Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis

Gang Cheng, Qi Zhang, Jing Pan, Yongik Lee, Olivier Ouari, Micael Hardy, Monika Zielonka, Charles R. Myers, Jacek Zielonka, Katherine Weh, Andrew C. Chang, Guoan Chen, Laura Kresty, Balaraman Kalyanaraman and Ming You ()
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Gang Cheng: Medical College of Wisconsin
Qi Zhang: Medical College of Wisconsin
Jing Pan: Medical College of Wisconsin
Yongik Lee: Medical College of Wisconsin
Olivier Ouari: CNRS
Micael Hardy: CNRS
Monika Zielonka: Medical College of Wisconsin
Charles R. Myers: Medical College of Wisconsin
Jacek Zielonka: Medical College of Wisconsin
Katherine Weh: University of Michigan
Andrew C. Chang: University of Michigan
Guoan Chen: University of Michigan
Laura Kresty: University of Michigan
Balaraman Kalyanaraman: Medical College of Wisconsin
Ming You: Medical College of Wisconsin

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Lung cancer often has a poor prognosis, with brain metastases a major reason for mortality. We modified lonidamine (LND), an antiglycolytic drug with limited efficacy, to mitochondria-targeted mito-lonidamine (Mito-LND) which is 100-fold more potent. Mito-LND, a tumor-selective inhibitor of oxidative phosphorylation, inhibits mitochondrial bioenergetics in lung cancer cells and mitigates lung cancer cell viability, growth, progression, and metastasis of lung cancer xenografts in mice. Mito-LND blocks lung tumor development and brain metastasis by inhibiting mitochondrial bioenergetics, stimulating the formation of reactive oxygen species, oxidizing mitochondrial peroxiredoxin, inactivating AKT/mTOR/p70S6K signaling, and inducing autophagic cell death in lung cancer cells. Mito-LND causes no toxicity in mice even when administered for eight weeks at 50 times the effective cancer inhibitory dose. Collectively, these findings show that mitochondrial targeting of LND is a promising therapeutic approach for investigating the role of autophagy in mitigating lung cancer development and brain metastasis.

Date: 2019
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DOI: 10.1038/s41467-019-10042-1

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