Cancer is a major health hazard formankind. Chemotherapy is the most prevalent way in the battle against cancer.However, its side effects may severely erode patients’ living standards. Forexample, oxaliplatin tends to induce acute neurotoxicity marked by coldallodynia in the hands and feet of patients. Unfortunately, there has been noeffective treatment against such neuropathy yet. The transient receptorpotential melastatin 8 (TRPM8) ion channel is critically involved in thepathogenesis of oxaliplatin-induced cold allodynia. The discoverer of TRPM8 andother temperature-sensing TRP channels won the Nobel Prize in Physiology orMedicine in 2021. Therefore, it is worthwhile to develop regulatory moleculesthat can precisely target the TRPM8 ion channel to reduce platinum-basedchemotherapy-induced neuropathic pain.
Prof. YANG Fan at the Zhejiang UniversitySchool of Medicine, Prof. XU Zhenzhong at the Zhejiang University School ofBrain Science and Brain Medicine, and Prof. YANG Shilong at Northeast ForestryUniversity conducted collaborative research in this field. Their researchfindings are published in a research article entitled “Rational design of amodality-specific inhibitor of TRPM8 channel against oxaliplatin-induced coldallodynia” in the journal Advanced Science on October 17.
Platinum-based drugs are commonly used inchemotherapy, but they may produce side effects. For instance, oxaliplatin isextensively applied as a first-line chemotherapeutic drug for many tumors, suchas colorectal and gastric cancers. However, it is inclined to induce acuteneurotoxicity in up to 89% of patients taking this drug, featured by coldallodynia in the hands and feet of patients where a normally cool temperatureis detected as extreme coldness to trigger pain sensation. So far, no effectivetreatment has been developed to cure this neuropathy.
The TRPM8 ion channel has a bearing on thepathogenesis of oxaliplatin-induced cold allodynia. TRPM8 is a non-selectivecation channel highly expressed in nociceptive neurons. As this channel isactivated at temperature lower than 28 °C, it is a sensor for coolness inmammalians. Moreover, TRPM8 is a polymodal receptor also activated by chemicalligands such as menthol and icilin, as well as membrane depolarization. In themouse model of oxaliplatin-induced cold allodynia, the expression level ofTRPM8 channel in the nociceptive dorsal root ganglion (DRG) neurons issignificantly elevated. More importantly, in TRPM8 knock-out mice, theoxaliplatin-induced cold allodynia is also abolished. Therefore, TRPM8 channelis a validated target for oxaliplatin-induced cold allodynia.
Though there is no peptide toxin targetingTRPM8 channel identified from venomous animals, many small molecules have beenscreened and developed as TRPM8 inhibitors. Most of these inhibitorsnon-discriminatively suppress all modes of TRPM8 activation, so they oftencause hypothermia and changes in acute cold sensation in patients and thus failuresin clinical trials. To address such limitations in pan-mode inhibitors, one ofthe effective strategies is to develop modality-specific TRPM8 inhibitor thatspares cold activation of this channel.
In vivo effect of DeC-1.2 againstoxaliplatin-induced cold allodynia To selectively target TRPM8 channelsagainst cold allodynia, a cyclic peptide DeC-1.2 is de novo designed with theoptimized hot-spot centric approach. DeC-1.2 can specifically inhibit theligand activation of TRPM8 but not the cold activation as measured insingle-channel patch clamp recordings. It is further demonstrated that DeC-1.2abolishes cold allodynia in oxaliplatin treated mice without altering bodytemperature.
