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

doi:10.1016/j.isci.2024.109591

Bisbiguanide analogs induce mitochondrial stress to inhibit lung cancer cell invasion

iScience. 2024 Mar 27;27(4):109591. doi: 10.1016/j.isci.2024.109591. eCollection 2024 Apr 19.

Authors

Christina M Knippler^{1

2}, Jamie L Arnst^{2

3}, Isaac E Robinson^{1

2

4}, Veronika Matsuk^{1

2

5}, Tala O Khatib^{1

2

6}, R Donald Harvey^{1

2

7}, Mala Shanmugam^{1

2}, Janna K Mouw^{1

2}, Haian Fu^{1

2

7}, Thota Ganesh^{2

7}, Adam I Marcus^{1

2}

Affiliations

¹ Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA.
² Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
³ Department of Medicine, Division of Endocrinology, Emory University, Atlanta, GA 30322, USA.
⁴ George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30318, USA.
⁵ Graduate Program in Cancer Biology, Emory University, Atlanta, GA 30322, USA.
⁶ Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, GA 30322, USA.
⁷ Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA 30322, USA.

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.

Keywords: Cancer; Cell biology; Cellular physiology.

Abstract

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