Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis

  • Nat Commun. 2019 May 17;10(1):2205. doi: 10.1038/s41467-019-10042-1.
Gang Cheng  1  2  3 ,  Qi Zhang  3  4 ,  Jing Pan  3  4 ,  Yongik Lee  4 ,  Olivier Ouari  5 ,  Micael Hardy  5 ,  Monika Zielonka  2  3 ,  Charles R Myers  3  4 ,  Jacek Zielonka  1  2  3 ,  Katherine Weh  6 ,  Andrew C Chang  6 ,  Guoan Chen  6 ,  Laura Kresty  6 ,  Balaraman Kalyanaraman  1  2  3 ,  Ming You  7  8
Affiliations
  • 1. Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
  • 2. Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
  • 3. Center for Disease Prevention Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
  • 4. Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
  • 5. Aix Marseille Univ, CNRS, ICR UMR 7273, 13013, Marseille, France.
  • 6. Section of Thoracic Surgery, Department of Surgery, Rogel Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA.
  • 7. Center for Disease Prevention Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA. [email protected].
  • 8. Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA. [email protected].
PMID: 31101821 DOI: 10.1038/s41467-019-10042-1
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.

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