{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:29:04Z","timestamp":1793413744095,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T00:00:00Z","timestamp":1653091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National Institutes of Health","award":["R01CA232433"],"award-info":[{"award-number":["R01CA232433"]}]},{"name":"The National Institutes of Health","award":["R01CA223804"],"award-info":[{"award-number":["R01CA223804"]}]},{"name":"The National Institutes of Health","award":["R01CA205633"],"award-info":[{"award-number":["R01CA205633"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Combined treatment targeting mitochondria may improve the efficacy of lung cancer chemoprevention. Here, mitochondria-targeted honokiol (Mito-HNK), an inhibitor of mitochondrial complex I and STAT3 phosphorylation, and mitochondria-targeted lonidamine (Mito-LND), an inhibitor of mitochondrial complexes I\/II and AKT\/mTOR\/p70S6K signaling, were evaluated for their combinational chemopreventive efficacy on mouse lung carcinogenesis. All chemopreventive treatments began one-week post-carcinogen treatment and continued daily for 24 weeks. No evidence of toxicity (including liver toxicity) was detected by monitoring serum levels of alanine aminotransferase and aspartate aminotransferase enzymes. Mito-HNK or Mito-LND treatment alone reduced tumor load by 56% and 48%, respectively, whereas the combination of Mito-HNK and Mito-LND reduced tumor load by 83%. To understand the potential mechanism(s) of action for the observed combinatorial effects, single-cell RNA sequencing was performed using mouse tumors treated with Mito-HNK, Mito-LND, and their combination. In lung tumor cells, Mito-HNK treatment blocked the expression of genes involved in mitochondrial complex \u01c0, oxidative phosphorylation, glycolysis, and STAT3 signaling. Mito-LND inhibited the expression of genes for mitochondrial complexes I\/II, oxidative phosphorylation, and AKT\/mTOR\/p70S6K signaling in lung tumor cells. In addition to these changes, a combination of Mito-HNK with Mito-LND decreased arginine and proline metabolism, N-glycan biosynthesis, and tryptophan metabolism in lung tumor cells. Our results demonstrate that Mito-LND enhanced the antitumor efficacy of Mito-HNK, where both compounds inhibited common targets (oxidative phosphorylation) as well as unique targets for each agent (STAT3 and mTOR signaling). Therefore, the combination of Mito-HNK with Mito-LND may present an effective strategy for lung cancer chemoprevention.<\/jats:p>","DOI":"10.3390\/cancers14102538","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T09:18:08Z","timestamp":1653124688000},"page":"2538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds"],"prefix":"10.3390","volume":"14","author":[{"given":"Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"Center for Cancer Prevention, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghai","family":"Xiong","sequence":"additional","affiliation":[{"name":"Center for Cancer Prevention, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Pan","sequence":"additional","affiliation":[{"name":"Center for Cancer Prevention, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yian","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Cancer Prevention, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2976-7785","authenticated-orcid":false,"given":"Micael","family":"Hardy","sequence":"additional","affiliation":[{"name":"Aix-Marseille University, CNRS, ICR, UMR 7273, 13013 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balaraman","family":"Kalyanaraman","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"},{"name":"Center for Disease Prevention Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"You","sequence":"additional","affiliation":[{"name":"Center for Cancer Prevention, Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1056\/NEJMra0802714","article-title":"Lung cancer","volume":"359","author":"Herbst","year":"2008","journal-title":"N. 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