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HSP Inhibitor Sensitize Resistant MCF-7 Cells to Doxorubicin through Suppressing HSP90AB4P Pseudogene and HSPB1

Kubra Acikalin Coskun1, Lütfi Tutar2, Elif Cansu Abay3

  • 1Division of Medicinal Biology, Department of Basic Medical Sciences, Istanbul Aydın University, Istanbul, Turkey.

Anti-Cancer Agents in Medicinal Chemistry
|June 13, 2025
PubMed
Abstract

Insights

A novel pyro-salicylic acid derivative (7A) effectively overcomes doxorubicin resistance in breast cancer by inhibiting heat shock proteins (HSPs), specifically HSP90AB4P and HSPB1. This combination therapy enhances apoptosis and cell cycle arrest, offering a promising strategy against treatment failure.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Doxorubicin resistance is a major challenge in treating breast cancer subtypes.
  • Heat shock proteins (HSPs), including HSP90 and its pseudogene HSP90AB4P, contribute to chemoresistance by regulating cancer cell survival pathways.
  • Investigating novel inhibitors to overcome this resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To evaluate the efficacy of a novel pyro-salicylic acid derivative (7A) in sensitizing doxorubicin-resistant breast cancer cells (MCF-7/ADR) to doxorubicin chemotherapy.
  • To investigate the molecular mechanisms underlying the action of 7A, focusing on HSPs and their pseudogenes.
  • To assess the synergistic effects of combining 7A with doxorubicin.

Main Methods:

  • Combination index (CI) analysis was used to determine synergistic and additive effects of 7A and doxorubicin at various concentrations.
  • Cell cycle progression was analyzed using flow cytometry.
  • Apoptosis assays were performed to quantify cell death.
  • Gene expression profiling via PCR arrays was employed to assess changes in molecular pathways.

Main Results:

  • The pyro-salicylic acid derivative (7A) demonstrated significant suppression of doxorubicin resistance in invasive breast ductal carcinoma cells.
  • Combination therapy with 7A and doxorubicin exhibited a synergistic effect (CI < 1), enhancing cytotoxicity.
  • 7A effectively decreased the expression of HSP90AB4P and HSPB1, key mediators of resistance.

Conclusions:

  • The novel inhibitor 7A successfully overcomes doxorubicin resistance in MCF-7/ADR cells by downregulating HSP90AB4P and HSPB1 expression.
  • This leads to increased apoptosis and cell cycle arrest, thereby enhancing the efficacy of doxorubicin treatment.
  • Targeting HSPB1 and HSP90AB4P with 7A presents a promising therapeutic strategy for overcoming doxorubicin resistance in breast cancer.
Keywords:
HSP inhibitorHSP90Pseudogenecell cyclechemotherapydoxorubicin resistance

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