Effective killing of leukemia cells by the natural product OSW-1 through disruption of cellular calcium homeostasis.

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.

• Authors: Celia Garcia-Prieto, Kausar Begam Riaz Ahmed, Zhao Chen, Yan Zhou, Naima Hammoudi, Ying Kang, Changgang Lou, Yan Mei, Zhendong Jin, Peng Huang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 5 Pg. 3240-50 (Feb 01 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23250754 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Biological Products
• Calcium Channels
• Cholestenones
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins
• Saponins
• Sodium-Calcium Exchanger
• mitochondrial calcium uniporter
• sodium-calcium exchanger 1
• OSW 1
• Thapsigargin
• Cyclosporine
• Cytochromes c
• Calpain
• Caspase 3
• Calcium

Topics

• Biological Products (pharmacology)
• Calcium (metabolism)
• Calcium Channels (metabolism)
• Calpain (metabolism)
• Caspase 3 (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cholestenones (pharmacology)
• Cyclosporine (pharmacology)
• Cytochromes c (metabolism)
• Cytosol (drug effects, metabolism)
• Drug Screening Assays, Antitumor
• Endoplasmic Reticulum (drug effects, metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Enzyme Activation (drug effects)
• Extracellular Space (drug effects, metabolism)
• Heat-Shock Proteins (metabolism)
• Homeostasis (drug effects)
• Humans
• Leukemia (enzymology, metabolism, pathology)
• Lymphoma (enzymology, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Saponins (pharmacology)
• Sodium-Calcium Exchanger (antagonists & inhibitors, metabolism)
• Thapsigargin (pharmacology)
• Time Factors