Faculty Collaboration Database

Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis. Nat Commun 2019 May 17;10(1):2205

Date

05/19/2019

Pubmed ID

31101821

Pubmed Central ID

PMC6525201

DOI

10.1038/s41467-019-10042-1

Scopus ID

2-s2.0-85065824371 (requires institutional sign-in at Scopus site)   149 Citations

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.

Author List

Cheng G, Zhang Q, Pan J, Lee Y, Ouari O, Hardy M, Zielonka M, Myers CR, Zielonka J, Weh K, Chang AC, Chen G, Kresty L, Kalyanaraman B, You M

Authors

Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
Micael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Autophagy
Brain Neoplasms
Carcinogenesis
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Drug Delivery Systems
Electron Transport Complex I
Electron Transport Complex II
Female
Humans
Indazoles
Lung Neoplasms
Mice
Mice, Inbred NOD
Mice, Nude
Mice, SCID
Mitochondria
Reactive Oxygen Species
Xenograft Model Antitumor Assays