Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis.
Gang ChengMing YouJing PanYongik LeeOlivier OuariMicael HardyMonika ZielonkaCharles R MyersJacek ZielonkaKatherine WehAndrew C ChangGuoan ChenLaura KrestyBalaraman KalyanaramanMing YouPublished in: Nature communications (2019)
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.
Keyphrases
- cell death
- oxidative stress
- poor prognosis
- reactive oxygen species
- resting state
- white matter
- brain metastases
- signaling pathway
- cancer therapy
- long non coding rna
- small cell lung cancer
- cell cycle arrest
- high fat diet induced
- cell proliferation
- cerebral ischemia
- functional connectivity
- emergency department
- squamous cell carcinoma
- cardiovascular disease
- papillary thyroid
- insulin resistance
- endoplasmic reticulum
- radiation therapy
- cardiovascular events
- radiation induced
- multiple sclerosis
- endoplasmic reticulum stress
- skeletal muscle
- drug induced
- squamous cell