Pilot study of angiotensin II receptor blocker in advanced hormone-refractory prostate cancer

Uemura, Hiroji; Hasumi, Hisashi; Kawahara, Takashi; Sugiura, Shinpei; Miyoshi, Yasuhide; Nakaigawa, Noboru; Teranishi, Jun‐ichi; Noguchi, Kazumi; Ishiguro, Hitoshi; Kubota, Yoshinobu

doi:10.1007/s10147-005-0520-y

Cited by 62 publications

(63 citation statements)

References 22 publications

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“…The first report of the potential utility of ACE inhibitors in preventing cancer development was that of Lever et al (1998) who surveyed data from patients receiving these medications for other reasons, but their findings were not confirmed by others (Meier et al 2000, Li et al 2003, Gonzalez-Perez et al 2004, Ronquist et al 2004, Fryzek et al 2006, Rosenthal & Gavras 2009, nor, in similar patient studies was the use of angiotensin II antagonists in any way linked with the disease (Fryzek et al 2006, Teo 2011. One report suggests that candesartan, an AT1 receptor blocker, when used at a dose similar to that used in patients for other reasons, has beneficial effects in prostate cancer, in that circulating prostate-specific antigen is reduced (Uemura et al 2005a), though this study does not appear to have been repeated. Others have even suggested a modest increase in cancers of all types in patients receiving angiotensin receptor blockers (Sipahi et al 2010), though this too has been contested (Volpe et al 2011).…”

Section: Angiotensin In Cancer Epidemiological Evidencementioning

confidence: 60%

The renin–angiotensin system in the breast and breast cancer

Vinson¹,

Barker²,

Puddefoot³

2011

Endocrine-Related Cancer

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Much evidence now suggests that angiotensin II has roles in normal functions of the breast that may be altered or attenuated in cancer. Both angiotensin type 1 (AT1) and type 2 (AT2) receptors are present particularly in the secretory epithelium. Additionally, all the elements of a tissue renin-angiotensin system, angiotensinogen, prorenin and angiotensin-converting enzyme (ACE), are also present and distributed in different cell types in a manner suggesting a close relationship with sites of angiotensin II activity. These findings are consistent with the concept that stromal elements and myoepithelium are instrumental in maintaining normal epithelial structure and function. In disease, this system becomes disrupted, particularly in invasive carcinoma. Both AT1 and AT2 receptors are present in tumours and may be up-regulated in some. Experimentally, angiotensin II, acting via the AT1 receptor, increases tumour cell proliferation and angiogenesis, both these are inhibited by blocking its production or function. Epidemiological evidence on the effect of expression levels of ACE or the distribution of ACE or AT1 receptor variants in many types of cancer gives indirect support to these concepts. It is possible that there is a case for the therapeutic use of high doses of ACE inhibitors and AT1 receptor blockers in breast cancer, as there may be for AT2 receptor agonists, though this awaits full investigation. Attention is drawn to the possibility of blocking specific AT1-mediated intracellular signalling pathways, for example by AT1-directed antibodies, which exploit the possibility that the extracellular N-terminus of the AT1 receptor may have previously unsuspected signalling roles.

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Section: Angiotensin In Cancer Epidemiological Evidencementioning

confidence: 60%

The renin–angiotensin system in the breast and breast cancer

Vinson¹,

Barker²,

Puddefoot³

2011

Endocrine-Related Cancer

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“…Concerning other tumor types, Kosugi et al (23) demonstrated that candesartan prevented the pulmonary metastasis of RCC and BC by inhibiting tumor angiogenesis through the suppression of VEGF in a xenograft model. Uemura et al (27) reported that, upon administering candesartan clinically to PC patients with hypertension, the level of prostate-specific antigen declined and the performance status of the patients improved. However, they also reported that candesartan had no effects on tumor growth in vitro, and did not detect apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Telmisartan inhibits human urological cancer cell growth through early apoptosis

Matsuyama

Funao²,

Kuratsukuri³

et al. 2010

Experimental and Therapeutic Medicine

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Abstract. Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agents. In addition, studies have provided evidence that ARBs have the potential to inhibit the growth of several types of cancer cells. It was reported that telmisartan (a type of ARB) has peroxisome proliferatoractivated receptor (PPAR)-γ activation activity. We previously reported that the PPAR-γ ligand induces growth arrest in human urological cancer cells through apoptosis. In this study, we evaluated the effects of telmisartan and other ARBs on cell proliferation in renal cell carcinoma (RCC), bladder cancer (BC), prostate cancer (PC) and testicular cancer (TC) cell lines. The inhibitory effects of telmisartan and other ARBs (candesartan, valsartan, irbesartan and losartan) on the growth of the RCC, BC, PC and TC cell lines was investigated using an MTT assay. Flow cytometry and Hoechst staining were used to determine whether the ARBs induced apoptosis. Telmisartan caused marked growth inhibition in the urological cancer cells in a dose-and time-dependent manner. Urological cancer cells treated with 100 µM telmisartan underwent early apoptosis and DNA fragmentation. However, the other ARBs had no effect on cell proliferation in any of the urological cancer cell lines. Telmisartan may mediate potent anti-proliferative effects in urological cancer cells through PPAR-γ. Thus, telmisartan is a potent target for the prevention and treatment of human urological cancer. IntroductionAngiogenetic factors play key roles in urological as well as other types of cancer. In recent years, the expression of angiogenic factors in solid human tumors has been widely reported (1). Growth factors secreted by tumor cells, such as fibroblast and transforming growth factors, increase neovascularization in vivo and in vitro (2). Studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-γ ligands inhibit the growth of cancer cells in vitro and in vivo (3). PPAR-γ, a nuclear hormone receptor, provides a strong link between lipid metabolism and the regulation of gene transcription (4). PPAR-γ acts in the adipose tissue and promotes lipogenesis under anabolic conditions. Recently, the receptor has also been implicated in inflammation and carcinogenesis. Significant evidence from many experimental systems suggests that PPAR-γ plays an important role in carcinogenesis.Angiotensin II is known as a key biological peptide in the renin-angiotensin system, which regulates blood pressure and renal hemodynamics, and angiotensin II receptor blockers (ARBs) are widely used as anti-hypertensive drugs (5). It is well known that angiogenesis is essential for tumor progression and metastasis (6,7). Several studies have shown that angiotensin II induces neovascularization and that ARBs inhibit vascular endothelial growth factor (VEGF) production (8,9). Benson et al discovered a structural resemblance between telmisartan (a type of ARB) and a PPAR-γ ligand approved for the treatment of type II diabetes, and reported that telmisartan has...

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“…Kosugi et al reported that Candesartan (an ARB) prevented the pulmonary metastasis of renal cancer and bladder tumors by inhibiting tumor angiogenesis through the suppression of VEGF in a xenograft model (28). In prostate cancer, some investigators reported that Candesartan inhibited the production of VEGF, one of the most potent and specific angiogenic factors, and decreased the prostate cancer (29,32). Kosaka et al reported that a specific ARB suppressed VEGF production, resulting in reduced tumor angiogenesis and a slower progression of prostate cancer in a tumor xenograft model (29).…”

Section: Discussionmentioning

confidence: 99%

“…Kosaka et al reported that a specific ARB suppressed VEGF production, resulting in reduced tumor angiogenesis and a slower progression of prostate cancer in a tumor xenograft model (29). Uemura et al reported that the clinical use of Candesartan in prostate cancer patients with hypertension resulted in a reduction of prostate-specific antigen, while patient performance status improved (32). However, they also reported that Candesartan had no effect on tumor growth in vitro, and did not detect apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Telmisartan as a peroxisome proliferator-activated receptor-γ ligand is a new target in the treatment of human renal cell carcinoma

Funao

Matsuyama²,

Kawahito³

et al. 2009

Mol Med Rep

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Abstract. Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agents. However, it has been reported that Telmisartan (a type of ARB) additionally activates peroxisome proliferator-activated receptor (PPAR)-Á. We previously reported that PPAR-Á ligand induced the growth arrest of renal cell carcinoma (RCC) cells through apoptosis, and that Telmisartan had the potential to inhibit prostate cancer cell growth through apoptosis. In this study, we evaluated the effects of Telmisartan and other ARBs on cell proliferation in an RCC cell line using normal proximal tubular endothelial cells (PRTECs) and the human RCC (Caki-1) cell line. The effects of Telmisartan as well as of other ARBs (Candesartan, Valsartan, Irbesartan and Losartan) on RCC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not the ARBs induced apoptosis. Telmisartan caused marked inhibition in RCC cells in a concentration-and time-dependent manner. Treatment with 100 μM of Telmisartan induced early apoptosis and DNA fragmentation in the RCC cells, but not in the PRTECs. None of the other ARBs had an effect on cell proliferation in the RCC cells or the PRTECs. Telmisartan may mediate potent antiproliferative effects against RCC cells through PPAR-Á. Thus, Telmisartan is a potential target for prevention and treatment in RCC.

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Pilot study of angiotensin II receptor blocker in advanced hormone-refractory prostate cancer

Abstract: These data showed that an ARB had potential biological effects on prostate cancer, suggesting the usefulness of the cytostatic activity of such agents on recurrent prostate cancer.

Cited by 62 publications

References 22 publications

The renin–angiotensin system in the breast and breast cancer

The renin–angiotensin system in the breast and breast cancer

Telmisartan inhibits human urological cancer cell growth through early apoptosis

Telmisartan as a peroxisome proliferator-activated receptor-γ ligand is a new target in the treatment of human renal cell carcinoma

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