Sensitization of lung cancer cells by altered dimerization of HSP27

Abstract

Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells.

Small Heat Shock Proteins in Cancers: Functions and Therapeutic Potential for Cancer Therapy

“…Despite studies showing that quercetin can be a suitable agent for cancer treatment, there are no ongoing anticancer trials for quercetin. J2, a synthetic chromone compound, can induce the crosslinking of HspB1 protein and form HspB1 abnormal dimerization, thereby inhibiting its functions [160]. Recently, ovatodiolide [132] and methyl antcinate [161], two plant-derived compounds, have been reported to decrease HspB1 protein expression in breast CSCs and inhibit CSCs.…”

Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment ?

“…Moreover, the altered dimerization of HSP27 can sensitize cancer cells with high HSP27 expression [32]. This strategy is expected to overcome drug development currently limited by the absence of HSP27 inhibitors and presents the possibility of the development of novel HSP27 inhibitors (Fig.…”

“…According to recent studies, zerumbone [45], isolated from a natural product, and SW15, a xanthone compound sensitized cancer cells in combination with radiation. J2, a synthetic chromone compound, has a pharmacophore structure and more potent cross-linking activity than SW15 [32]. Therefore, the alteration of cross-linking is considered to be a novel strategy for the Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 4 July 2019 doi:10.20944/preprints201907.0081.v1…”

“…Increased HSP27 expression correlates with shorter survival of NSCLC patients. [32,70,71] Gastric Meta-analysis of gastric cancer is strongly dependent on the overexpression of HSP27. [72,73] Rectal High expression of HSP27 represents poor survival in rectal cancer.…”

The Association Between Heat-Shock Protein Polymorphisms and Prognosis in Lung Cancer Patients Treated With Platinum-Based Chemotherapy

“…The SNPs of HSPB1 rs7459185 was associated with radiation esophagitis in lung cancer through the regulation of HSPB1 expression level (Delgado et al, 2019). HSPB can regulate aggressive tumor behavior, metastasis, poor prognosis, and resistance to chemotherapy through the interference with theses effectiveness of targeted agents (Choi et al, 2017). There was one report about HSPB polymorphism found to be associated with NSCLC prognosis, in the US patients, it found that the CC genotype of HSPB1 rs2868371 was associated with poorer overall survival in US patients with NSCLC after radio (chemo)therapy (Xu et al, 2012).…”