In-vitro evaluation of HSP27 inhibitors function through HER2 pathway for ovarian cancer therapy

Abstract

Background: Heat shock protein 27 (HSP27) and human epidermal growth factor receptor 2 (HER2) are both attractive molecular targets for cancer therapy because of their cellular functions, which are proportionally up and down regulated in cancer cells. Previously, we synthesized a series of compounds known as HSP27 inhibitors using a nimesulide drug as a lead compound. Therefore, our hypothesis is to target HSP27 with inhibitors to stabilize HER2 receptor through HER2 pathway and reduce its expression.Methods: Three ovarian cancer cell lines (OVCAR3, SKOV3, and HEY1B) tested for HER2 over-expression by western blot assay and their cell growth inhibition were determined by the standard MTT assay.Results: Our findings using western blot assay revealed that SKOV3 cell line is an HER2 over-expression ovarian cancer cell line. In addition, the IC 50 data from MTT assay also proved that SKOV3 cell line adapted cell growth inhibition. Overall, the data indicated that down regulation of HSP27 in SKOV3 cells stabilized HER2 receptor expression through HER2 pathway. Conclusions:The development of series of anticancer agents that inhibit dual proteins may overcome the chemotherapy drug resistance and improve the survival of future ovarian cancer patients.

Nimesulide derivatives reduced cell proliferation against breast and ovarian cancer: synthesis, characterization, biological assessment, and crystal structure.

“…HSP27 expression is affected by stress conditions such as chemotherapy drugs (Ferms et al, 2006;Jego et al, 2013;Jaragh-Alhadad, 2018;Venugopal et al, 2019). Over-expression of HSP27 in cancer cells causes anti-apoptotic mechanism (Arya et al, 2007;Garrido et al, 2006;Paul et al, 2010) and cancer cell survival to lethal levels (Lianos et al, 2015;Vidyasagar et al, 2012) and metastasis (Pavan et al, 2013;Zhao et al, 2012).…”

“…It is a perfect strategy to treat breast and ovarian cancer cells with nimesulide derivatives to target multi-cellular proteins in one shot (Jaragh-Alhadad 2018;Jaragh-Alhadad et al, 2021).…”

Methoxybenzamide derivative of nimesulide from anti-fever to anti-cancer: Chemical characterization and cytotoxicity

“…In addition, studies proved that the nimesulide drug is one of the NSAID drugs ( Ward and Broagden, 1988 ; Giuliano & Warner, 1999 ) and is characterized for its anti-proliferation property ( Banti et al, 2016 , Catarro et al, 2019 , Jaragh-Alhadad, 2018 , Jaragh-Alhadad et al, 2022 ). Furthermore, Banti et al synthesized and characterized nimesulide derivatives silver metallodrugs.…”

Development of Nimesulide Analogues as Dual Tubulin and HSP27 Inhibitor for Treating Female Cancers

“…In the previous reports, the scientists established many potent agents that targeted HSP27 function and showed cytotoxicity against ovarian cancer cell lines. 22 Based on these dual reliable protein biomarkers 15 tubulin and HSP27. 8,9 In the last years, new agents were developed with dual targeting both tubulin and HSP27 proteins for breast cancer treatment using chaperonin and tubulin polymerization inhibition assays.…”