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Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice
Masaaki Ishibashi1, Masakazu Ishii1, Shinichiro Yamamoto2
1Division of Physiology and Pathology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Nakano, Tokyo, 164-8530, Japan; Division of Physiology and Pathology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, Shinagawa, Tokyo, 142-8555, Japan.
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.
Insights
Transient receptor potential melastatin 2 (TRPM2) channels are activated by 5-Fluorouracil (5-FU), contributing to chemotherapy-induced myelosuppression. Blocking TRPM2 alleviates 5-FU
Area of Science:
- Molecular Biology
- Pharmacology
- Toxicology
Background:
- Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress-sensitive calcium channel.
- 5-Fluorouracil (5-FU) is an anticancer drug known to cause myelosuppression, partly via oxidative stress.
- Bone marrow cells express TRPM2, suggesting its potential role in 5-FU's adverse effects.
Purpose of the Study:
- To investigate the involvement of TRPM2 in 5-FU-induced myelosuppression.
- To determine if 5-FU activates TRPM2 channels.
Main Methods:
- Assessed 5-FU effects on H2O2-induced intracellular calcium ([Ca2+]i) increases in TRPM2-expressing HEK cells and wild-type (WT) vs. Trpm2 knockout (KO) mouse bone marrow cells.
- Utilized CFU-GM colony assays to evaluate 5-FU's impact on bone marrow progenitor cells.
- Administered 5-FU to WT and Trpm2 KO mice to assess in vivo myelosuppression by monitoring leukocyte counts.
Main Results:
- 5-FU enhanced H2O2-induced [Ca2+]i increases in TRPM2-expressing cells, indicating TRPM2 activation by 5-FU.
- This enhancement was absent in non-TRPM2 expressing cells and in bone marrow cells from Trpm2 KO mice.
- Trpm2 deficiency alleviated 5-FU-induced reduction in CFU-GM colonies and mitigated leukopenia in vivo.
Conclusions:
- TRPM2 activation by 5-FU contributes to chemotherapy-induced myelosuppression.
- Targeting TRPM2 may offer a strategy to reduce 5-FU's adverse effects on bone marrow.
- TRPM2 plays a significant role in the bone marrow toxicity of 5-FU.
