Abstract
To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma.
Highlights
Uveal melanoma is the most common primary intraocular malignancy in adult population[1,2]
ABT-263 triggers apoptotic cell death of uveal melanoma cells We first conducted experiments to assess the effect of three ABT drugs, ABT-199, ABT-737 and ABT-263 on uveal melanoma cell proliferation using four human uveal melanoma cell lines
Uveal melanomas are genetically different from cutaneous melanomas and are highly resistant to the therapeutic options used to treat cutaneous melanomas
Summary
Uveal melanoma is the most common primary intraocular malignancy in adult population[1,2]. Despite enucleation or radiotherapy of the primary lesion, metastases develop in 50% of patients, mainly to the liver. These metastases are remarkably refractory to conventional chemotherapies, immunotherapy with checkpoint inhibitors and external radiotherapy[3,4]. The median survival of patients who develop liver metastasis is reported to be 4 to 15 months, and the one-year survival rate is estimated to be 10–15%4. This highlights an urgent need for an efficient treatment. Defective apoptosis, which contributes to sustained cell survival, is a major causative factor in the development and progression of cancer. The ability of a cell to undergo apoptosis is governed by members of the BCL-2 protein
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