Blood pressure drugs, angiotensin-receptor blockers, and risk of cancer: meta-analysis of randomized controlled trials

A recent study by Sipahi et al. published in The Lancet Oncology suggests that angiotensin-receptor blockers (ARBs) may be associated with a "modestly" increased risk of cancer. However, conclusions about the exact risk of cancer associated with each particular drug were not possible to draw due to study limitations.

ARBs are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression.

This study assessed whether ARBs affect cancer occurrence with a meta-analysis of randomized controlled trials of these drugs by searching Medline, Scopus (including Embase), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the US Food and Drug Administration website for studies published before November, 2009, that included any of the seven currently available ARBs.* Randomized controlled trials with an ARB given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included. The following information was available:

• New-cancer data for 61, 590 patients from five trials
• Data on common types of solid organ cancers for 68, 402 patients from five trials
• Data on cancer deaths for 93, 515 patients from eight trials.

Telmisartan was the study drug in 30, 014 (85.7%) patients who received ARBs as part of the trials with new cancer data. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7.2% vs 6.0%, risk ratio [RR] 1.08, 95% CI 1.01—1.15; p=0.016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1.11 (95% CI 1.04—1.18, p=0.001). Among specific solid organ cancers examined, only new lung cancer occurrence was significantly higher in patients randomly assigned to receive ARBs than in those assigned to receive control (0.9% vs 0.7%, RR 1.25, 1.05—1.49; p=0.01). No statistically significant difference in cancer deaths was observed (1.8% vs 1.6%, RR 1.07, 0.97—1.18; p=0.183).

This meta-analysis of randomized controlled trials suggested that ARBs were associated with a modestly increased risk of new cancer diagnosis. The researchers concluded that due to the limited data, it was not possible to draw conclusions about the exact risk of cancer associated with each particular drug, and these findings warranted further investigation.

*Drugs in this class include:

• Atacand (candesartan) (AstraZeneca)
• Avapro (irbesartan) (sanofi-aventis and Bristol Myers Squibb)
• Benicar (omesartan) (Daiichi Sankyo) 
• Cozaar (losartan) (Merck & Co.)
• Diovan (valsartan) (Novartis)
• Mycardis (telmisartan) (Boehringer Ingelheim and Astellas)
• Teveten (eprosartan) (Solvay)
  

Reference
Sipahi I, Debanne SM, Rowland DY, et al. Blood pressure drugs, angiotensin-receptor blockers and risk of cancer: meta-analysis of randomized controlled trials. Lancet Oncol, Early Online Publication, 14 June 2010, doi:10.1016/S1470-2045(10)70106-6 .

Stem-cell-like properties of normal and malignant epithelial cells contribute to cell-death resistance

It is not well understood why carcinomas reemerge after chemotherapy and/or radiation treatments. Cancer recurrence and treatment failure seems to be associated with stem-cell-like properties and resistance to apoptosis (programmed cell death) in a subset of cells that have been previously isolated from human epithelial cancers.
One study investigated the mechanisms of apoptosis resistance of cells with stem-cell-like properties in both normal and malignant human epithelia, and whether altered cell cycle regulation played a role.

To address these questions, the following methodology was employed:

• Cells were isolated from fresh human head and neck carcinomas (n = 11), cell lines derived from head and neck, prostate and breast human carcinomas (n = 7), and from normal human oral mucosa (n = 5)
• All cells were exposed to various apoptosis-inducing stimuli (UV, tumour necrosis factor, cisplatin, etoposide, and neocarzinostatin)
• The subset of cells with stem-cell-like properties were identified by flow cytometry for CD44 and epithelial-specific antigen (ESA) expression, colony morphology, tumour sphere formation and rapid adherence assays
• Apoptosis, cell cycle and expression of various cell cycle checkpoint proteins were assessed by Western Blot and quantitative PCR (qPCR)
•  Debromohymenialdisine (DBH) and small interfering RNA (siRNA) were used to investigate the role of G2-checkpoint regulators Chk1 and Chk2

 The study demonstrated the following:

•  A subset of CD44high cells were found in both cancer biopsies and carcinoma cell lines that showed increased clonogenicity, a significantly lower rate of apoptosis, and a significantly higher proportion of cells in the G2-phase of the cell cycle. An inverse correlation between the Percentage of cells in G2-phase and the rate of apoptosis revealed an inverse correlation.
• It appeared that CD44high carcinoma cells spent longer time in G2, even in untreated controls as shown by pulse-chase with iododeoxyuridine (IdU). These cells expressed higher levels of G2 checkpoint proteins, and their release from G2 with BDH or Chk1 siRNA increased their rate of apoptosis.
• Interestingly, low passage cultures of normal keratinocytes were found to contain a subset of CD44high cells which also showed increased clonogenicity, and a similar pattern of G2-block associated with apoptotic resistance.

Conclusions

The results of this study suggested that not only malignant, but also normal human epithelial cells with stem-cell-like properties have extended G2 cell cycle phase which is associated with greater resistance to apoptosis, and that this property is not a consequence of neoplastic (cancerous) transformation (i.e. not unique to cancer cells). This knowledge provides an opportunity for novel therapeutic approaches targeting G2 checkpoint proteins to release these cells from the G2-block and make them more prone to apoptosis.

Abbreviations
PCR = polymerase chain reaction; RNA = ribonucleic acid

Reference

Harper LJ, Costea DE, Gammon L, et al. Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance. BMC Cancer 2010, 10:166doi:10.1186/1471-2407-10-166.

Free full-text article available at: http://www.biomedcentral.com/1471-2407/10/166