Bisbiguanide analogs induce mitochondrial stress to inhibit lung cancer cell invasion
Christina M. Knippler,
Jamie L. Arnst,
Isaac E. Robinson,
Veronika Matsuk,
Tala O. Khatib,
R. Donald Harvey,
Mala Shanmugam,
Janna K. Mouw,
Haian Fu,
Thota Ganesh,
Adam I. Marcus
Affiliations
Christina M. Knippler
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
Jamie L. Arnst
Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Medicine, Division of Endocrinology, Emory University, Atlanta, GA 30322, USA
Isaac E. Robinson
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30318, USA
Veronika Matsuk
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Graduate Program in Cancer Biology, Emory University, Atlanta, GA 30322, USA
Tala O. Khatib
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, GA 30322, USA
R. Donald Harvey
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA
Mala Shanmugam
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
Janna K. Mouw
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
Haian Fu
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA
Thota Ganesh
Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA
Adam I. Marcus
Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Corresponding author
Summary: 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.
