 ± 0.42 µM) in p53 wild-type A549 cells. Significant increase in apoptosis that occurred independently of cell cycle arrest was observed after concurrent treatment. This result was corroborated by greater formation of cleaved caspase-8, caspase-3 and PARP. Up-regulation of p53 and truncated BID protein levels was seen while Mcl-1 and XIAP protein levels were down-regulated upon combined treatment. Further analysis of apoptotic pathways revealed that caspase inhibitors, but not p53 silencing, significantly abrogated the cytotoxic enhancement. Moreover, the enhanced efficacy of this combination was additionally confirmed in p53 null H2444 cells, suggesting the potential of this combination for treatment of NSCLC that are not amenable to effects of conventional p53-inducing agents.

PMID: 27461583