Heat shock protein 90α inhibitor, PU-H71 in combination with DHEA promoting apoptosis in triple-negative breast cancer cell line MDA-MB-231

Abstract

Due to the lack of markers (ER, PR, and HER-2/Neu) for the molecular-targeted therapies triple-negative breast cancer (TNBC) is more challenging than other subtypes of breast cancer. Moreover, the conventional chemotherapeutic agents are still the mainstay of most therapeutic protocols and eventually turn into a refractory drug-resistance , hence, more efficient therapeutic regimens are urgently required. The present study aimed to elucidate the effects of PU-H71 combined with DHEA on triple-negative breast cancer cell line MDA-MB-231 and to assess the synergy using the Chou-Talalay method. The combined therapy controlled the expression of an array of antioxidants and metabolizing enzymes, leading to the induction of oxidative stress which in turn induced apoptotic cell death. Our results indicated that the combined treatment with PU-H71 and DHEA exerts a synergistic anti-tumor effect on MDA-MB-231 triple-negative breast cancer cell line.

Unraveling Biomarker Signatures in Triple-Negative Breast Cancer: A Systematic Review for Targeted Approaches

“…Notably, heat shock protein 90 (Hsp90), found to be highly expressed in BC, plays a vital role in sustaining cancer cell survival, and is involved in several molecular processes contributing to carcinogenesis. Therefore, inhibiting its function represents a promising avenue for therapeutic intervention [ 41 , 42 ]. In a study targeting TNBC xenografts with the Hsp90 inhibitor, PU-H71, tumor growth was suppressed and a significant killing of TNBC cells was induced.…”

“…Additionally, Hsp90 inhibition resulted in a downregulation or inactivation of the Ras/Raf/MAPK pathway and G2M phase, degradation of Akt and Bcl-XL, and inhibition of NF-kb, ERK2, Tyk2, and PKC, both in vivo and in vitro, suggesting that the anti-proliferative effect of PU-H71 directly stems from depleting TNBC cells of these malignancy-driving proteins and that Hsp90 represents a pivotal multimodal target for future therapeutic strategies [ 42 ]. In another study, the combination of PU-H71 with DHEA, a glucose-6-phosphate dehydrogenase (G6PD) inhibitor, demonstrated a synergistic anti-tumor effect on TNBC cells by suppressing Nrf2, a key transcription factor regulating antioxidants and metabolic enzymes and leading to apoptosis, suggesting that G6PD inhibitors could be valuable additions to combination therapies targeting cellular oxidative balance [ 41 ].…”

Heat shock protein 90: biological functions, diseases, and therapeutic targets

“…Studies have shown that PU-H71 triggers apoptosis of triple-negative breast cancer (TNBC) cells and downregulates expression of key factors such as VEGF, EGFR and Akt, thus inhibiting tumor growth. [217][218][219] A phase I clinical trial assessed the safety and feasibility of combining PU-H71 with nab-paclitaxel in patients with metastatic breast cancer, showing promising results (No: NCT03166085). 220 BIIB021 is a synthetic, novel, and orally available HSP90 inhibitor commonly used for the clinical treatment of solid tumors.…”

“…Further structural modification results in the development of PU‐H71. Studies have shown that PU‐H71 triggers apoptosis of triple‐negative breast cancer (TNBC) cells and downregulates expression of key factors such as VEGF, EGFR and Akt, thus inhibiting tumor growth 217–219 . A phase I clinical trial assessed the safety and feasibility of combining PU‐H71 with nab‐paclitaxel in patients with metastatic breast cancer, showing promising results (No: NCT03166085) 220 …”