Synergistic Anti-Cancer Effects of Arsenic Trioxide and Paclitaxel On Human Malignant Lymphocytes.

Abstract 4809

Arsenic trioxide (ATO), an effective drug in the treatment of acute promyelocytic leukemia (APL), and its combination with other chemotherapeutic drugs have been shown to present some activities in other malignant cells besides APL. Increasing reports showed that ATO produces mitotic arrest possibly through targeting to tubulins before apoptosis induction in human tumor cells. Aberrations in the control of cell cycle progression occur in the majority of human malignancies; hence, tubulins are promising targets for anticancer therapy. Here, we define the cellular effects with ATO, alone or in association with paclitaxel, the first identified microtubules stabilizing agent, with respect to inhibition of cell proliferation and cell cycle progression and induction of apoptosis in malignant lymphocytic cell lines Jurkat, Raji, and NAMALWA as well as fresh acute lymphocytic leukemic (ALL) cells. Our results showed that the co-treatment of ATO and PTX at their lower concentrations could significantly induce mitotic arrest followed by growth inhibition and apoptosis in these cell lines. The combined treatment of ATO with PTX also synergistically decreased the cell viability in primary ALL cells. In vivo and in vitro experiments showed that the combination treatment did not increase the microtubules polymerization compared to ATO or PTX treatment alone. Instead, this synergistic action was attributed to the increase of phosphorylation of cyclin-dependent kinase 1 (Cdk1) on Thr161 and the promotion of the dysregulated activation of Cdk1. Furthermore, we found that the ATO/PTX combination significantly enhanced the activation of spindle checkpoint by inducing the formation of the inhibitory checkpoint complex BubR1/Cdc20. These results provide a rational basis for clinical trials of the combined regimen of ATO and PTX in the treatment of lymphocytic neoplasm.