# CCK-1R-selective and non-selective cholecystokinin antagonists, lorglumide, and proglumide increased toxicity of carboplatin to granulocyte–macrophage progenitor cells (CFU-GM) of bone marrow of rats

## TL;DR

This study shows that cholecystokinin antagonists increase the toxicity of carboplatin on bone marrow progenitor cells, especially in obese rats.

## Contribution

It is the first proof of the presence and possible role of CCK-1 receptor in granulopoiesis.

## Key findings

- Lorglumide, a CCK-1R-selective antagonist, caused stronger inhibition of CFU-GM than proglumide.
- Carboplatin toxicity was higher in CFU-GM of OLETF rats with CCK-1R deficiency.
- Both CCK-1R and CCK-2R were detected in bone marrow progenitors.

## Abstract

Cholecystokinin antagonists are investigated to use against pancreas and hepatocarcinomas, the risks of which are higher in obesity with poorer prognosis than in nonobese patients. We studied their effects on granulocyte–macrophage progenitor (CFU-GM), the key target of myelotoxicity of chemotherapy. Colony formation of CFU-GM was studied after the same molar doses of proglumide or lorglumide (iv, 5 days). Direct toxicity of carboplatin was determined against CFU-GM progenitors of LETO rats pre-treated with proglumide or lorglumide and against progenitors of their obese counterparts OLETF rats. Cholecystokinin receptors were studied by qPCR. Proglumide and lorglumide damaged granulopoiesis in vivo and inhibited CFU-GM of LETO rats dose-dependently in vitro. The CCK-1R-selective lorglumide caused more powerful inhibition than non-selective proglumide both in vitro and in vivo. Increased carboplatin toxicity was measured in vitro against CFU-GM obtained from either proglumide or lorglumide pre-treated rats. Carboplatin toxicity was significantly higher after lorglumide than proglumide pre-treatment, which confirmed protective effects via CCK-1R. Carboplatin damage was higher on CFU-GM progenitors of OLETF rats with CCK-1R deficiency than that of LETO rats. We detected both CCK-1R and CCK-2R in progenitors of bone marrow. Gene expressions of both CCK-Rs decreased after proglumide administration. Cholecystokinin antagonists affected granulopoiesis and sensitized granulocyte–macrophage progenitors against carboplatin toxicity presumably by inhibition of the protective role of cholecystokinin via CCK-1R. It is the first proof about the presence and possible role of CCK-1 receptor in granulopoiesis. These might have value if CCK antagonists are used in malignancies, obesity, or with immunosuppressive therapies.