A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC

• Published in: British journal of cancer 2010-01, Vol.102 (1), p.97-103
• Main Authors: Dean, E J, Ward, T, Pinilla, C, Houghten, R, Welsh, K, Makin, G, Ranson, M, Dive, C
• Format: Article
• Language: English
• Subjects: Aniline Compounds - administration & dosage; Aniline Compounds - pharmacology; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor - drug effects; Cisplatin - administration & dosage; Cisplatin - pharmacology; Cytotoxins - administration & dosage; Cytotoxins - pharmacology; Drug Administration Schedule; Drug Resistance; Drug Screening Assays, Antitumor; Drug Synergism; Epidemiology; Humans; Lung Neoplasms - pathology; Medical sciences; Molecular Medicine; Neoplasm Proteins - antagonists & inhibitors; Oncology; Pneumology; Translational Therapeutics; Tumor Stem Cell Assay; Tumors; Tumors of the respiratory system and mediastinum; Vinblastine - administration & dosage; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605418

Background: Evasion of apoptosis contributes to the pathogenesis of solid tumours including non-small cell lung cancer (NSCLC). Malignant cells resist apoptosis through over-expression of inhibitor of apoptosis proteins (IAPs), such as X-linked IAP (XIAP). Methods: A phenylurea-based small molecule inhibitor of XIAP, XIAP antagonist compound (XAC) 1396-11, was investigated preclincally to determine its ability to sensitise to clinically relevant cytotoxics, potentially allowing dose reduction while maintaining therapeutic efficacy. Results: XIAP protein expression was detected in six NSCLC cell lines examined. The cytotoxicity of XAC 1396-11 against cultured NSCLC cell lines in vitro was concentration- and time-dependent in both short-term and clonogenic assays. XAC 1396-11-induced apoptosis was confirmed by PARP cleavage and characteristic nuclear morphology. XAC 1396-11 synergised with vinorelbine±cisplatin in H460 and A549 NSCLC cells. The mechanism of synergy was enhanced apoptosis, shown by increased cleavage of caspase-3 and PARP and by the reversal of synergy by a pan-caspase inhibitor. Synergy between XAC 1396-11 and vinorelbine was augmented by optimising drug scheduling with superior effects when XAC 1396-11 was administered before vinorelbine. Conclusion: These preclinical data suggest that XIAP inhibition in combination with vinorelbine holds potential as a therapeutic strategy in NSCLC.