Telmisartan anti-cancer activities mechanism through targeting N-cadherin by mimicking ADH-1 function

Abstract

This study aimed to investigate if Telmisartan as a novel N-cadherin antagonist, can overcome cell migration of cancer cells. We investigated the mechanism and influence of Docetaxel and Telmisartan (as an analogous to ADH-1, which is a well-known N-cadherin antagonist) on cancer cells. The effect of ADH-1 and Telmisartan on cell attachment in PC3, DU145, MDA-MB-468 cell lines using recombinant human N-cadherin was studied. Cell viability assay was performed to examine the anti-proliferative effects of Telmisartan, ADH-1 and Docetaxel. Migration was examined via wound healing assay, and apoptosis was determined by flow cytometry. The expression of AKT-1 as a downstream gene of N-cadherin signalling pathway was assayed by real-time PCR. Treatment of PC3, MDA-MB-468 and DU145 cells with Telmisartan (0.1 µM) and ADH-1 (40 µM) resulted in 50%, 58% and approximately 20% reduction in cell attachment to N-cadherin coated plate respectively. It shows reduction of cell attachment in PC3 and MDA-MB-468 cell lines appeared to be more sensitive than that of DU145 cells to the Telmisartan and ADH-1 treatments. Telmisartan (0.1 µM) and Docetaxel (0.01 nM) significantly reduced cell migration in PC3 and MDA-MB-468 cell lines compared with the control group. Using Real-time PCR, we found that Telmisartan, Docetaxel and ADH-1 had significant influence on the AKT-1 mRNA level. The results of the current study for the first time suggest that, Telmisartan, exerts anti-proliferation and anti-migration effects by targeting antagonistically N-cadherin. Also, these data suggest that Telmisartan as a less expensive alternative to ADH-1 could potentiate Docetaxel anticancer effects.

Keywords: ADH-1; N-cadherin; cancer; cell attachment; docetaxel; telmisartan.

Conflict of interest statement

The authors confirm that there are no conflicts of interest.

© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Figures

FIGURE 1

Effect of DTX, Tel and ADH‐1 on viability of prostate (PC3, DU145) and breast cancer (MDA‐MB‐468) cell lines. The cells were treated with different doses of DTX (0.001–100 nM), Tel and ADH‐1 (0.001–500 µM) for 48 hours. The control cells were treated only with the cell culture medium. Data are expressed as the mean ±SD of three independent experiments (n = 12). DTX; Docetaxel, Tel; Telmisartan

FIGURE 2

Effect of DTX and Tel on migration of prostate and breast cancer cell lines. The scratch wound was created using 10 µl sterile pipette in 70% confluency of PC3, DU‐145 and MDA‐MB‐468 cells. Media containing certain concentration of each drug was added to defined wells, and the images were taken at 0 and 24 hours by an inverted microscope (×40 magnification). The lines show the area where the scratch wound was created. The scratch wound assay was performed in triplicate wells for each concentration. Data are expressed as the mean ±SD of three independent experiments (n = 9). DTX; Docetaxel, Tel; Telmisartan. *p < 0.05, ** p < 0.01, ***p < 0.001

FIGURE 3

Effect of Tel 0.1 μM and ADH‐1 40 μM on PC3, DU145 and MDA‐MB‐468 cell attachment to recombinant human N‐cadherin (5 μg/mL). The level of nonspecific binding, determined from these cells attachment to wells coated with BSA alone, was subtracted. Values are mean ±SD of three independent experiments. Results show representative of repeated experiments and normalized to 100% binding for untreated cells as control. Tel, Telmisartan. *p < 0.05, ** p < 0.01, ***p < 0.001

FIGURE 4

Effect of DTX, Tel and ADH‐1 on AKT‐1 mRNA expression following 48 hours of treatment of PC3, DU145 and MDA‐MB‐468 cell lines that performed by RT‐qPCR. Level of AKT‐1 mRNA expression in various cell lines following treatment with DTX (0.01 nM), Tel (0.1 µM) and ADH‐1 (40 µM) relative to the controls. Each experiment was performed in three independent times. GUSB (β‐Glucuronidase) was used as the loading control. RT‐qPCR, reverse transcription‐quantitative polymerase chain reaction; mRNA, messenger RNA; DTX, Docetaxel; Tel, Telmisartan. *p < 0.05, ** p < 0.01, ***p < 0.001

FIGURE 5

Effect of DTX, Tel and ADH‐1 on cell apoptosis following 48 hours treatment of PC3, DU145 and MDA‐MB‐468cell lines that performed by flow cytometry. Percentage of early apoptosis in various cell lines following treatment with DTX (0.01 nM), Tel (0.1 µM) and ADH‐1 (40 µM). Each experiment was performed in three independent times. DTX, Docetaxel; Tel, Telmisartan. *p < 0.05, **p < 0.01, ***p < 0.001