Therapeutic Value of Voltage-Gated Sodium Channel Inhibitors in Breast, Colorectal, and Prostate Cancer: A Systematic Review

Abstract

Although survival rates of breast, colon, and prostate cancers are improving, deaths from these tumors frequently occur due to metastasis. Voltage-gated Na+ channels (VGSCs) are membrane proteins, which regulate membrane current and cellular migration during nervous system organogenesis. VGSCs are also expressed in fibroblasts, immune cells, glia, and metastatic cancer cells. VGSCs regulate migration and invasion of breast, bowel, and prostate cancer cells, suggesting that they may be novel anti-metastatic targets. We conducted a systematic review of clinical and preclinical studies testing the effects of VGSC-inhibiting drugs in cancer. Two-hundred and four publications were identified, of which two human, two mouse, and 20 in vitro publications were included. In the clinical studies, the effect of these drugs on survival and metastatic relapse is not clear. The 22 preclinical studies collectively suggest that several VGSC-inhibiting drugs inhibit cancer proliferation, migration, and invasion. None of the human and only six of the preclinical studies directly investigated the effect of the drugs on VGSC activity. Studies were difficult to compare due to lack of standardized methodology and outcome measures. We conclude that the benefits of VGSC inhibitors require further investigation. Standardization of future studies and outcome measures should enable meaningful study comparisons.

Voltage-dependent activation of Rac1 by Nav1.5 channels promotes cell migration

“…Black & Waxman, 2013). For example, the Nav1.5 subtype is upregulated in breast cancer cells where it plays a critical role in promoting cellular migration, invasion and metastasis (Besson et al, 2015;Brackenbury, 2012;Brackenbury, Chioni, Diss, & Djamgoz, 2007;Fraser et al, 2005;Martin, Ufodiama, Watt, Bland, & Brackenbury, 2015;Nelson, Yang, Dowle, Thomas, & Brackenbury, 2015;Nelson, Yang, Millican-Slater, & Brackenbury, 2015;Roger, Besson, & Le Guennec, 2003).…”

Mechanistic insights into Nav1.7‐dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis

“…These Navs are mainly expressed in excitable cells, such as neurons in the central/peripheral nervous system, as well as cardiac and skeletal muscle cells, and they are responsible for generating and propagating action potentials . In addition, Navs are also expressed in non‐excitable cells—including glia, fibroblasts, immune cells, and metastatic cancer cells . Recently, more and more studies suggested that Navs are involved in the cancer process .…”

“…In addition, Navs are also expressed in non‐excitable cells—including glia, fibroblasts, immune cells, and metastatic cancer cells . Recently, more and more studies suggested that Navs are involved in the cancer process .…”

A medicinal chemistry perspective of drug repositioning: Recent advances and challenges in drug discovery

“…In human leukemia and human glioma cells, drug 33 was able to suppress the production of IL-6 and TNF-α [82]. In prostate cancer cells, drug 33 suppressed the IL-6 through inhibition of NF-κB activity [83]. Prednisolone potentiated the activity of pitavastatin in several assays measuring the growth, survival or apoptosis in several ovarian cancer cells lines.…”