Effective killing of cancer cells and regression of tumor growth by K27 targeting sulfiredoxin.
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.
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
Jiwon
J
Kim
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
Gong-Rak
GR
Lee
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
Hojin
H
Kim
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
You-Jin
YJ
Jo
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
Seong-Eun
SE
Hong
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
Jiae
J
Lee
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
Hye In
HI
Lee
Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, South Korea.
Yeong-Su
YS
Jang
Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, South Korea.
Seung-Hyun
SH
Oh
College of Pharmacy, Ewha Womans University, Seoul 120-750, South Korea.
Hwa Jeong
HJ
Lee
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Ju-Seog
JS
Lee
Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea. Electronic address: jeongw@ewha.ac.kr.
Woojin
W
Jeong
D000072283:A549 Cells; D000111:Acetylcysteine / Q000494:pharmacology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress / Q000187:drug effects; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; D004791:Enzyme Inhibitors; C000625730:N-(7-chloro-2-(4-fluorophenyl)-4-quinazolinyl)-N-(2-phenylethyl)-beta-alanine; D011799:Quinazolines; D017382:Reactive Oxygen Species; D015091:beta-Alanine; D050862:Oxidoreductases Acting on Sulfur Group Donors; C504024:SRXN1 protein, human; D000111:Acetylcysteine
Apoptosis; Cancer; Mitochondrial damage; Reactive oxygen species; Sulfiredoxin