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Supra-additive Growth Inhibition by a Celecoxib Analogue and Carboxyamido-triazole Is Primarily Mediated through Apoptosis

¹ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, ² FDA-NCI Clinical Proteomics Program and ³ Office of Cellular and Gene Therapy, Center for Biologics Evaluation and Research, Food and Drug Administration, ⁴ Howard Hughes Medical Institute, Bethesda, Maryland; and ⁵ Tufts University School of Medicine, Boston, Massachusetts

Requests for reprints: Lance A. Liotta, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Building 10, Room B1B41, Bethesda, MD 20892. Phone: 301-435-5471; Fax: 301-402-0043; E-mail: liottal{at}mail.nih.gov.

Combination studies of celecoxib and chemotherapeutic agents suggest that combining cyclooxygenase-2 inhibitors with other agents may have supra-additive or synergistic effects on tumor growth inhibition. Carboxyamido-triazole (CAI), a voltage-independent calcium channel inhibitor, has been shown to induce growth inhibition and apoptosis in cancer cells. We found that continuous exposure to cytostatic doses of CAI and LM-1685, a celecoxib analogue, reduced the proliferation and survival of seven human cancer cell lines by at least one log (P 0.001) over either agent alone. To explore the mechanism of action of this combination, we further studied the effects of LM-1685/CAI on CCL-250 colorectal carcinoma cells. We found that the supra-additive antiproliferative effects occurred throughout a range of LM-1685 doses (5-25 µmol/L) and paralleled a decrease in COX-2 activity as measured by prostaglandin E₂ production. In these cells, treatment with LM-1685/CAI suppressed the extracellular signal-regulated kinase pathway within the first hour but ultimately results in high, sustained activation of ERK over a 9-day period (P = 0.0005). Suppression of cyclin D1 and phospho-AKT, and cleavage of caspase-3 and PARP were concomitant with persistent ERK activation. Addition of PD98059, a MEK-1 inhibitor, suppressed ERK activation and significantly but incompletely reversed these signaling events and apoptosis. Flow cytometry experiments revealed that the CAI/LM-1685 combination induced a 3-fold increase in apoptosis over control (P = 0.005) in 3 days. We show that the combination of CAI and LM-1685 produces a cytotoxic effect by suppressing proliferation and triggering apoptosis.

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