Induction of excessive levels of reactive oxygen species (ROS) by small-molecule compounds has been considered a potentially effective therapeutic strategy against cancer cells, which are often subjected to chronic oxidative stress. However, to elucidate the mechanisms of action of bioactive compounds is generally a time-consuming process. We have recently identified NPD926, a small molecule that induces rapid cell death in cancer cells. Using a combination of two comprehensive and complementary approaches, proteomic profiling and affinity purification, together with the subsequent biochemical assays, we have elucidated the mechanism of action underlying NPD926-induced cell death: conjugation with glutathione mediated by GST, depletion of cellular glutathione and subsequent ROS generation. NPD926 preferentially induced effects in KRAS-transformed fibroblast cells, compared with their untransformed counterparts. Furthermore, NPD926 sensitized cells to inhibitors of system xc−, a cystine-glutamate antiporter considered to be a potential therapeutic target in cancers including cancer stem cells. These data show the effectiveness of a newly identified ROS inducer, which targets glutathione metabolism, in cancer treatment.
Skip Nav Destination
Article navigation
October 2014
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
September 08 2014
A small molecule that induces reactive oxygen species via cellular glutathione depletion
Tatsuro Kawamura;
Tatsuro Kawamura
*Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Search for other works by this author on:
Yasumitsu Kondoh;
Yasumitsu Kondoh
*Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
†Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Search for other works by this author on:
Makoto Muroi;
Makoto Muroi
*Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
†Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Search for other works by this author on:
Makoto Kawatani;
Makoto Kawatani
*Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Search for other works by this author on:
Hiroyuki Osada
Hiroyuki Osada
1
*Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
†Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
1To whom correspondence should be addressed (email hisyo@riken.jp).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
May 28 2014
Revision Received:
July 07 2014
Accepted:
July 11 2014
Accepted Manuscript online:
July 11 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 463 (1): 53–63.
Article history
Received:
May 28 2014
Revision Received:
July 07 2014
Accepted:
July 11 2014
Accepted Manuscript online:
July 11 2014
Citation
Tatsuro Kawamura, Yasumitsu Kondoh, Makoto Muroi, Makoto Kawatani, Hiroyuki Osada; A small molecule that induces reactive oxygen species via cellular glutathione depletion. Biochem J 1 October 2014; 463 (1): 53–63. doi: https://doi.org/10.1042/BJ20140669
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.