Journal
ANTI-CANCER DRUGS
Volume 14, Issue 3, Pages 219-225Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00001813-200303000-00005
Keywords
apoptosis; lactacystin; p815 mastocytoma; proteasome; synthetic chenodeoxycholic acid derivative
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The antitumor activity of a synthetic chenodeoxycholic acid derivative, HS-1200, on the p815 mastocytoma cell line was investigated. We present several lines of evidence indicating that HS-1200 at 35 muM induced apoptosis of p815 cells. Reduction of mitochondrial membrane potential, the release of cytochrome c to cytosol, activation of caspase-3, nuclear condensation, production of poly(ADPribose) polymerase cleavage, generation of DNA fragmentation and nuclear condensation were demonstrated. Importantly, HS-1200 inhibited proteasome activity. Next, the combination treatment of HS-1200 or a proteasome inhibitor lactacystin was undertaken. Although the single treatment of 20 muM HS-1200 or 1 muM lactacystin induced apoptosis slightly, the combination treatment of them augmented prominently the extent of apoptosis. The combination therapy of HS-1200 and lactacystin could be potentially a therapeutic strategy reducing the extent and severity of treatment-related toxicity.
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