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2000 Abstract: 2228: Sensitization of Human Colon Cancer Cells to Trail-Mediated Apoptosis.

Abstracts
2000 Digestive Disease Week

# 2228 Sensitization of Human Colon Cancer Cells to Trail-Mediated Apoptosis.
Ambrosio Hernandez, Stephanie A Schwartz, Qingding Wang, B. Mark Evers, Galveston, TX

Trail, a novel TNF family member, binds to its receptor to induce cell death in certain cancer cells through activation of the caspase pathway; however, not all cancers are susceptible to Trail-mediated apoptosis. We have shown that the human colon cancers KM12C and KM20 are resistant to Trail despite expression of Trail receptors. The purpose of our study was to determine whether various agents could sensitize resistant colon cancers to Trail and assess potential mechanisms for this effect. METHODS: KM12C and KM20 cells were treated with Trail (100 ng/ml) alone or combined with actinomycin D (Act D; 10 mg/ml), cycloheximide (CHX; 10 mg/ml) or sodium butyrate (NaBT; 5 mM). Cell viability was determined by MTT colorimetric assays (Results are expressed as mean % control ± SD; * = p<0.05 vs. control; † = p<0.05 vs. single agent without Trail). Cells were harvested for protein at 24 h and 48 h. Expression of Flip (a caspase inhibitor) was determined by Western blot analysis. RESULTS: Treatment of KM12C and KM20 with Trail alone had no effect on cell viability; however, treatment with Act D, CHX or NaBT rendered these cells sensitive to the effects of Trail with significant decreases in cell viability compared with single agent alone (Fig. 1). Cellular levels of Flip protein were dramatically reduced at 48h after treatment with all three agents (Fig. 2). CONCLUSIONS: Our results demonstrate that treatment of the colon cancer cells KM12C and KM20 with Act D, CHX or NaBT sensitizes these cells to Trail-mediated apoptosis. Moreover, our findings suggest that the marked decrease in Flip levels may account for this increased sensitivity. Priming colon cancer cells with agents such as Act D, CHX or NaBT may render these cancers more susceptible to the effects of Trail thus providing for a more effective therapeutic strategy.




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