Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue Cancers Année : 2022

Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds

Résumé

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.
Fichier principal
Vignette du fichier
mica6.pdf (5.97 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte
Licence

Dates et versions

hal-04114988 , version 1 (02-06-2023)

Licence

Identifiants

Citer

Qi Zhang, Donghai Xiong, Jing Pan, Yian Wang, Micael Hardy, et al.. Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds. Cancers, 2022, 14 (10), pp.2538. ⟨10.3390/cancers14102538⟩. ⟨hal-04114988⟩
12 Consultations
9 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More