ANTIPROLIFERATIVE ACTIVITY OF QUERCETIN ON NORMAL BONE-MARROW AND LEUKEMIC PROGENITORS

We used an in vitro clonogenic assay in semi-solid medium to test the sensitivity of normal bone marrow and acute myeloid and lymphoid leukaemia progenitors to the flavonol quercetin. We have studied 14 acute myeloid (AML) and four acute lymphoid (ALL) leukaemias. All ALL and the vast majority of AML (12/14) had a high sensitivity to quercetin with more than 50% growth inhibition at 2 x 10(-6) M quercetin. One M3-AML was partially quercetin-sensitive displaying 60% surviving AML-colony forming units (CFU-AML) at a quercetin concentration of 10(-5) M. One M1-AML was resistant to the growth inhibitory effect of quercetin at a concentration of 2 x 10(-5) M. The clonogenic efficiency of both AML and ALL positively correlated with leukaemic colony-forming unit (CFU-L) sensitivity to quercetin suggesting that this parameter can be useful in predicting quercetin responsiveness of leukaemic cells. We have also studied the effect of various quercetin concentrations on colony formation by normal bone marrow cells. At a quercetin concentration of 10(-5) M, we observed (in five different experiments) a mean recovery of 53% and 65% of erythroid blast-forming units (BFU-E) and granulocyte-macrophage colony-forming units (CFU-GM), respectively. Thus, normal bone marrow appeared partially resistant to quercetin, being inhibited less than 50% by quercetin concentration higher than 2 x 10(-5). When normal bone marrow were deprived in CD34+ haematopoietic progenitors the resultant population became highly sensitive to quercetin, with a mean recovery of BFU-E and CFU-GM of 5% and 12% of controls respectively in the presence of 2 x 10(-5) M quercetin. Furthermore, CD34 progenitors, positively selected, appeared fully resistant to quercetin concentrations as high as 2 x 10(-5) M. Thus, CD34+ progenitors are a quercetin-resistant component in normal bone marrow. In conclusion, our results further provide a biological basis for the therapeutic use of quercetin, considering that this compound could inhibit leukaemic cell growth without suppressing normal haematopoiesis.