Efeito da interação entre fármacos indutores de morte celular imunogênica e proteínas de choque térmico no estresse de retículo endoplasmático

Abstract

Tumor resistance represents a significant challenge in oncology therapy, underscoring the necessity for new targets and treatment approaches. Immunogenic cell death (ICD)

is a distinct form of regulated cell death characterized by the presentation of damage- associated molecular patterns (DAMPs). This process can elicit a tumor-specific

immune response, thereby improving patient prognosis and overcoming resistance to treatment. Heat shock proteins (HSPs) have emerged as promising targets in oncology. Chemotherapeutic agents that induce ICD, such as cisplatin and paclitaxel, have the capacity to inhibit the chaperone HSP90. This study utilized in silico methodologies to examine the interactions between the chemotherapeutics doxorubicin (DOX), daunorubicin (DAU), etoposide, mitoxantrone (ICD inducers), geldanamycin, 17-AAG (pan-inhibitors of HSP90), staurosporine (STA), and 5-fluorouracil (5-FU) (non-ICD inducers) with the N-terminal subunits of the chaperones HSP90A and GRP94. The most favorable in silico interactions were observed between DOX, DAU, and 17-AAG with the chaperone GRP94, and between STA and the chaperone HSP90A. The effects of DOX and STA on endoplasmic reticulum (ER) stress were investigated in human breast cancer cell lines MDA-MB-231 and MCF-7. The modulation of ER-related protein expression was assessed via western blotting, and the drugs were tested both individually and in combination with IRE1α (Kira6, 1μM) and PERK (GSK2606414, 5μM) inhibitors. STA treatment led to an increase in BiP protein expression in the MDA-MB-231 cell line, whereas DOX treatment resulted in a decrease in BiP expression in MCF-7 cells. Phosphorylation of eIF2α was elevated in response to both DOX and STA treatments, with GSK2606414 effectively reversing this effect in MCF-7 cells. Colony formation assays revealed a significant reduction in cell growth across all chemotherapeutic treatments. Inhibitors of IRE1α and PERK had no significant impact on colony formation, except for Kira6 in the MDA-MB-231 cell line. The results of this study are consistent with existing literature on DOX and provide new insights into ER stress induced by STA.