Work

Effective Killing of Leukemia Cells by the Natural Product OSW-1 through Disruption of Cellular Calcium Homeostasis

Year: 2012

Type: article

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 Ca 2+ 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 Ca 2+ and a decrease in cytosolic Na + . The elevated cytosolic Ca 2+ 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 Ca 2+ -dependent cleavage of the survival factor GRP78. Inhibition of Ca 2+ 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.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m112.384776