Publicación: Evaluación de la eficacia terapéutica de sulforafano y docetaxel sobre un modelo in vitro de cáncer de próstata
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Prostate cancer (PC) is the fifth leading cause of death worldwide and the second most diagnosed malignancy in men, being the leading cause of death in the Colombian male population. Prostate cancer cells show abnormal metabolic and redox activity, and emerging evidence indicates that the behavior of this type of cancer has been related to aggressive tumor characteristics such as chemoresistance, invasiveness, and metastatic potential, among others. In addition, drugs used in clinical oncology have narrow therapeutic indexes with adverse toxicity, often involving oxidative damage to normal tissues. Docetaxel (DCT) is an antineoplastic drug used to treat PC; its cytotoxicity and emerging resistance have limited its efficacy. Combination therapies are intended to sensitize tumors and protect unaffected tissues, which increases the therapeutic index. Sulforaphane (SFN) is a phytochemical of broad clinical interest due to its anticancer properties and promising effects in combination therapies. Consequently, the present research aimed to evaluate the therapeutic efficacy of SFN and DCT on an in vitro model of PC with different sensitivity to chemotherapy as an antitumor strategy. In this experimental-type investigation, PC cell lines with different levels of tumorigenicity and chemoresistance, as well as the non-tumorigenic counterpart, were used to offer different redox and metabolic characteristics. RWPE-1, LNCAP, and PC3 cell lines were seeded at a density of 5x103 cells/well in 96-well culture plates and treated with SFN and DCT for 72 h to determine effects on viability, mitochondrial activity, and cell death. Possible interactions of treatments were analyzed by isobologram analysis at 48 h. At the same time, promising mean concentrations in a combination of IC50 of SFN and DCT were evaluated for their effect on glycolytic and redox metabolism by analysis of glucose consumption and lactate production, intracellular levels of Reactive Oxygen Species (ROS), relative mitochondrial mass; the antioxidant status with the measurement of reduced (GSH) and oxidized (GSSG) Glutathione, finally the expression of SOD2 and LDHA genes regulated by Nrf2 and HIF1- α. The results obtained showed reduced viability of LNCAP and PC3 tumor cells after SFN and DCT treatments in a dose- and time-dependent manner. Lower sensitivity to treatments was observed in non-tumor RWPE-1 cells. Isobologram analysis indicated a possible synergistic effect between SFN and DCT. SFN IC50s showed mitochondrial activity measured by MTT in tumor cells. The combination of SFN and DCT triggered apoptosis in tumor models by inducing an increase in ROS levels, an increase in mitochondrial mass in LNCAP cells, a down-regulation of LDHA, and a decrease in lactate levels. Despite the induction of apoptosis by the treatments in PC3 cells, no significant chemo sensitization of redox and glycolytic metabolism was observed, suggesting the existence of differences in the glycolytic pathway of the tumor cell models, as well as an essential antioxidant defense system that could be evading cell death induced by the combination treatments, the findings of this study could link other sensitization pathways that modulate the viability or death of these cells. These results are the first to demonstrate effects on redox and glycolytic metabolism of SFN and DCT interaction in CP cells.