Effective killing of cancer cells and regression of tumor growth by K27 targeting sulfiredoxin

Jiwon Kim; Gong Rak Lee; Hojin Kim; You Jin Jo; Seong Eun Hong; Jiae Lee; Hye In Lee; Yeong Su Jang; Seung Hyun Oh; Hwa Jeong Lee; Ju Seog Lee; Woojin Jeong

doi:10.1016/j.freeradbiomed.2016.11.001

Effective killing of cancer cells and regression of tumor growth by K27 targeting sulfiredoxin

Jiwon Kim, Gong Rak Lee, Hojin Kim, You Jin Jo, Seong Eun Hong, Jiae Lee, Hye In Lee, Yeong Su Jang, Seung Hyun Oh, Hwa Jeong Lee, Ju Seog Lee, Woojin Jeong

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	384-392
Number of pages	9
Journal	Free Radical Biology and Medicine
Volume	101
DOIs	https://doi.org/10.1016/j.freeradbiomed.2016.11.001
State	Published - 1 Dec 2016

Bibliographical note

Funding 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.

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

Apoptosis
Cancer
Mitochondrial damage
Reactive oxygen species
Sulfiredoxin

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10.1016/j.freeradbiomed.2016.11.001

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title = "Effective killing of cancer cells and regression of tumor growth by K27 targeting sulfiredoxin",

abstract = "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.",

keywords = "Apoptosis, Cancer, Mitochondrial damage, Reactive oxygen species, Sulfiredoxin",

author = "Jiwon Kim and Lee, {Gong Rak} and Hojin Kim and Jo, {You Jin} and Hong, {Seong Eun} and Jiae Lee and Lee, {Hye In} and Jang, {Yeong Su} and Oh, {Seung Hyun} and Lee, {Hwa Jeong} and Lee, {Ju Seog} and Woojin Jeong",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

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doi = "10.1016/j.freeradbiomed.2016.11.001",

language = "English",

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AU - Kim, Jiwon

AU - Lee, Gong Rak

AU - Kim, Hojin

AU - Jo, You Jin

AU - Hong, Seong Eun

AU - Lee, Jiae

AU - Lee, Hye In

AU - Jang, Yeong Su

AU - Oh, Seung Hyun

AU - Lee, Hwa Jeong

AU - Lee, Ju Seog

AU - Jeong, Woojin

N1 - Funding 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. Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

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KW - Cancer

KW - Mitochondrial damage

KW - Reactive oxygen species

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SN - 0891-5849

VL - 101

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EP - 392

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

ER -

Effective killing of cancer cells and regression of tumor growth by K27 targeting sulfiredoxin

Abstract

Bibliographical note

Keywords

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