title: A novel combinatorial strategy using Seliciclib(®) and Belinostat(®) for eradication of non-small cell lung cancer via apoptosis induction and BID activation.
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.
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Pei-Shi
authors.initials: PS
authors.lastname: Ong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Deborah Miao-Hui
authors.initials: DM
authors.lastname: Chia
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Jolyn Yu-Xin
authors.initials: JY
authors.lastname: Seah
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Li-Ren
authors.initials: LR
authors.lastname: Kong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Win-Lwin
authors.initials: WL
authors.lastname: Thuya
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Arunachalam
authors.initials: A
authors.lastname: Chinnathambi
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Jie-Ying Amelia
authors.initials: JY
authors.lastname: Lau
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Hematology & Oncology, National University Health System, Singapore.
authors.forename: Andrea Li-Ann
authors.initials: AL
authors.lastname: Wong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Hematology & Oncology, National University Health System, Singapore.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Department of Biological Science, National University of Singapore, Singapore.
authors.forename: Daiwen
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Paul Chi-Lui
authors.initials: PC
authors.lastname: Ho
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore. Electronic address: gautam_sethi@nuhs.edu.sg.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Cancer 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.
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
mesh_terms: D000072283:A549 Cells; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000819:agonists* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D034622:RNA Interference; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D061945:Caspase Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011687:Purines; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077546:Roscovitine; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; C487081:belinostat
keywords: Belinostat(®); Caspase-8 activation; Non-small cell lung cancer; Seliciclib(®); Truncated BID