Sodium meta-arsenite induces reactiveoxygen species-dependent apoptosis.necrosis,
and autophagy in bothandrogen-sensitive and androgen-insensitive prostate cancer cells.
Yunlim Kima, In Gab Jeong, Dalsan You, Sang Hoon Song, Nayoung Suh, Sung-Wuk Jang,
Sujong Kim, Jung Jin Hwang, Choung-Soo Kim
Abstract
Sodium meta-arsenite(NaAsO2), a novel compound synthesized by KomiphamInternational Co. Ltd, is an orally bioavailable, water-soluble trivalent
arsenical that has shown potent cytotoxicactivity in human solid cancer cells in vitro and in vivo, and is currently undergoing phase I/II clinical trials for the treatment of prostate cancer. In this study, mechanisms of cell death induced by sodium meta-arsenitewere investigated. Sodium meta-
arsenitereduced cell viability and increased the sub-G1 population in cell cycle analysis in both androgen-sensitive LNCaP and androgen-insensitive CWR22RV1 cells. The apoptosis induced by sodium meta-arsenitewas associated with cleavage of caspases3, 8, and 9, and poly (ADP-ribose) polymerase (PARP) and increased annexinV-positive cells, and was inhibited by the pan-caspaseinhibitor Z-VAD-fmk. Sodium meta- rsenitealso increased the level of the autophagymarker microtubule-associated protein 1 light chain 3 (LC3)-II and the number of autophagicvacuoles as shown by electron microscopy. Both the autophagyinhibitor 3-methyladenine and the necrosis inhibitor necrostatin-1 blocked cell death induced by sodium meta-arsenite. Moreover, sodium meta-arsenite led to the accumulation of intracellular reactive oxygen species (ROS) and N-acetyl-L-cysteine(NAC), a ROS scavenger, decreased sodium meta-arsenite-induced levels of cleaved PARP and LC3-II. Propidiumiodide (PI) staining also showed that NAC restored membrane integrity, damaged by sodium meta-arsenite. Therefore, these results suggest that sodium meta-arsenite induces apoptotic, necrotic, and autophagiccell death through intracellular ROS accumulation in both androgen-sensitive and androgen-insensitive prostate cancer cells and may be used as a new anticancer drug for the treatment of prostate cancer.
