[Cytotoxicity of beta-lapachone, an naphthoquinone with possible therapeutic use].
beta-lapachone (beta-lap) is a lipophilic o-naphthoquinone isolated from the bark of the lapacho tree. Initial observations proved its capability for inhibiting growth of Yoshida tumor and Walker 256 carcinosarcoma. beta-Lap redox-cycling in the presence of reductants and oxygen yields "reactive oxygen species" (ROS: O2-, OH and H2O2) which cytotoxicity led to assume its role in beta-lap activity in cells. beta-Lap inhibited DNA synthesis in Trypanosoma cruzi as well as topoisomerases I and II, poly(ADP-ribose) polymerase (PARP) in different cells. These enzymes are essential for maintaining DNA structure. beta-Lap inhibited growth of a large variety of tumor cells including epidermoid laringeal cancer, prostate, colon, ovary and breast cancer and also different types of leukemia cells. Advances in knowledge of apoptosis ("programmed cell death") and necrosis provided useful information for understanding the mechanism of beta-lap cytotoxicity. Thiol-dependent proteases (Calpaine), kinases (e.g. c-JUN NH2-terminal kinase), caspases and nucleases are involved in beta-lap cytotoxicity. These enzymes activity, as well as ROS production by beta-lap redox-cycling, would be essential for beta-lap cytotoxicity. Diaphorase and NAD(P)H-quinone reductase, which catalyse beta-lap redox-cycling and ROS production, seem to play an essential role in beta-lap activity. On these grounds, clinical applications of beta-lap have been suggested.
Dubin
M
M
Centro de Investigaciones Bioenergéticas, Facultad de Medicina (UBA-CONICET), Universidad de Buenos Aires.
Fernandez Villamil
S H
SH
Stoppani
A O
AO
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002279:Carcinoma 256, Walker / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000502:physiology*; D012517:Sarcoma, Yoshida / Q000188:drug therapy / Q000201:enzymology; D059004:Topoisomerase I Inhibitors
D000903:Antibiotics, Antineoplastic; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D059004:Topoisomerase I Inhibitors; C014638:beta-lapachone; D011065:Poly(ADP-ribose) Polymerases