[Mechanism of DNA damage and apoptosis induced by anticancer drugs through generation of reactive oxygen species].
A number of anticancer drugs exert their effect by causing DNA damage and subsequent apoptosis induction. Reactive oxygen species (ROS), such as hydrogen peroxide (H(2)O(2)) and super oxide anion (O(2)(-)), participate in apoptosis and DNA damage induced by some anticancer drugs, however, the precise mechanism of apoptosis via ROS formation remains to be clarified. I investigated the mechanism of apoptosis and DNA damage induced by anticancer drugs, especially topoisomerase inhibitors, using human cultured cells. TAS-103, a topoisomerase inhibitor, induces apoptosis through DNA cleavage and subsequent H(2)O(2) generation mediated by poly (ADP-ribose) polymerase (PARP) and NAD(P)H oxidase activation. Doxorubicin (DOX), an anthracycline antibiotic and topoisomerase inhibitor, induces apoptosis through direct oxidative DNA damage leading to indirect H(2)O(2) generation mediated by PARP and NAD(P)H oxidase activation. DOX caused site-specific oxidative DNA damage in the presence of copper(II), which may contribute to apoptosis. These findings suggest that ROS formation plays important roles in apoptosis induced by anticancer drugs. Furthermore, these studies may provide an insight into the development of new effective chemotherapeutic drugs.
Mizutani
Hideki
H
College of Pharmacy, Kinjo Gakuin University, Omori, Nagoya, Japan. mizu@kinjo-u.ac.jp
D000634:Aminoquinolines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D009249:NADP / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D059003:Topoisomerase Inhibitors
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D007192:Indenes; D017382:Reactive Oxygen Species; D059003:Topoisomerase Inhibitors; D009249:NADP; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one