HSP inhibitor sensitize resistant MCF-7 cells to doxorubicin through suppressing HSP90AB4P pseudogene and HSPB1 expression

Abstract

Introduction: Doxorubicin, a first-line chemotherapeutic agent, often faces resistance in breast cancer subtypes, leading to treatment failure. HSPs (Heat shock proteins), especially HSP90, and their pseudogenes like HSP90AB4P have been implicated in fostering resistance mechanisms by regulating apoptotic and survival pathways in cancer cells. The aim of this study is to investigate how inhibiting HSPs using a novel pyro-salicylic acid derivative (7A) can sensitize doxorubicin-resistant breast cancer cells (MCF-7/ADR) to chemotherapy. Methods: The potential role of HSP inhibitor with doxorubicin at different concentrations was tested to reveal synergetic and additive effects by combination index (CI) analysis. Cell cycle analysis, apoptosis assays, and gene expression profiling via PCR arrays supported the impact of 7A over MCF-7/ADR cells' molecular pathways. Results: HSP inhibitor efficiently suppressed doxorubicin resistance over invasive breast ductal carcinoma and has a synergetic effect. The inhibitor decreases HSP90AB4P and small HSPB1 expression efficiently. Conclusion: Our findings demonstrate that 7A suppresses doxorubicin resistance in MCF-7/ADR cells by reducing the expression of HSP90AB4P and small HSPB1, leading to an increase in apoptosis and cell cycle arrest. The combination of 7A and doxorubicin exhibits a synergistic effect (CI < 1), enhancing cytotoxicity and overcoming resistance mechanisms. The cells are driven to apoptosis and the inhibitor significantly decreases doxorubicin resistance. Targeting HSPB1 and its pseudogene HSP90AB4P with 7A offers a promising therapeutic strategy to overcome doxorubicin resistance in breast cancer.