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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
- Source :
- Pharmaceutics, Vol 13, Iss 630, p 630 (2021), Pharmaceutics, Volume 13, Issue 5
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
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.
- Subjects :
- endocrine system
animal structures
EGFR
heat shock protein
Pharmaceutical Science
HSP27
HSP27 inhibitor
NSCLC
Article
Metastasis
combination therapy
03 medical and health sciences
T790M
0302 clinical medicine
Gefitinib
Pharmacy and materia medica
Epidermal growth factor
medicine
Lung cancer
030304 developmental biology
Cisplatin
0303 health sciences
drug resistance
Chemistry
Cancer
medicine.disease
respiratory tract diseases
RS1-441
030220 oncology & carcinogenesis
Cancer cell
embryonic structures
Cancer research
NA49
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19994923
- Volume :
- 13
- Issue :
- 630
- Database :
- OpenAIRE
- Journal :
- Pharmaceutics
- Accession number :
- edsair.doi.dedup.....b4b83136e77d37af44acd81793600bdd