Mechanism of DNA Damage and Apoptosis Induced by Anticancer Drugs through Generation of Reactive Oxygen Species

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  • 抗がん剤による活性酸素種を介したDNA損傷及びアポトーシス誘導機構
  • コウガンザイ ニ ヨル カッセイ サンソシュ オ カイシタ DNA ソンショウ オヨビ アポトーシス ユウドウ キコウ

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Abstract

  A number of anticancer drugs exert their effect by causing DNA damage and subsequent apoptosis induction. Reactive oxygen species (ROS), such as hydrogen peroxide (H2O2) and super oxide anion (O2-), 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 H2O2 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 H2O2 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.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 127 (11), 1837-1842, 2007-11-01

    The Pharmaceutical Society of Japan

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