Mitochondrial Apoptosis and G0/G1-Phase Blockade: Key Mechanisms Underlying Triphenyltin(IV) Dithiocarbamate-Mediated Cytotoxicity in Human Lymphoblastic Leukemia Cells

Abstract Recent findings highlight organotin(IV) compounds as effective anticancer agents, especially for leukemia, offering a potential advancement in cancer therapy by inhibiting cell proliferation with reduced toxicity and resistance issues. Five novel di- and triphenyltin(IV) dithiocarbamate compounds (OC1-OC5) were tested against Jurkat E6.1 human lymphoblastic leukemia cells. All compounds produced potent cytotoxic effects by inducing 55% − 86% of apoptotic events at their respective IC₅₀ values, 7.1 µM (OC1), 0.1 µM (OC2), 2.8 µM (OC3), 0.2 µM (OC4) and 0.35 µM (OC5). OC2 [Ph3Sn(N,N-diisopropyldithiocarbamate)] was the most potent, with an IC₅₀ of 0.1 µM and a selectivity index (SI) of 5.5, leading to further investigation. Mechanistic studies revealed that OC2 triggers apoptosis in Jurkat cells via the intrinsic pathway by disrupting mitochondrial membranes. This was initiated by DNA damage, leading to excessive reactive oxygen species (ROS) production and activation of caspase cascade (-9, -8, -3). Pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) significantly reduced apoptosis, confirming oxidative stress involvement. OC2 also caused G₀/G₁ cell cycle arrest and upregulated cleaved-PARP and p21. These findings reveal the anti-proliferative ability of OC2 in a Jurkat T lymphoblastic leukemia cell model, which warrants further investigation for its antileukemic potential and therapeutic value.