HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Supra-additive growth inhibition by a celecoxib analogue and carboxyamido-triazole is primarily mediated through apoptosis.

Abstract
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 < or = 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 micromol/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.
AuthorsMary E Winters, Arpita I Mehta, Emanuel F Petricoin 3rd, Elise C Kohn, Lance A Liotta
JournalCancer research (Cancer Res) Vol. 65 Issue 9 Pg. 3853-60 (May 01 2005) ISSN: 0008-5472 [Print] United States
PMID15867384 (Publication Type: Journal Article)
Chemical References
  • Calcium Channel Blockers
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Indoles
  • LM-1685
  • Membrane Proteins
  • Pyrazoles
  • Sulfonamides
  • Triazoles
  • carboxyamido-triazole
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • ErbB Receptors
  • Celecoxib
  • Dinoprostone
Topics
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Calcium Channel Blockers (administration & dosage, pharmacology)
  • Celecoxib
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors (administration & dosage, pharmacology)
  • Dinoprostone (pharmacology)
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • ErbB Receptors
  • Humans
  • Indoles (pharmacology)
  • Membrane Proteins
  • Prostaglandin-Endoperoxide Synthases (metabolism)
  • Pyrazoles (administration & dosage)
  • Signal Transduction (drug effects)
  • Sulfonamides (administration & dosage)
  • Transcriptional Activation (drug effects)
  • Triazoles (administration & dosage, pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: