Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis. Nat Commun 2019 May 17;10(1):2205
Date
05/19/2019Pubmed ID
31101821Pubmed Central ID
PMC6525201DOI
10.1038/s41467-019-10042-1Scopus ID
2-s2.0-85065824371 (requires institutional sign-in at Scopus site) 144 CitationsAbstract
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 MAuthors
Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMicael 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
AnimalsAntineoplastic 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