Inhibition of Mitochondrial Respiration
Open accessAbstract
Cancer cells are under intrinsic increased oxidative stress and vulnerable to free radical-induced apoptosis. Here, we report a strategy to hinder mitochondrial electron transport and increase superoxide O2. radical generation in human leukemia cells as a novel mechanism to enhance apoptosis induced by anticancer agents. This strategy was first tested in a proof-of-principle study using rotenone, a specific inhibitor of mitochondrial electron transport complex I. Partial inhibition of mitochondrial respiration enhances electron leakage from the transport chain, leading to an increase in O2. generation and sensitization of the leukemia cells to anticancer agents whose action involve free radical generation. Using leukemia cells with genetic alterations in mitochondrial DNA and biochemical approaches, we further demonstrated that As2O3, a clinically active anti-leukemia agent, inhibits mitochondrial respiratory function, increases free radical generation, and enhances the activity of another O2.-generating agent against cultured leukemia cells and primary leukemia cells isolated from patients. Our study shows that interfering mitochondrial respiration is a novel mechanism by which As2O3 increases generation of free radicals. This novel mechanism of action provides a biochemical basis for developing new drug combination strategies using As2O3 to enhance the activity of anticancer agents by promoting generation of free radicals.
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Cancer cells are sensitive to mitochondrial poisons such as rotenone.
“Cancer cells are sensitive to mitochondrial poisons such as rotenone (36), suggesting that mitochondria can be targeted for cancer therapeutics.”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [36]
The Discussion (page unavailable) says cancer cells may be more vulnerable to agents that interfere with mitochondrial function, and the Results identify rotenone as a mitochondrial complex I inhibitor. But the tested leukemia cells showed little apoptosis from sub-toxic rotenone alone; the strong effect occurred when it was combined with other agents. The source therefore supports rotenone as a way to sensitize these cells, not the unqualified claim that cancer cells are sensitive to rotenone itself. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRotenone inhibits complex I of the electron transport chain, leading to an increase in superoxide production by this complex.
“Rotenone inhibits complex I of the electron transport chain, leading to an increase in the production of superoxide by this complex (36, 38).”
From Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence (2009) · cites this paper as [36]
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- Authors
- Pelicano, H., Feng, L., Zhou, Y., Carew, J. S., Hileman, E. O., Plunkett, W., Keating, M. J., & Huang, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Huang, Peng
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 278
- Issue
- 39
- Pages
- 37832-37839
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2041992938
- Cited by
- 495
- References
- 1
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 12 · 2023: 14 · 2022: 20 · 2021: 16 · 2020: 18 · 2019: 11 · 2018: 18 · 2017: 28 · 2016: 21 · 2015: 28 · 2014: 41 · 2013: 25 · 2012: 38
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29ca077339-05, CA100428)
- National Cancer Institute (CA81534, R01CA085563, CA85563, R01CA100428, CA100428, CA77339)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- mitochondrial respiration inhibition, mitochondrial electron transport chain, superoxide production, leukemia cells, apoptosis, rotenone, mitochondrial complex I inhibition, arsenic trioxide, oxidative stress, free radicals, combination therapy, anticancer agents, mitochondrial DNA mutations
- MeSH terms
- Arsenic Trioxide, 2-Methoxyestradiol, Antineoplastic Agents, Arsenicals, Cells, Cultured, Estradiol, Humans, Mitochondria, Oxides, Oxygen Consumption, Rotenone, Superoxides, Leukemia, Lymphocytic, Chronic, B-Cell, Apoptosis, Reactive Oxygen Species
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