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.
Highlights
Gynecologic cancer is an uncontrolled growth and spread of malignant cells arising from the female reproductive tract
This study revealed that the KCNJ8, KCNJ11, ABCC8, ABCC9 genes are downregulated in cancer of the female reproductive tract when compared with the correspondent normal tissues (Figures 1B, C)
This investigation revealed that high expression of the SUR2 gene is associated with improved overall survival (OS) in all ovarian cancer patients [Hazard Ratio (HR)= 0.7 (0.55-0.86); Figures 1E–G] with a 49% reduction in mortality and improved progression-free survival PFS [HR=0.73 (0.6–0.88); Figure 1H]
Summary
Gynecologic cancer is an uncontrolled growth and spread of malignant cells arising from the female reproductive tract. Gynecologic cancers are a leading cause of death worldwide, they are under-studied. Endometrial cancer is the most common cancer of the female reproductive system for which the death rate has increased more than 100% in the past two decades. Ovarian cancer is a significant contributor to cancer disparities, since AfricanAmerican women die at almost twice the rate as other racial groups (Mannhold, 2004). Failure to treat these cancers is related to a variety of causes including late diagnosis and cancer heterogeneity. It is important to identify novel targets and approaches to treat gynecologic cancers
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