Repurposing Kir6/SUR2 Channel Activator Minoxidil to Arrests Growth of Gynecologic Cancers

Abstract

Gynecologic cancers are among the most lethal cancers found in women, and, advanced stage cancers are still a treatment challenge. Ion channels are known to contribute to cellular homeostasis in all cells and mounting evidence indicates that ion channels could be considered potential therapeutic targets against cancer. Nevertheless, the pharmacologic effect of targeting ion channels in cancer is still understudied. We found that the expression of Kir6.2/SUR2 potassium channel is a potential favorable prognostic factor in gynecologic cancers. Also, pharmacological stimulation of the Kir6.2/SUR2 channel activity with the selective activator molecule minoxidil arrests tumor growth in a xenograft model of ovarian cancer. Investigation on the mechanism linking the Kir6.2/ SUR2 to tumor growth revealed that minoxidil alters the metabolic and oxidative state of cancer cells by producing mitochondrial disruption and extensive DNA damage. Consequently, application of minoxidil results in activation of a caspase-3 independent cell death pathway. Our data show that repurposing of FDA approved K + channel activators may represent a novel, safe adjuvant therapeutic approach to traditional chemotherapy for the treatment of gynecologic cancers.

Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

“…Such channel results from the combination of the inward rectifier K + channel Kir6.2 (encoded by KCNJ11) and the sulfonylurea receptor SUR2 (encoded by ABCC9) that is essential for the modulation of channel gating in response to the binding of nucleotides or drugs [124]. Recently, it was reported that Kir6.2 and SUR2 genes are downregulated in OC compared to healthy tissues and that high expression of the SUR2 gene is associated with improved overall survival in all OC patients [67]. The stimulation of the Kir6.2/SUR2 channel activity with the pharmacological activator minoxidil (Table 1) caused a reduction of OC cells proliferation and tumor growth in an OC xenograft model, producing mitochondrial disruption and severe DNA damage [67].…”

“…Recently, it was reported that Kir6.2 and SUR2 genes are downregulated in OC compared to healthy tissues and that high expression of the SUR2 gene is associated with improved overall survival in all OC patients [67]. The stimulation of the Kir6.2/SUR2 channel activity with the pharmacological activator minoxidil (Table 1) caused a reduction of OC cells proliferation and tumor growth in an OC xenograft model, producing mitochondrial disruption and severe DNA damage [67]. Thus, repurposing of regulatory agency approved K + channel activators could pave the way for novel therapeutic approach in OC, able to improve OC patients' benefits.…”

An Ovarian Cancer Susceptible Gene Prediction Method Based on Deep Learning Methods

“…Natanzon et al (2018) observed a significant association between methylation WDPCP expression in OC. KCNJ11 could be considered a favorable prognostic factor since they are observed to be expressed in OC according to the investigation of Fukushiro-Lopes et al (2020). TBL2 was identified by Kim et al (2012) as a DNA methylation regulated cancer antigen in OC.…”

Anti-invasive effects of minoxidil on human breast cancer cells: combination with ranolazine

“…Conversely, a K ATP channel blocker, glibenclamide, inhibited proliferation of breast and cervical cancer cells [ 37 , 38 ]. In contrast, in a more recent study, minoxidil was shown to have anti-proliferative and pro-apoptotic effects on ovarian cancer in vitro and in vivo [ 39 ]. Possible effects of minoxidil on invasiveness has not previously been studied.…”