2. Academic Validation
  3. KS10076, a chelator for redox-active metal ions, induces ROS-mediated STAT3 degradation in autophagic cell death and eliminates ALDH1+ stem cells

KS10076, a chelator for redox-active metal ions, induces ROS-mediated STAT3 degradation in autophagic cell death and eliminates ALDH1+ stem cells

  • Cell Rep. 2022 Jul 19;40(3):111077. doi: 10.1016/j.celrep.2022.111077.
Jaehee Kim 1,  Areum Park 2,  Jieon Hwang 1,  Xianghua Zhao 3,  Jaesung Kwak 4,  Hyun Woo Kim 5,  Minhee Ku 6,  Jaemoon Yang 6,  Tae Il Kim 7,  Kyu-Sung Jeong 8,  Uyeong Choi 1,  Hyuk Lee 9,  Sang Joon Shin 10
Affiliations

Affiliations

  • 1 Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
  • 2 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.
  • 3 Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
  • 4 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 5 Chemical Data-Driven Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea.
  • 6 Department of Radiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Severance of Radiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
  • 7 Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
  • 8 Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.
  • 9 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: leeh@krict.re.kr.
  • 10 Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address: ssj338@yuhs.ac.
PMID: 35858554 DOI: 10.1016/j.celrep.2022.111077
Abstract

Redox-active metal ions are pivotal for rapid metabolism, proliferation, and aggression across Cancer types, and this presents metal chelation as an attractive Cancer cell-targeting strategy. Here, we identify a metal chelator, KS10076, as a potent anti-cancer drug candidate. A metal-bound KS10076 complex with redox potential for generating hydrogen peroxide and superoxide anions induces intracellular Reactive Oxygen Species (ROS). The elevation of ROS by KS10076 promotes the destabilization of signal transducer and activator of transcription 3, removes aldehyde dehydrogenase isoform 1-positive Cancer Stem Cells, and subsequently induces autophagic cell death. Bioinformatic analysis of KS10076 susceptibility in pan-cancer cells shows that KS10076 potentially targets Cancer cells with increased mitochondrial function. Furthermore, patient-derived Organoid models demonstrate that KS10076 efficiently represses Cancer cells with active KRAS, and fluorouracil resistance, which suggests clinical advantages.

Keywords

ALDH1+ stem cell elimination; CP: Cancer; ROS-induced STAT3 degradation; autophagic cell death; metal chelator; pan-cancer therapeutics.

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