Telmisartan induces growth inhibition, DNA double-strand breaks and apoptosis in human endometrial cancer cells
Naoko Koyama, Yoshihiro Nishida, Terukazu Ishii, Toshie Yoshida, Yuichi Furukawa, Hisashi Narahara, Naoko Koyama, Yoshihiro Nishida, Terukazu Ishii, Toshie Yoshida, Yuichi Furukawa, Hisashi Narahara
Abstract
Telmisartan, an angiotensin II receptor type 1 blocker, is often used as an antihypertension drug, and it has also been characterized as a peroxisome proliferator-activated receptor-gamma (PPARγ) ligand. The purpose of this study was to elucidate the antitumor effects of telmisartan on endometrial cancer cells. We treated three endometrial cancer cell lines with various concentrations of telmisartan, and we investigated the effects of the telmisartan on the cell proliferation, apoptosis, and their related measurements in vitro. We also administered telmisartan to nude mice with experimental tumors to determine its in vivo effects and toxicity. All three endometrial cancer cell lines were sensitive to the growth-inhibitory effect of telmisartan. The induction of apoptosis was confirmed in concert with the altered expression of genes and proteins related to the apoptosis. We also observed that DNA double-strand breaks (DSBs) were induced in HHUA (human endometrial cancer) cells by telmisartan treatment. In addition, experiments in nude mice showed that telmisartan significantly inhibited human endometrial tumor growth, without toxic side effects. Our results suggest that telmisartan might be a new therapeutic option for the treatment of endometrial cancers.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Evans T, Sany O, Pearmain P, Ganesan R, Blann A, et al. (2011) Differential trends in the rising incidence of endometrial cancer by type: data from a UK population-based registry from 1994 to 2006. Br J Cancer 104: 1505–1510.
- Obel JC, Friberg G, Fleming GF (2006) Chemotherapy in endometrial cancer. Clin Adv Hematol Oncol 4: 459–468.
- Vale CL, Tierney J, Bull SJ, Symonds PR (2012) Chemotherapy for advanced, recurrent or metastatic endometrial carcinoma. Cochrane Database Syst Rev 8: CD003915.
- Ota K, Ito K, Suzuki T, Saito S, Tamura M, et al. (2006) Peroxisome proliferator-activated receptor gamma and growth inhibition by its ligands in uterine endometrial carcinoma. Clin Cancer Res 12: 4200–4208.
- Xin B, Yokoyama Y, Shigeto T, Futagami M, Mizunuma H (2007) Inhibitory effect of meloxicam, a selective cyclooxygenase-2 inhibitor, and ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, on the growth of human ovarian cancers. Cancer 110: 791–800.
- Yang YC, Tsao YP, Ho TC, Choung IP (2007) Peroxisome proliferator-activated receptor-gamma agonists cause growth arrest and apoptosis in human ovarian carcinoma cell lines. Int J Gynecol Cancer 17: 418–425.
- Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, et al. (2004) Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 43: 993–1002.
- Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J, et al. (2008) Telmisartan is a potent target for prevention and treatment in human prostate cancer. Oncol Rep 20: 295–300.
- Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J, et al. (2009) Telmisartan as a peroxisome proliferator-activated receptor-gamma ligand is a new target in the treatment of human renal cell carcinoma. Mol Med Rep 2: 193–198.
- Ishiguro H, Ishiguro Y, Kubota Y, Uemura H (2007) Regulation of prostate cancer cell growth and PSA expression by angiotensin II receptor blocker with peroxisome proliferator-activated receptor gamma ligand like action. Prostate 67: 924–932.
- Nishida M (2002) The Ishikawa cells from birth to the present. Hum Cell 15: 104–117.
- Nishida M, Kasahara K, Kaneko M, Iwasaki H, Hayashi K (1985) [Establishment of a new human endometrial adenocarcinoma cell line, Ishikawa cells, containing estrogen and progesterone receptors]. Nihon Sanka Fujinka Gakkai Zasshi 37: 1103–1111.
- Nishida M, Kasahara K, Oki A, Satoh T, Arai Y, et al. (1996) Establishment of eighteen clones of Ishikawa cells. Hum Cell 9: 109–116.
- Boisvert M, Cote S, Vargas A, Pasvanis S, Bounou S, et al. (2008) PGJ2 antagonizes NF-kappaB-induced HIV-1 LTR activation in colonic epithelial cells. Virology 380: 1–11.
- Doyle MC, Tremblay S, Dumais N (2013) 15-Deoxy-Delta(12,14)-prostaglandin J2 inhibits IL-13 production in T cells via an NF-kappaB-dependent mechanism. Biochem Biophys Res Commun 431: 472–477.
- Hanada K, Budzowska M, Davies SL, van Drunen E, Onizawa H, et al. (2007) The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nat Struct Mol Biol 14: 1096–1104.
- Hanada K, Budzowska M, Modesti M, Maas A, Wyman C, et al. (2006) The structure-specific endonuclease Mus81-Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks. EMBO J 25: 4921–4932.
- Ghous Z, Akhter J, Pourgholami MH, Morris DL (2008) Inhibition of hepatocellular cancer by EB1089: in vitro and in vive study. Anticancer Res 28: 3757–3761.
- Rimon G, Bazenet CE, Philpott KL, Rubin LL (1997) Increased surface phosphatidylserine is an early marker of neuronal apoptosis. J Neurosci Res 48: 563–570.
- Chen Y, Kramer DL, Diegelman P, Vujcic S, Porter CW (2001) Apoptotic signaling in polyamine analogue-treated SK-MEL-28 human melanoma cells. Cancer Res 61: 6437–6444.
- Hardwick JM, Chen YB, Jonas EA (2012) Multipolar functions of BCL-2 proteins link energetics to apoptosis. Trends Cell Biol 22: 318–328.
- Berstein LM, Kvatchevskaya JO, Poroshina TE, Kovalenko IG, Tsyrlina EV, et al. (2004) Insulin resistance, its consequences for the clinical course of the disease, and possibilities of correction in endometrial cancer. J Cancer Res Clin Oncol 130: 687–693.
- Chen LM, Berek JS (2013) Endometrial carcinoma: Clinical features and diagnosis. In: UpToDate. In: Goff B, editor. UpToDate. MA: Waltham.
- Hu FB (2003) Overweight and obesity in women: health risks and consequences. J Womens Health (Larchmt) 12: 163–172.
- Kociecka B, Surazynski A, Miltyk W, Palka J (2010) The effect of Telmisartan on collagen biosynthesis depends on the status of estrogen activation in breast cancer cells. Eur J Pharmacol 628: 51–56.
- Wang T, Xu J, Yu X, Yang R, Han ZC (2006) Peroxisome proliferator-activated receptor gamma in malignant diseases. Crit Rev Oncol Hematol 58: 1–14.
- Keller H, Givel F, Perroud M, Wahli W (1995) Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. Mol Endocrinol 9: 794–804.
- Wang X, Kilgore MW (2002) Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells. Mol Cell Endocrinol 194: 123–133.
- Matsuyama M, Funao K, Kuratsukuri K, Tanaka T, Kawahito Y, et al. (2010) Telmisartan inhibits human urological cancer cell growth through early apoptosis. Exp Ther Med 1: 301–306.
- You H, Kong MM, Wang LP, Xiao X, Liao HL, et al. (2013) Inhibition of DNA-dependent protein kinase catalytic subunit by small molecule inhibitor NU7026 sensitizes human leukemic K562 cells to benzene metabolite-induced apoptosis. J Huazhong Univ Sci Technolog Med Sci 33: 43–50.
- O’Driscoll M, Jeggo PA (2006) The role of double-strand break repair - insights from human genetics. Nat Rev Genet 7: 45–54.
- Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273: 5858–5868.
- Rothkamm K, Lobrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci U S A 100: 5057–5062.
- Nusuetrong P, Saito M, Kikuchi H, Oshima Y, Moriya T, et al. (2012) Apoptotic effects of satratoxin H is mediated through DNA double-stranded break in PC12 cells. J Toxicol Sci 37: 803–812.
- de Feraudy S, Revet I, Bezrookove V, Feeney L, Cleaver JE (2010) A minority of foci or pan-nuclear apoptotic staining of gammaH2AX in the S phase after UV damage contain DNA double-strand breaks. Proc Natl Acad Sci U S A 107: 6870–6875.
- Plesca D, Mazumder S, Almasan A (2008) DNA damage response and apoptosis. Methods Enzymol 446: 107–122.
- Koike M, Yutoku Y, Koike A (2013) The defect of ku70 affects sensitivity to x-ray and radiation-induced caspase-dependent apoptosis in lung cells. J Vet Med Sci 75: 415–420.
- Khanna KK, Jackson SP (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27: 247–254.
- Rich T, Allen RL, Wyllie AH (2000) Defying death after DNA damage. Nature 407: 777–783.
- Uemura H, Ishiguro H, Nakaigawa N, Nagashima Y, Miyoshi Y, et al. (2003) Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor. Mol Cancer Ther 2: 1139–1147.
- Isobe A, Takeda T, Sakata M, Miyake A, Yamamoto T, et al. (2008) Dual repressive effect of angiotensin II-type 1 receptor blocker telmisartan on angiotensin II-induced and estradiol-induced uterine leiomyoma cell proliferation. Hum Reprod 23: 440–446.
- Yamamoto K, Ohishi M, Ho C, Kurtz TW, Rakugi H (2009) Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation. Hypertension 54: 1353–1359.
- Wang L, Zhao L, Zhang D, Chen JZ, Xue JL (2012) Different effects of telmisartan and valsartan on human aortic vascular smooth muscle cell proliferation. Chin Med J (Engl) 125: 2200–2204.
- Benson SC, Iguchi R, Ho CI, Yamamoto K, Kurtz TW (2008) Inhibition of cardiovascular cell proliferation by angiotensin receptor blockers: are all molecules the same? J Hypertens 26: 973–980.
Source: PubMed