Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice

Abstract

Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress-sensitive Ca²⁺-permeable channel. The activation of TRPM2 by H₂O₂ causes cell death in various types of cells. 5-Fluorouracil (5-FU) is an important anticancer drug, but myelosuppression is one of the most frequent adverse effects. The involvement of oxidative stress in 5-FU-induced myelosuppression has been reported, and bone marrow cells are known to express TRPM2. The aim of this study was to investigate whether TRPM2 is involved in 5-FU-induced myelosuppression. Enhancement of H₂O₂-induced intracellular Ca²⁺ concentration ([Ca²⁺]_i) increase by 5-FU treatment was observed in human embryonic kidney 293 (HEK) cells stably expressing TRPM2 but not in HEK cells, indicating that 5-FU stimulates TRPM2 activation. In CD117 positive cells from wild type (WT) mouse bone marrow, 5-FU also enhanced the H₂O₂-induced [Ca²⁺]_i increases, but not in cells from Trpm2 knockout (KO) mice. In the CFU-GM colony assay, the 5-FU-induced reduction of colony number was alleviated by Trpm2 deficiency. Moreover, the reduction of leukocytes in blood by administration with 5-FU in WT mice was also alleviated in Trpm2 KO mice. The activation of TRPM2 in bone marrow cells seems to be involved in 5-FU-induced myelosuppression.

Keywords: 5-Fluorouracil; Bone marrow; Myelosuppression; Oxidative stress; TRPM2.