Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells
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Mitochondria play important roles in tumor cell physiology and survival by providing energy and metabolites for proliferation and metastasis. As part of their oncogenic status, cancer cells frequently produce increased levels of mitochondrial-generated reactive oxygen species (ROS). However, extensive stimulation of ROS generation in mitochondria has been shown to be able to induce cancer cell death, and is one of the major mechanisms of action of many anticancer agents. We hypothesized that enhancing mitochondrial ROS generation through direct targeting of a ROS generator into mitochondria will exhibit tumor cell selectivity, as well as high efficacy in inducing cancer cell death. We thus synthesized a mitochondrial targeted version of β-lapachone (XJB-Lapachone) based on our XJB mitochondrial targeting platform. We found that the mitochondrial targeted β-lapachone is more efficient in inducing apoptosis compared to unconjugated β-lapachone, and the tumor cell selectivity is maintained. XJB-Lapachone also induced extensive cellular vacuolization and autophagy at a concentration not observed with unconjugated β-lapachone. Through characterization of mitochondrial function we revealed that XJB-Lapachone is indeed more capable of stimulating ROS generation in mitochondria, which led to a dramatic mitochondrial uncoupling and autophagic degradation of mitochondria. Taken together, we have demonstrated that targeting β-lapachone accomplishes higher efficacy through inducing ROS generation directly in mitochondria, resulting in extensive mitochondrial and cellular damage. XJB-Lapachone will thus help to establish a novel platform for the design of next generation mitochondrial targeted ROS generators for cancer therapy.
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Excessive ROS production damages mitochondria and induces secondary mitochondrial respiration uncoupling.
“In fine, excessive ROS production damages mitochondria and induces secondary mitochondrial respiration uncoupling [158].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [158]
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Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma
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Single cell kinetic modeling of redox-based drug metabolism in head and neck squamous cell carcinomaPreprint
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- Authors
- Ma, J., Lim, C., Sacher, J. R., Van Houten, B., Qian, W., & Wipf, P.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Qian, Wei
- Wipf, Peter
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 25
- Issue
- 21
- Pages
- 4828-4833
- ISSN
- 0960-894X (ISSN-L)
- PMC
- PMC4607627
- OpenAlex
- W833232761
- Cited by
- 27
- References
- 74
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 6 · 2016: 4
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (GM102989, GM067082)
- Univ. of Pittsburgh Cancer Institute (P30CA047904)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- β-lapachone, mitochondrial targeting, reactive oxygen species, mitochondrial dysfunction, mitochondrial uncoupling, vacuolization, autophagy, apoptosis, cancer cell death, tumor selectivity, anticancer agents
- MeSH terms
- Cell Survival, Dose-Response Relationship, Drug, Humans, Mitochondria, Naphthoquinones, Neoplasms, Structure-Activity Relationship, Vacuoles, Molecular Structure, Cell Death, Apoptosis, Reactive Oxygen Species, Cell Line, Tumor
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