![]() Indeed, tumor cells are extremely stingy with iron that is involved and required in various biochemical pathways during tumor progression. In pathological conditions like cancer, iron has been found to be closely related to the key processes regulating tumor onset and progression. Iron (Fe) is an essential redox element directly involved in many pivotal cell functions ranging from oxygen transport through hemoglobin to cell detoxification. ![]() In most cases, after an initial and successful response of about 12–24 months, prostate tumors regrow and become independent from androgens originating the so called stage termed castration-resistance prostate cancer (CRPC), that is characterized by poor prognosis. To date, the standard care for PCa patients is represented by the androgen deprivation therapy (ADT). In the clinic, prostate lesions are extremely heterogeneous and characterized by different clinical behaviors ranging from premalignant to very aggressive lethal tumors. Prostate cancer (PCa) represents the third most common malignancy worldwide and is a leading cause of death in the male population. These data open new perspectives in the use of pro-ferroptotic approaches alone or in combination with enzalutamide for the treatment of PCa. Moreover, the combination with the second generation anti-androgen drug enzalutamide potentiates the effect of the RS元 + iron combination leading to superior inhibition of PCa and preventing the onset of CRPC in the TRAMP mouse model. ![]() Exploiting in vitro and in vivo human and murine PCa models and the multistage transgenic TRAMP model of PCa we show that RS元 induces ferroptosis in PCa cells and demonstrate for the first time that iron supplementation significantly increases the effect of RS元 triggering lipid peroxidation, enhanced intracellular stress and leading to cancer cell death. ![]() Ferroptosis is a recently described form of cell death that requires abundant cytosolic labile iron to promote membrane lipid peroxidation and which can be induced by agents that inhibit the glutathione peroxidase-4 activity such as RS元. Prostate cancer (PCa) is a leading cause of death in the male population commonly treated with androgen deprivation therapy that often relapses as androgen-independent and aggressive castration-resistant prostate cancer (CRPC). ![]()
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