Journal article
Effective Killing of Leukemia Cells by the Natural Product OSW-1 through Disruption of Cellular Calcium Homeostasis
The Journal of biological chemistry, Vol.288(5), pp.3240-3250
02/01/2013
DOI: 10.1074/jbc.M112.384776
PMCID: PMC3561545
PMID: 23250754
Abstract
3β,16β,17α-Trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-β-d-xylopyranosyl)-(1→3)-2-O-acetyl-α-l-arabinopyranoside (OSW-1) is a natural product with potent antitumor activity against various types of cancer cells, but the exact mechanisms of action remain to be defined. In this study, we showed that OSW-1 effectively killed leukemia cells at subnanomolar concentrations through a unique mechanism by causing a time-dependent elevation of cytosolic Ca2+ prior to induction of apoptosis. A mechanistic study revealed that this compound inhibited the sodium-calcium exchanger 1 on the plasma membrane, leading to an increase in cytosolic Ca2+ and a decrease in cytosolic Na+. The elevated cytosolic Ca2+ caused mitochondrial calcium overload and resulted in a loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3. Furthermore, OSW-1 also caused a Ca2+-dependent cleavage of the survival factor GRP78. Inhibition of Ca2+ entry into the mitochondria by the uniporter inhibitor RU360 or by cyclosporin A significantly prevented the OSW-1-induced cell death, indicating the important role of mitochondria in mediating the cytotoxic activity. The extremely potent activity of OSW-1 against leukemia cells and its unique mechanism of action suggest that this compound may be potentially useful in the treatment of leukemia.
Background: The mechanistic action of antitumor agent OSW-1 is not clearly understood.
Results: OSW-1 triggers a calcium-dependent cell death through inhibition of sodium-calcium exchanger 1 (NCX1) and mitochondrial calcium overload.
Conclusion: Potency and efficacy of OSW-1 in eliminating leukemia cells are dependent on homeostatic calcium disruption.
Significance: New insights on the role of calcium in the mechanism of OSW-1 reveal potential in therapeutics.
Details
- Title: Subtitle
- Effective Killing of Leukemia Cells by the Natural Product OSW-1 through Disruption of Cellular Calcium Homeostasis
- Creators
- Celia Garcia-Prieto - The University of Texas MD Anderson Cancer CenterKausar Begam Riaz Ahmed - From the Department of Translational Molecular Pathology and The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030Zhao Chen - The University of Texas MD Anderson Cancer CenterYan Zhou - East Tennessee State UniversityNaima Hammoudi - Cancer Systems ImagingYing Kang - University of IowaChanggang Lou - University of IowaYan Mei - University of IowaZhendong Jin - University of IowaPeng Huang - Center for Translational Molecular Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.288(5), pp.3240-3250
- DOI
- 10.1074/jbc.M112.384776
- PMID
- 23250754
- PMCID
- PMC3561545
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 02/01/2013
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366033302771
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