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Antiproliferative effect of a novel cholecystokinin-B/gastrin receptor antagonist, YM022
T Murayama1, Y Matsumori, N Iwata
1Third Division, Department of Medicine, Kobe University School of Medicine.
Abstract:
Cholecystokinin (CCK)-B and gastrin receptors are expressed on a variety of human tumor cells. Recently, we have demonstrated that the human brain CCK-B receptors are identical to the gastrin receptors derived from the stomach mucosa, and that the brain-gut peptides, CCK-8 and gastrin I are mitogenic for mouse NIH 3T3 fibroblasts expressing human CCK-B/gastrin receptors (N-hCCKBR). In this report, we evaluated the antiproliferative potency of CCK-B/gastrin receptor antagonists by using N-hCCKBR cells. Among several antagonists, a benzodiazepine derivative, YM022 had the most potent activities in competing with [125I]CCK-8 or [125I]gastrin I binding, inhibition of CCK-8- or gastrin I-induced phosphoinositide hydrolysis and increasing cytoplasmic free calcium. Interestingly, a potent antagonist for rat CCK-B/gastrin receptors did not have such activities in N-hCCKBR cells. YM022 inhibited the CCK-8- or gastrin I-induced [methyl-3H]thymidine incorporation of N-hCCKBR cells in a dose-dependent manner. In the absence of exogenous peptide ligands, YM022 also inhibited the proliferation of several human cancer cell lines expressing the genes for both gastrin and its receptor. These results suggest that YM022 could intervene in the autocrine stimulation of human tumor cell lines through CCK-B/gastrin receptors. N-hCCKBR cells are an excellent tool to screen for novel human CCK-B/gastrin receptor antagonists possessing antiproliferative activity for human cancer cells.
Insights
The study identifies YM022 as a potent antagonist for cholecystokinin (CCK)-B/gastrin receptors, effectively inhibiting human cancer cell proliferation by blocking autocrine stimulation. This finding highlights YM022
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cholecystokinin (CCK)-B and gastrin receptors are present on various human tumor cells.
- CCK-B receptors in the brain are identical to stomach-derived gastrin receptors.
- Brain-gut peptides CCK-8 and gastrin I stimulate proliferation in cells with human CCK-B/gastrin receptors.
Purpose of the Study:
- To evaluate the antiproliferative efficacy of CCK-B/gastrin receptor antagonists.
- To identify potent antagonists for human CCK-B/gastrin receptors.
- To assess the potential of antagonists in blocking tumor cell autocrine stimulation.
Main Methods:
- Utilized N-hCCKBR cells (fibroblasts expressing human CCK-B/gastrin receptors) for antagonist screening.
- Assessed antagonist activity via competitive binding assays with radiolabeled CCK-8 and gastrin I.
- Measured inhibition of CCK-8/gastrin I-induced phosphoinositide hydrolysis and calcium signaling.
- Quantified inhibition of [methyl-3H]thymidine incorporation and cell proliferation.
Main Results:
- YM022, a benzodiazepine derivative, demonstrated the most potent antagonist activity.
- YM022 effectively competed with radioligands and inhibited downstream signaling pathways.
- YM022 dose-dependently inhibited proliferation in N-hCCKBR cells and human cancer cell lines.
- Antagonist potency for rat receptors did not translate to human N-hCCKBR cells.
Conclusions:
- YM022 shows significant antiproliferative activity against human cancer cells expressing CCK-B/gastrin receptors.
- YM022 can potentially block autocrine tumor cell stimulation mediated by these receptors.
- N-hCCKBR cells serve as a valuable model for screening novel human CCK-B/gastrin receptor antagonists with anticancer potential.