Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis - Archive ouverte HAL
Article Dans Une Revue Nature Communications Année : 2019

Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis

Résumé

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.

Domaines

Chimie

Dates et versions

hal-02491552 , version 1 (26-02-2020)

Identifiants

Citer

Gang Cheng, Qi Zhang, Jing Pan, Yongik Lee, Olivier Ouari, et al.. Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis. Nature Communications, 2019, 10, pp.2205. ⟨10.1038/s41467-019-10042-1⟩. ⟨hal-02491552⟩
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