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

Kanako Miyano,Koichiro Minami,Toru Yokoyama,Miki Nonaka,Masami Suzuki,Hiroaki Murata,Yasuhito Uezono,Seiji Shiraishi,Kiyoshi Terawaki,Yuka Sudo,Yoshikazu Higami

doi:10.3390/ijms20133271

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.

Highlights

Carboplatin, a platinum-based anticancer drug, is widely used as a chemotherapy for various types of tumors, including ovarian cancer, cervical cancer, non-small-cell lung cancer, and malignant lymphoma [1,2,3]
To elucidate the role of Transient receptor potential ankyrin 1 (TRPA1) activation in carboplatin-induced peripheral neuropathy, we examined the effects of a TRPA1 inhibitor on both mechanical allodynia and cold hyperalgesia induced by carboplatin
We investigated the effects of an A-kinase anchoring protein (AKAP) inhibitor on TRPA1 activation in human TRPA1 (hTRPA1)-expressing human embryonic kidney 293 (HEK293) cells, on mechanical allodynia and cold hyperalgesia in carboplatin-induced peripheral neuropathy

Summary

Introduction

Carboplatin, a platinum-based anticancer drug, is widely used as a chemotherapy for various types of tumors, including ovarian cancer, cervical cancer, non-small-cell lung cancer, and malignant lymphoma [1,2,3]. Carboplatin is neurotoxic to sensory neurons, where it primarily damages dorsal root ganglia (DRG) and leads to development of chemotherapy-induced peripheral neuropathy (CIPN), such as allodynia and hyperalgesia [4,5,6,7,8]. There are few ways to effectively prevent and palliate CIPN [9] These drugs decrease the quality of life of cancer patients, and led patients to change or abort cancer chemotherapy, implicating serious problems for the prognosis of cancer patients [9]. This study aimed to reveal the pathogenic mechanisms of carboplatin-induced peripheral neuropathy. We investigated the mechanisms of effects of carboplatin on the activity or sensitivity to TRPA1 using human TRPA1 (hTRPA1)-expressing human embryonic kidney 293 (HEK293) cells

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