Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis

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.