title: VER-155008, a small molecule inhibitor of HSP70 with potent anti-cancer activity on lung cancer cell lines.
abstract: Lung cancer is the most common malignancy and exhibits significant morbidity and mortality worldwide. Among all lung cancer subtypes, non-small-cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Although there have been intensive investigations on the underlying mechanism of NSCLC development and progression, the exact molecular basis is not well understood. Further insights on important molecular regulators of lung cancer are needed for development of novel therapeutics. The heat shock protein (HSP) family is a group of molecular chaperones that assist in protein folding, modification, and transportation. Different HSPs are essential for tumor cell survival by binding diverse client proteins and regulating homeostasis. In the current study, we sought to characterize HSP70 and HSP90 as potent regulators of NSCLC growth. Our results indicate that differential expression of HSP70 is associated with the malignant phenotype of NSCLC cell lines and plays an important regulatory role in NSCLC cell proliferation. Moreover, a specific inhibitor of HSP70, VER-155008 significantly inhibits NSCLC proliferation and cell cycle progression. We showed that this effect is largely abolished by HSP70 overexpression, indicating that the inhibitory effect of VER-155008 on cell growth is specifically through HSP70 inhibition. In addition, 17-AAD, an inhibitor of HSP90, exerts a potent synergistic effect on NSCLC proliferation with VER-155008. We also observed that inhibition of HSP70 by VER-155008 can sensitize A549 cells to ionizing radiation. These data provide proof-of-principle that VER-155008 can be a good candidate for NSCLC treatment and HSP machinery is a good target for developing NSCLC therapeutics.
authors.affiliation: Department of Thoracic Surgery, People's Hospital of Jiangsu Province, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.forename: Wuxin
authors.initials: W
authors.lastname: Liu
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shao
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D011684:Purine Nucleosides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D011684:Purine Nucleosides; C550733:VER 155008
keywords: 17-AAD; Heat shock protein 70; VER-155008; heat shock protein 90; non-small-cell lung cancer