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Bisbiguanide analogs induce mitochondrial stress to inhibit lung cancer cell invasion.
Knippler, Christina M; Arnst, Jamie L; Robinson, Isaac E; Matsuk, Veronika; Khatib, Tala O; Harvey, R Donald; Shanmugam, Mala; Mouw, Janna K; Fu, Haian; Ganesh, Thota; Marcus, Adam I.
Affiliation
  • Knippler CM; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
  • Arnst JL; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
  • Robinson IE; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
  • Matsuk V; Department of Medicine, Division of Endocrinology, Emory University, Atlanta, GA 30322, USA.
  • Khatib TO; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
  • Harvey RD; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
  • Shanmugam M; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30318, USA.
  • Mouw JK; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
  • Fu H; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
  • Ganesh T; Graduate Program in Cancer Biology, Emory University, Atlanta, GA 30322, USA.
  • Marcus AI; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
iScience ; 27(4): 109591, 2024 Apr 19.
Article in En | MEDLINE | ID: mdl-38632988
ABSTRACT
Targeting cancer metabolism to limit cellular energy and metabolite production is an attractive therapeutic approach. Here, we developed analogs of the bisbiguanide, alexidine, to target lung cancer cell metabolism and assess a structure-activity relationship (SAR). The SAR led to the identification of two analogs, AX-4 and AX-7, that limit cell growth via G1/G0 cell-cycle arrest and are tolerated in vivo with favorable pharmacokinetics. Mechanistic evaluation revealed that AX-4 and AX-7 induce potent mitochondrial defects; mitochondrial cristae were deformed and the mitochondrial membrane potential was depolarized. Additionally, cell metabolism was rewired, as indicated by reduced oxygen consumption and mitochondrial ATP production, with an increase in extracellular lactate. Importantly, AX-4 and AX-7 impacted overall cell behavior, as these compounds reduced collective cell invasion. Taken together, our study establishes a class of bisbiguanides as effective mitochondria and cell invasion disrupters, and proposes bisbiguanides as promising approaches to limiting cancer metastasis.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: IScience Year: 2024 Document type: Article Affiliation country: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: IScience Year: 2024 Document type: Article Affiliation country: Estados Unidos
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