4,4'-Diisothiocyanatostilbene-2,2'-disulfonate modulates voltage-gated K+ current and influences cell cycle arrest in androgen sensitive and insensitive human prostate cancer cell lines.

The stilbene derivative, 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), an anion channel blocker is used in the present study to evaluate its modulatory effect on voltage-gated K+ current (IK) in human prostate cancer cell lines (LNCaP and PC-3). Voltage-gated K+ (KV) channels in the plasma membrane are critically involved in the proliferation of tumor cells. Therefore, KV channels are considered as a novel potential target for cancer treatment. The results of the present study show that the external perfusion of DIDS activates IK in a concentration-dependent manner, although the known K+ channel blocker TEA failed to block the DIDS activated IK in PC-3 cells. Whereas, in LNCaP cells, the higher concentration of DIDS blocked IK, though this effect was not completely recovered after washout. The difference in function of DIDS might be due to the expression of different Kv channel isoforms in LNCaP and PC-3 cells. Further, the anticancer studies show that treatment of DIDS significantly induced G2/M phase cell cycle arrest and induced moderate and low level of cell death in LNCaP and PC-3 cells respectively. This finding reveals that DIDS modulates IK and exerts cell cycle arrest and cell death in LNCaP and PC-3 cells.

Modulatory Effect of Selected Dietary Phytochemicals on Delayed Rectifier K+ Current in Human Prostate Cancer Cells.

Phytochemicals are ubiquitous in naturally occurring dietary elements that exhibits diverse pharmacological properties over various pathological disorders, including cancer. Voltage gated K+ (KV) channel in the plasma membrane contributes to wide range of cellular processes including cancer progression. Therefore, modulation of KV channel is being considered as a novel potential target for cancer therapy. The whole cell patch clamp technique was used to record the modulatory effect of chrysin, naringenin, caffeic acid, gallic acid, and zingerone on delayed rectifier potassium current (IK) in human prostate cancer cells LNCaP and PC-3. Among the tested compounds, zingerone blocked IK in a concentration-dependent manner in LNCaP cells and estimated the IC50 value of 141 µM and Emax was 81.3%. Further analysis of KV channel activation kinetics showed that zingerone induces a positive shift in the activation curve in LNCaP cells, whereas the inhibitory effect of gallic acid on IK was significantly less potent than the inhibition caused by zingerone. However, chrysin, naringenin, and caffeic acid did not modulate the KV channel conductance in LNCaP or PC-3 cells. Our findings confirmed that not all the tested phytochemicals to be effective modulators of IK and suggested that IK inhibitory effect of zingerone and gallic acid may be responsible for their anticancer effects in prostate cancer cells.

Piperine blocks voltage gated K+ current and inhibits proliferation in androgen sensitive and insensitive human prostate cancer cell lines.

Piperine is an attractive therapeutic alkaloid from black pepper that exhibits a broad spectrum of pharmacological properties over various pathological disorders including cancer. Voltage gated K+ (KV) channels play an important role in regulating cancer cell proliferation and are considered as potential target for cancer treatment. However, the implication of piperine in KV associated anticancer activities on human prostate cancer cells LNCaP and PC-3 remains unrevealed. The electrophysiological and pharmacological data identifies that both androgen sensitive (LNCaP) and insensitive (PC-3) prostate cancer cells typically expressed voltage gated K+ current (IK). This current was significantly blocked by piperine in a concentration-dependent manner with an IC50 value 39.91 µM in LNCaP and 49.45 µM in PC-3 cells. Analysis of voltage-dependence of activation kinetics showed that piperine induces a positive shift in the relative activation curve in both the cells. Piperine also depolarized the resting membrane potential by an average of 10.2 mV and 8.3 mV in LNCaP and PC-3 cells, respectively. The anticancer studies showed that, treatment with piperine concentration dependently induced G1 phase cell cycle arrest and apoptosis in LNCaP and PC-3 cells. These results unravel that the IK inhibition might be responsible for the anticancer effect of piperine on androgen sensitive and insensitive human prostate cancer cells.