Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of \u3b4-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. \u3b4-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, \u3b4-TT exerted its antitumor effect through activation of the PERK/p-eIF2\u3b1/ATF4/CHOP, IRE1\u3b1 and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of \u3b4-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that \u3b4-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by \u3b4-TT treatment. In conclusion, \u3b4-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. \u3b4-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma

Ozarelix, a fourth generation GnRH antagonist, induces apoptosis in hormone refractory androgen receptor negative prostate cancer cells modulating expression and activity of death receptors

BACKGROUND AND AIMS. Antagonistic or agonistic analogues of gonadotropin-releasing hormone are extensively used for the treatment of advanced hormone-dependent prostate cancer. However, the majority of recurrent prostate tumors is androgen independent. This study explored the in vitro effects on DU145 and PC3 cell lines, two models of androgenindependent prostate cancer, of a fourth generation GnRH antagonist (Ozarelix). METHODS. Ozarelix was added to cultures and toxicity, cell cycle modifications, cell viability and caspase activity were investigated. RESULTS. Ozarelix showed antiproliferative effects and produced an accumulation of cells in G2/M cell cycle phase. Apoptosis was related with caspase-8-dependent caspase 3 activation with down-regulation of c-FLIP (L) and a sensitization to TRAIL-induced apoptosis linked also to increased expression and activity of death receptors DR4/5 and Fas. CONCLUSIONS. TRAIL-resistant cancer cells can be sensitized to TRAIL by Ozarelix. This effect may be achieved by the activation of apoptotic pathway improving the therapeutic effects in androgen independent tumor cell lines. However, a better understanding of molecular mechanisms by which GnRH antagonists may act in androgen independent models is necessary