Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate.
Reactive oxygen species (ROS) stimulate cell proliferation and induce genetic instability, and their increase in cancer cells is often viewed as an adverse event. Here, we show that such abnormal increases in ROS can be exploited to selectively kill cancer cells using beta-phenylethyl isothiocyanate (PEITC). Oncogenic transformation of ovarian epithelial cells with H-Ras(V12) or expression of Bcr-Abl in hematopoietic cells causes elevated ROS generation and renders the malignant cells highly sensitive to PEITC, which effectively disables the glutathione antioxidant system and causes severe ROS accumulation preferentially in the transformed cells due to their active ROS output. Excessive ROS causes oxidative mitochondrial damage, inactivation of redox-sensitive molecules, and massive cell death. In vivo, PEITC exhibits therapeutic activity and prolongs animal survival.
Trachootham
Dunyaporn
D
Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Zhou
Yan
Y
Zhang
Hui
H
Demizu
Yusuke
Y
Chen
Zhao
Z
Pelicano
Helene
H
Chiao
Paul J
PJ
Achanta
Geetha
G
Arlinghaus
Ralph B
RB
Liu
Jinsong
J
Huang
Peng
P
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D000975:Antioxidants; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; C058305:phenethyl isothiocyanate; D016044:Fusion Proteins, bcr-abl; D015689:Oncogene Protein p21(ras); D005978:Glutathione