Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.
Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.
复制标题
线粒体靶向化合物联合用于肺癌的化学预防。
DOI：
10.3390/cancers14102538
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发表时间：
2022-05-21
期刊：
影响因子：
5.2
通讯作者：
You, Ming
中科院分区：
文献类型：
--
作者：
Zhang, Qi;Xiong, Donghai;Pan, Jing;Wang, Yian;Hardy, Micael;Kalyanaraman, Balaraman;You, Ming
关键词：
Previous reports showed that mitochondria-targeted honokiol and mitochondria-targeted lonidamine potently inhibit complex-I- and complexes-I/II-induced respiration and cancer cell proliferation. In this study, we investigated the efficacy of combining mitochondria-targeted honokiol and mitochondria-targeted lonidamine treatments for lung cancer prevention. We found that their combination exhibited striking tumor inhibition in the benzo[a]pyrene-induced murine lung tumor model without causing detectable side effects. Using single-cell RNA sequencing, we found combined treatment has a clear advantage in that it can significantly inhibit two oncogenic pathways—STAT3 signaling and AKT/mTOR/p70S6K signaling. Such dual inhibition may contribute to the greater efficacy of the combined drug treatment. Therefore, the combination provides a novel option for lung cancer chemoprevention. 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 ǀ, 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.
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影响因子：
8.8
作者：
Newman AC;Maddocks ODK
通讯作者：
Maddocks ODK
DOI：
10.1158/1940-6207.capr-20-0425
发表时间：
2021-03
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Huang M;Myers CR;Wang Y;You M
通讯作者：
You M
DOI：
10.1158/1940-6207.capr-14-0091
发表时间：
2014-11
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Pan J;Zhang Q;Liu Q;Komas SM;Kalyanaraman B;Lubet RA;Wang Y;You M
通讯作者：
You M
影响因子：
5.8
作者：
Pan J;Lee Y;Cheng G;Zielonka J;Zhang Q;Bajzikova M;Xiong D;Tsaih SW;Hardy M;Flister M;Olsen CM;Wang Y;Vang O;Neuzil J;Myers CR;Kalyanaraman B;You M
通讯作者：
You M
DOI：
10.1152/ajpendo.00202.2013
发表时间：
2014-01-01
影响因子：
5.1
作者：
Li, Hongliang;Lee, Jiyeon;Xie, Zhonglin
通讯作者：
Xie, Zhonglin