Arsenic trioxide as an anti-tumour agent: mechanisms of action and strategies of sensitization

Arsenic trioxide (As(2)O(3), ATO) is a very efficacious, clinically established agent for the treatment of acute promyelocytic leukaemia, and also potentially useful against other haematological and non-haematological malignancies. Nonetheless, the relative resistance of many tumour cell types requires the generation of sensitizing strategies. One of the properties of ATO which might be exploited for therapeutic purposes is its sensitivity to the intracellular oxidant state, as revealed by increased apoptosis production under conditions of reduced glutathione (GSH) depletion and/or elevated reactive oxygen species (ROS) content. This review summarizes some studies from our laboratory demonstrating that experimental modulation of protein kinase activities (PI3K/Akt, JNK, MEK/ERK) potentiates ATO-provoked apoptosis in relatively resistant human acute myeloid leukaemia (U937, HL60) cell lines by mechanisms involving GSH depletion and/or increased ROS content. In a similar manner, co-treatment with dietary flavonoides such as genistein, normally considered as anti-oxidants, may potentiate apoptosis via generation of moderate oxidative stress and activation of ROS-inducible protein kinases. Finally, co-treatment with ATO may sensitize otherwise refractory leukaemia cells to TNF alpha-family cytokine-produced apoptosis, by mechanisms involving the interplay between the "intrinsic" (mitochondrial) and "extrinsic" (death receptor-mediated) pathways.