Relationships between
heat shock protein 27 (HSP27) and
cancer aggressiveness,
metastasis, drug resistance, and poor patient outcomes in various
cancer types including
non-small cell lung cancer (NSCLC) were reported, and inhibition of HSP27 expression is suggested to be a possible strategy for
cancer therapy. Unlike HSP90 or HSP70, HSP27 does not have an
ATP-binding pocket, and no effective HSP27 inhibitors have been identified. Previously, NSCLC
cancer cells were sensitized to radiation and
chemotherapy when co-treated with small molecule HSP27 functional inhibitors such as
zerumbone (ZER), SW15, and J2 that can induce abnormal cross-linked HSP27 dimer. In this study,
cancer inhibition effects of NA49, a chromenone compound with better solubility, longer circulation time, and less toxicity than J2, were examined in combination with anticancer drugs such as
cisplatin and
gefitinib in NSCLC cell lines. When the cytotoxic
drug cisplatin was treated in combination with NA49 in
epidermal growth factor receptors (EGFRs) WT cell lines, sensitization was induced in an HSP27 expression-dependent manner. With
gefitinib treatment, NA49 showed increased combination effects in both EGFR WT and Mut cell lines, also with HSP27 expression-dependent patterns. Moreover, NA49 induced sensitization in EGFR Mut cells with a secondary mutation of T790M when combined with
gefitinib. Augmented
tumor growth inhibition was shown with the combination of
cisplatin or
gefitinib and NA49 in nude mouse xenograft models. These results suggest the combination of HSP27 inhibitor NA49 and
anticancer agents as a candidate for overcoming HSP27-mediated drug resistance in NSCLC patients.