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Int J Mol Sci. 2019 Jul 3;20(13). pii: E3271. doi: 10.3390/ijms20133271.

Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways.

Author information

1
Division of Cancer Pathophysiology, National Cancer Research Institute, Tokyo 104-0045, Japan.
2
Emergency Life-Saving Technique Academy of Tokyo (ELSTA TOKYO), Hachioji-shi, Tokyo 192-0364, Japan.
3
Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
4
Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
5
Department of Anesthesiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan.
6
Translational Research Center, Research Institute of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan.
7
Division of Cancer Pathophysiology, National Cancer Research Institute, Tokyo 104-0045, Japan. yuezono@ncc.go.jp.
8
Division of Supportive Care Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104-0045, Japan. yuezono@ncc.go.jp.
9
Innovation Center for Supportive, Palliative and Psychosocial Care, National Cancer Center, Tokyo 104-0045, Japan. yuezono@ncc.go.jp.
10
Department of Comprehensive Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan. yuezono@ncc.go.jp.

Abstract

Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca2+ concentration ([Ca2+]i); however, carboplatin pretreatment enhanced the increase in [Ca2+]i induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca2+]i and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca2+]i induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.

KEYWORDS:

AKAP; CIPN; PKA; TRPA1; cAMP; carboplatin

PMID:
31277262
DOI:
10.3390/ijms20133271
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