Drug-Like Small Molecule HSP27 Functional Inhibitor Sensitizes Lung Cancer Cells to Gefitinib or Cisplatin by Inducing Altered Cross-Linked Hsp27 Dimers.

So Hyeon Park,Jaeok Lee,Youngjoo Kwon,Soo-Yeon Hwang,Yun-Sil Lee,Hawon Yoo,Younghwa Na,Seul-Ki Choi,Hwa Jeong Lee,Jae-Ho Shin,You Na Park

doi:10.3390/pharmaceutics13050630

Drug-Like Small Molecule HSP27 Functional Inhibitor Sensitizes Lung Cancer Cells to Gefitinib or Cisplatin by Inducing Altered Cross-Linked Hsp27 Dimers.

So Hyeon Park, Jaeok Lee + Show 9 more

Open Access

https://doi.org/10.3390/pharmaceutics13050630

Copy DOI

Journal: Pharmaceutics	Publication Date: Apr 28, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: Ewha Womans University, CHA University

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.

Highlights

We previously reported that J2, a chromenone, is an anticancer compound that inhibits heat shock protein 27 (HSP27) chaperonic activity by acting as a crosslinker to form altered dimerization of
We confirmed that NA49 formed altered dimerization of HSP27 with a very similar degree to that produced by the interaction of HSP27 with J2
HSP27 expression was reported to involve chemotherapy resistance, and our results suggest that a combination of cisplatin with HSP27 cross-linkers produced synergistic sensitization to non-small cell lung cancer (NSCLC) in epidermal growth factor receptors (EGFRs)-wild type (WT)

Summary

Introduction

Heat shock proteins (HSPs) are evolutionally conserved molecular chaperones that assist the conformational protein folding or unfolding for performing their normal biological functions and are required for protein homeostasis and cell survival, protecting organisms from environmental stresses such as heat shock, irradiation, and chemical agents [1]. Of several HSPs including HSP70, HSP90, and HSP60, overexpression of small heat shock protein. HSP27 ( known as HSPB1) is critical for cancer progression and metastasis and for the development of resistance to anticancer drugs [2]. HSP27 is frequently upregulated in the lung, breast, and pancreatic cancer cells and is involved in the cellular mechanisms of DNA repair, inhibition of apoptosis, and drug resistance [3,4,5].

Objectives

Results

Conclusion