期刊
MOLECULAR CANCER THERAPEUTICS
卷 5, 期 6, 页码 1520-1529出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-05-0513
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- NATIONAL CANCER INSTITUTE [P01CA097132] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG016583] Funding Source: NIH RePORTER
- NCI NIH HHS [CA97132] Funding Source: Medline
- NIA NIH HHS [AG16583] Funding Source: Medline
Ceramides are sphingolipid second messengers that are involved in the mediation of cell death. There is accumulating evidence that mitochondria play a central role in ceramide-derived toxicity. We designed a novel cationic long-chain ceramide [omega-pyridinium bromide D-erythro-C-16-ceramide (LCL-30)] targeting negatively charged mitochondria. Our results show that LCL-30 is highly cytotoxic to SW403 cells (and other cancer cell lines) and preferentially accumulates in mitochondria, resulting in a decrease of the mitochondrial membrane potential, release of mitochondrial cytochrome c, and activation of caspase-3 and caspase-9. Ultrastructural analyses support the concept of mitochondrial selectivity. Interestingly, levels of endogenous mitochondrial C-16-ceramide decreased by more than half, whereas levels of sphingosine-1-phosphate increased dramatically and selectively in mitochondria after administration of LCL-30, suggesting the presence of a mitochondrial sphingosine kinase. Of note, intracellular long-chain ceramide levels and sphingosine-1 phosphate remained unaffected in the cytosolic and extramitochondrial (nuclei/cellular membranes) cellular fractions. Furthermore, a synergistic effect of cotreatment of LCL-30 and doxorubicin was observed, which was not related to alterations in endogenous ceramide levels. Cationic long-chain pyridinium ceramides might be promising new drugs for cancer therapy through their mitochondrial preference.
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