Tasisulam-induced suicidal death of human erythrocytes.

Tasisulam, an acyl-sulfonamide compound, is being investigated in clinical trials for the treatment of several malignancies, including non-small cell lung cancer, lymphoma, breast cancer, melanoma, ovarian cancer, colon cancer, and other solid tumors, by promoting apoptosis. However, anemia is among the adverse consequences of tasisulam therapy and is potentially caused by increased eryptosis or premature erythrocyte senescence, characterized by cell contraction and phosphatidylserine (PS) translocation. Underlying signals associated with eryptosis include increased intercellular calcium activity ([Ca2+]i), oxidative stress, excess ceramide production, and stimulation of various kinases (protein kinase C, p38 kinase, casein kinase-1, etc.) or caspases. This research investigated the potential of tasisulam to induce eryptosis and its underlying signaling pathways. Human erythrocytes (0.4%) were incubated with 75, 150, or 300 μg/ml tasisulam for 48 h at 37°C. Flow cytometry revealed that tasisulam (≥300 μg/ml) significantly increased erythrocyte apoptosis, [Ca2+]i, reactive oxygen species (ROS), and ceramide formation without causing cell membrane shrinkage. The effect of tasisulam on erythrocyte death was significantly reduced by the removal of extracellular calcium or the inhibition of casein kinase. In conclusion, tasisulam triggers eryptosis by stimulating calcium influx, ceramide generation, oxidative stress, and casein kinase 1 activation, which may be associated with tasisulam-associated anemia.