Cancer cells have been suggested to be more susceptible to oxidative damages and highly dependent on antioxidant capacity in comparison with normal cells, and thus targeting antioxidant enzymes has been a strategy for effective cancer treatment. Sulfiredoxin (Srx) is an enzyme that catalyzes the reduction of sulfinylated peroxiredoxins and thereby reactivates them. In this study we developed a Srx inhibitor, K27 (N-[7-chloro-2-(4-fluorophenyl)-4-quinazolinyl]-N-(2-phenylethyl)-β-alanine), and showed that it induces the accumulation of sulfinylated peroxiredoxins and oxidative stress, which leads to mitochondrial damage and apoptotic death of cancer cells. The effects of K27 were significantly reversed by ectopic expression of Srx or antioxidant N-acetyl cysteine. In addition, K27 led to preferential death of tumorigenic cells over non-tumorigenic cells, and suppressed the growth of xenograft tumor without acute toxicity. Our results suggest that targeting Srx might be an effective therapeutic strategy for cancer treatment through redox-mediated cell death.
|Number of pages||9|
|Journal||Free Radical Biology and Medicine|
|State||Published - 1 Dec 2016|
Bibliographical noteFunding Information:
We would like to acknowledge the University of Texas MD Anderson Cancer Center (UTMDACC), which provided the T80 and T80H cell lines. This work was supported by the National Research Foundation (NRF) grants ( 2014R1A2A2A01003983 , 2012R1A5A1048236 , 2012M3A9C5048708 and 2010-0014648 ) funded by the Korean Ministry of Science, ICT and future Planning (MSIP), and the Brain Korea 21 Program (to J. Kim) funded by the Korean Ministry of Education.
© 2016 Elsevier Inc.
- Mitochondrial damage
- Reactive oxygen species