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Drug-like small molecule HSP27 functional inhibitor sensitizes lung cancer cells to gefitinib or cisplatin by inducing altered cross-linked Hsp27 dimers

Title
Drug-like small molecule HSP27 functional inhibitor sensitizes lung cancer cells to gefitinib or cisplatin by inducing altered cross-linked Hsp27 dimers
Authors
Yoo H.Choi S.-K.Lee J.Park S.H.Park Y.N.Hwang S.-Y.Shin J.-H.Na Y.Kwon Y.Lee H.J.Lee Y.-S.
Ewha Authors
이화정권영주이윤실이재옥황수연
SCOPUS Author ID
이화정scopusscopus; 권영주scopus; 이윤실scopus; 이재옥scopus
Issue Date
2021
Journal Title
Pharmaceutics
ISSN
1999-4923JCR Link
Citation
Pharmaceutics vol. 13, no. 5
Keywords
Combination therapyDrug resistanceEGFRHeat shock proteinHSP27HSP27 inhibitorNA49NSCLC
Publisher
MDPI AG
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
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. © 2021 by the authors.
DOI
10.3390/pharmaceutics13050630
Appears in Collections:
약학대학 > 약학과 > Journal papers
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