Inhibition of leukemic cell growth by a novel anti-cancer drug (GUT-70) from Calophyllum brasiliense that acts by induction of apoptosis

Abstract

During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT-70, isolated from the stem bark of Calophyllum brasiliense collected in Brazil, significantly inhibits the growth of leukemic cells. GUT-70, characterized as a tricyclic coumarin, 5-methoxy-2,2-dimethyl-6-(2-methyl-1-oxo-2-butenyl) -10-propyl-2H,8H-benzo[1,2- b;3,4-b′]dipyran-8-one (C23H26O5), inhibited all 6 human leukemic cell lines evaluated, including the P-glycoprotein overexpressing cell line, in a concentration and time-dependent manner with IC50 values from 2-5 μM. Furthermore, GUT-70 did not inhibit colony formation by normal hematopoietic progenitors up to 30 μM and also did not inhibit the proliferation of normal human hepatocytes up to 30 μM. GUT-70 activated the caspase 2, 3, 8 and 9, and induced the apoptosis in leukemic cells, which was inhibited by caspase inhibitors. GUT-70 induced anti-leukemic effects independent of the p53-p21WAF1/CIP1 pathway and increased the overall expression of p27KIP1 and p57KIP2, to stop the cell cycle at the G1/S transition. Thus, a novel anti-cancer drug, GUT-70 isolated from the stem bark of C. brasiliense induces caspase-mediated and p53-independent apoptosis to overcome multidrug resistance and may become a potent leukemia therapeutics. © 2004 Wiley-Liss, Inc.