Antiproliferative and apoptotic effects of telmisartan in human colon cancer cells

Abstract

Telmisartan is an angiotensin I (AT₁) receptor blocker used in the treatment of essential hypertension, with partial peroxisome proliferator-activated receptor γ (PPARγ) agonism. In prior studies, PPARγ activation led to apoptosis and cell cycle inhibition in various cancer cells. The aim of the present study was to investigate the potential antiproliferative and apoptotic effects of telmisartan by partially activating PPARγ. HT-29, SW-480 and SW-620 cells were incubated with telmisartan (0.2-5 μM) or the full agonist, pioglitazone (0.2-5.0 μM). The antiproliferative and apoptotic effects of telmisartan in the human colon cancer cells were significant at therapeutic serum concentrations, and telmisartan exhibited a potency at least equivalent to the full PPARγ agonist, pioglitazone. The antiproliferative and apoptotic effects of pioglitazone in the human colon cancer cells were not completely deregulated by PPARγ blockade with GW9662. In the telmisartan-treated cells, PPARγ blockade resulted in an increased antiproliferative and apoptotic effect. These effects are not entirely explained by PPARγ activation, however, possible hypotheses that require further experimental investigation are as follows: i) Ligand-independent PPARγ activation through the activation-function 1 domain; ii) a PPARγ-independent mechanism; or iii) independent antiproliferative and apoptotic effects through GW9662.

Keywords: angiotensin I receptor blocker; antiproliferative; apoptosis; colon cancer; peroxisome proliferator-activated receptor γ; telmisartan.

Figure 1

Determination of antiproliferative effect by cell count in a Neubauer cell chamber. (A) HT-29, (B) SW-480 and (C) SW-620 cells were incubated with pioglitazone (0–5 μM) and telmisartan (0–5 μM) for 24 h. The percentage of vital cells revealed that the antiproliferative effect of the partial PPARγ-agonist, telmisartan, was greater than that of the full PPARγ agonist, pioglitazone. PPARγ, peroxizome proliferator-activated receptor γ; DMSO, dimethyl sulfoxide.

Figure 2

Determination of cell viability by MTT assay. (A) HT29, (B) SW-480 and (C) SW620 cells were incubated with pioglitazone (0.2–5 μM) and telmisartan (0.2–5 μM) for 24 h. The percentages of vital cells are shown with respect to ligand concentration. DMSO, dimethyl sulfoxide; Pio, pioglitazone.

Figure 3

Caspase 3/7 assay of (A) HT-29, (B) SW-480 and (C) SW-620 cells following 24 h of incubation with pioglitazone and telmisartan, in the absence or presence of 2.5 μM of the peroxizome proliferator-activated receptor γ antagonist, GW9662. DMSO, dimethyl sulfoxide.

Figure 4

Relative mRNA expression of PPARγ, the PPARγ target gene, CSTA and AT1R following 24 h of incubation with DMSO, pioglitazone and telmisartan. (A) HT-29 without and (B) with the PPARγ antagonist, GW9662. (C) SW-480 without and (D) with the PPARγ antagonist, GW9662. (E) SW-620 without and (F) with the PPARγ antagonist, GW9662. PPARγ, peroxizome proliferator-activated receptor γ; DMSO, dimethyl sulfoxide; CSTA, cystatin A; AT1R, angitensin I receptor.