Abstract
Purpose
The incidence and mortality of lung cancer are continuously rising in recent years. Mitochondrial energy metabolism malfunction is found to be crucial in cancer proliferation and bioenergetic reprogramming, especially for lung cancer. In this study, we attempted to use mitochondrial-targeted drug therapy to change the energy metabolism pattern of cancer cells to inhibit the development of lung cancer, and investigated its mechanism of action and key targets through multi-omics studies.
Methods
In this study, we established the in vivo tumor mouse mode, treated mice with multiple mitochondrial-targeted drug combinations and DDP, severally. Then, we investigated the differences between the 7-drug group with the control group and the DDP treatment group by transcriptomics, proteomics and metabolomics to find the therapeutic targets.
Results
We found that mitochondria-targeting drug cocktail therapy, especially the 7-drug regimen, effectively improved mitochondrial metabolism, changed energy supply patterns in lung cancer cells, significantly increased NK cells in tumor tissues, and decreased tumor markers in plasma. Multi-omics analysis informed that the combination of 7-drug could up-regulate mitochondrial oxidative phosphorylation, ATP synthesis and autophagy related genes, and down-regulate proliferation and immune-related genes compared with the control group. By further mapping the protein interaction network, we identified a key target for 7-drug therapy to reverse tumor metabolic reprogramming and validated it in metabolomics.
Conclusions
Mitochondrial-targeted drug cocktail therapy can effectively inhibit the occurrence and development of tumors, through the reprogramming of energy metabolism and the increase in immune cells in tumor tissues. Thus, we provide a novel approach for the treatment of lung cancer and present evidence-based clues for the combined use of targeted mitochondrial drugs.
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Data availability statement
The original contributions presented in the study are included in the article/supplementary material, and further inquiries can be directed to the corresponding author/s.
Abbreviations
- OXPHOS:
-
Oxidative phosphorylation
- T3:
-
Thyroxine
- MLT:
-
Melatonin
- Pre:
-
Pregnenolone
- GSH:
-
Glutathione
- LA:
-
Lipoic acid
- Q10:
-
Coenzyme Q10
- Se:
-
Selenium
- Bif:
-
Bifidobacteria
- LLC:
-
Lewis lung cancer
- DDP:
-
Cisplatin
- ROS:
-
Reactive oxygen species
- ETC:
-
Electron transport chain
- TME:
-
Tumor microenvironment
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Funding
This work was financially supported by the National Natural Science Foundation of China (Nos. 31770131, 81473469 to L.F.), International Cooperation Project of the Belt and Road (No. 20400750600), Shanghai Municipal Commission of Health and Family Plan (201840056), Construction project of Shanghai TCM-intigrated innovative flagship hospital (ZY(2021-2023)-0205-05, ZXXT-202203) and National Administration of Traditional Chinese Medicine, Special TCM emergency response program for COVID-19 (2023ZYLCYJ02-6).
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LF and ML conceptualized and designed the study. TZ and LY performed animal experiment. CL, YZ, and YH contributes to omics data collation. CL, QX and BH performed the data analyses and wrote the manuscript. All authors have agreed with the content and that all gave explicit consent to submit and that they obtained consent from the responsible authorities at the institute/organization where the work has been carried out, before the work is submitted.
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Approval was obtained from Laboratory Animal Ethics Committee of Tongji University (Shanghai, China) and complied with legal requirements and national guidelines on the care and maintenance of laboratory animals. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
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Li, C., Zhang, Y., Xia, Q. et al. Multi-omics analysis revealed the mitochondrial-targeted drug combination to suppress the development of lung cancer. J Cancer Res Clin Oncol 149, 17159–17174 (2023). https://doi.org/10.1007/s00432-023-05376-9
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DOI: https://doi.org/10.1007/s00432-023-05376-9