Mitochondrial functional and structural impairment is involved in the antitumor activity of δ-tocotrienol in prostate cancer cells.

The therapeutic options for castration resistance prostate cancer (CRPC) are still limited. Natural bioactive compounds were shown to possess pro-death properties in different tumors. We previously reported that δ-tocotrienol (δ-TT) induces apoptosis, paraptosis and autophagy in CRPC cells. Here, we investigated whether δ-TT might exert its activity by impairing mitochondrial functions. We demonstrated that, in PC3 and DU145 cells, δ-TT impairs mitochondrial respiration and structural dynamics. In both cell lines, δ-TT triggers mitochondrial Ca2+ and ROS overload. In PC3 cells, both Ca2+ and ROS mediate the δ-TT-related anticancer activities (decrease of cell viability, apoptosis, paraptosis, autophagy and mitophagy). As expected, in autophagy-defective DU145 cells, Ca2+ overload was involved in δ-TT-induced pro-death effects but not in autophagy and mitophagy. In this cell line, we also demonstrated that ROS overload is not involved in the anticancer activities of δ-TT, supporting a low susceptibility of these cells to ROS-related oxidative stress. Taken together, these data demonstrate that, in CRPC cells, δ-TT triggers cell death by inducing mitochondrial functional and structural impairments, providing novel mechanistic insights in its antitumor activity.

Free radical biology & medicine. 2020 Jul 29 [Epub ahead of print]

Fabrizio Fontana, Michela Raimondi, Monica Marzagalli, Matteo Audano, Giangiacomo Beretta, Patrizia Procacci, Patrizia Sartori, Nico Mitro, Patrizia Limonta

Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Environmental Science and Policy, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Biomedical Sciences for Health, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Biomedical Sciences for Health, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy. Electronic address: ., Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy. Electronic address: .