Potential anti-melanoma activity of Imidazoline I1 receptor agonists

Abstract

Melanoma is the deadliest form of skin cancer. Despite the advancements in targeted BRAF and MEK therapy and immunotherapies, metastatic melanoma patients still have poor prognosis with a median survival of 9 months and a long-term survival rate of 10%. There is an urgent need for novel treatment modalities that target metastatic melanoma. Imidazoline I1 receptor (IR1, IRAS, NISCH) is a scaffolding protein that has been shown to be a tumor suppressor in breast cancer through regulation of cancer cell survival, motility and invasion. IR1 role in metastatic melanoma has not been investigated to date. Of importance, several IR1 agonists are clinically approved for treatment of hypertension. The aim of this study was to examine the IR1 expression in melanoma and the effects of IR1 agonists on melanoma cell viability. To confirm the target expression, we first determined IR1 levels in primary and metastatic melanoma patient samples by qRT-PCR and immunohistochemistry. We found that it is expressed in primary tumors and liver metastases and, to a lesser extent, in metastatic lymph nodes. Next, we examined the activity of IR1 agonists – rilmenidine, clonidine and moxonidine – in a panel of metastatic melanoma cell lines (HTB140, FemX-1, A375 and 518a2) and found that rilmenidine most potently inhibited cell viability. Notably, it was not toxic towards human dermal fibroblasts and keratinocytes. Furthermore, rilmenidine time- and dose- dependently induced cell cycle arrest in G2/M phase and consequent apoptosis. Our results imply that imidazoline I1 receptor is potentially novel anti-melanoma target, and that its already clinically approved agents have promising anti-cancer activity.