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Our results from quantitative RT-PCR, Western blotting, immunohistochemistry, and the tissue microarray of medullary thyroid cancer (MTC) cell lines and patient specimens confirm that VGSC subtype NaV1.7 is uniquely expressed in aggressive MTC and not expressed in normal thyroid cells and tissues. We establish the druggability of NaV1.7 in MTC by identifying a novel inhibitor (SV188) and investigate its mode of binding and ability to inhibit INa current in NaV1.7. The whole-cell patch-clamp studies of the SV188 in the NaV1.7 channels expressed in HEK-293 cells show that SV188 inhibited the INa current in NaV1.7 with an IC50 value of 3.6 µM by a voltage- and use-dependent blockade mechanism, and the maximum inhibitory effect is observed when the channel is open. SV188 inhibited the viability of MTC cell lines, MZ-CRC-1 and TT, with IC50 values of 8.47 μM and 9.32 μM, respectively, and significantly inhibited the invasion of MZ-CRC-1 cells by 35% and 52% at 3 μM and 6 μM, respectively. In contrast, SV188 had no effect on the invasion of TT cells derived from primary tumor, which have lower basal expression of NaV1.7. In addition, SV188 at 3 μM significantly inhibited the migration of MZ-CRC-1 and TT cells by 27% and 57%, respectively.

Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (Na

Dental caries is a bacterial infectious disease characterized by demineralization of the tooth enamel. Treatment of this disease with conventional antibiotics is largely ineffective as the cariogenic bacteria form tenacious biofilms that are resistant to such treatments. The main etiological agent for dental caries is the bacterium Streptococcus mutans. S. mutans readily forms biofilms on the tooth surface and rapidly produces lactic acid from dietary sucrose. Glucosyl transferases (Gtfs) secreted by S. mutans are mainly responsible for the production of exopolysaccharides that are crucial for the biofilm architecture. Thus, inhibiting S. mutans' Gtfs is an effective approach to develop selective biofilm inhibitors that do not affect the growth of oral commensals. Herein, we report a library of 90 analogs of the previously identified lead compound, G43, and exploration of its structure activity relationships (SAR). All compounds were evaluated for the inhibition of S. mutans biofilms and bacterial growth. Selected compounds from this library were further evaluated for enzyme inhibition against Gtfs using a zymogram assay and for growth inhibition against oral commensal bacterial species such as Streptococcus gordonii and Streptococcus sanguinis. This study has led to the discovery of several new biofilm inhibitors with enhanced potency and selectivity. One of the leads, III F1 , showed marked reduction in buccal, sulcal, and proximal caries scores in a rat model of dental caries.

Summary Voltage-gated sodium (NaV) channels, initially characterized in excitable cells, have been shown to be aberrantly expressed in non-excitable cancer tissues and cells from epithelial origins such as in breast, lung, prostate, colon, and cervix, whereas they are not expressed in cognate non-cancer tissues. Their activity was demonstrated to promote aggressive and invasive potencies of cancer cells, both in vitro and in vivo, whereas their deregulated expression in cancer tissues has been associated with metastatic progression and cancer-related death. This review proposes NaV channels as pharmacological targets for anticancer treatments providing opportunities for repurposing existing NaV-inhibitors or developing new pharmacological and nutritional interventions., Graphical abstract, Cell Biology; Cancer

[Image: see text] Dental caries is a bacterial infectious disease characterized by demineralization of the tooth enamel. Treatment of this disease with conventional antibiotics is largely ineffective as the cariogenic bacteria form tenacious biofilms that are resistant to such treatments. The main etiological agent for dental caries is the bacterium Streptococcus mutans. S. mutans readily forms biofilms on the tooth surface and rapidly produces lactic acid from dietary sucrose. Glucosyl transferases (Gtfs) secreted by S. mutans are mainly responsible for the production of exopolysaccharides that are crucial for the biofilm architecture. Thus, inhibiting S. mutans’ Gtfs is an effective approach to develop selective biofilm inhibitors that do not affect the growth of oral commensals. Herein, we report a library of 90 analogs of the previously identified lead compound, G43, and exploration of its structure activity relationships (SAR). All compounds were evaluated for the inhibition of S. mutans biofilms and bacterial growth. Selected compounds from this library were further evaluated for enzyme inhibition against Gtfs using a zymogram assay and for growth inhibition against oral commensal bacterial species such as Streptococcus gordonii and Streptococcus sanguinis. This study has led to the discovery of several new biofilm inhibitors with enhanced potency and selectivity. One of the leads, III(F1), showed marked reduction in buccal, sulcal, and proximal caries scores in a rat model of dental caries.