Is the antioxidant capacity of flavonoids responsible for their anticancer effects? The case of quercetin in leukemia.

The concept that flavonoids, possessing well-known and characterized antioxidant capacity, can fight cancer is deeply rooted in the general population. On the opposite, a current of thought, argued by eminent scientists, attributes to free radical-destroying antioxidants the responsibility to negatively affect cancer incidence and therapy. The field is even more challenging considering that flavonoids possess both antioxidants and pro-oxidant activities and recent publications suggest that their beneficial anticancer effects can be easier explaining evoking the pro-oxidant capacity than the antioxidant one. In the present communication, we will analyze clinical and pre-clinical studies facing these sometimes paradoxical and contradictory concepts proposing that a clear distinction must be done between the use of flavonoids in cancer treatment versus cancer prevention, starting from adequate and specifically selected cellular and animal models. Among the multiple examples, the case of quercetin in chronic lymphocytic leukemia (CLL) will be considered. Quercetin, the most abundant flavonoid present in the diet, is able to modulate several hallmarks of cancer, including resistance to apoptosis. Our studies on this compound allowed us to decipher the biochemical pathway triggered by quercetin leading to demonstrate its capacity to synergistically sensitize several leukemia cell lines and B-cells isolated from CLL patients when associated with different classes of anticancer drugs. We also identified in the protein kinase CK2 the direct and primary target of quercetin, whose inhibition is correlated with the down-regulation of the PI₃K/Akt signaling pathway and the massive apoptosis observed in CLL-derived cells. These data will be commented at the light of the very rapidly cellular uptake of quercetin and its capacity to lower intracellular concentrations of free radical species. Finally, considering the low toxicity of quercetin in normal peripheral blood cells, we will propose the design of clinical trials aimed to demonstrate its efficacy as a potential chemopreventive agent in the early phase of CLL.