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J Am Coll Cardiol, 1999; 34:1857-1866
© 1999 by the American College of Cardiology Foundation
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REVIEW ARTICLES

Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?

R. Preston Mason, PhDa

a Membrane Biophysics Laboratory, Cardiovascular and Pulmonary Research Institute, Departments of Biochemistry and Medicine, MCP Hahnemann University School of Medicine, Allegheny Campus, Pittsburgh, Pennsylvania, USA

Manuscript received March 4, 1999; revised manuscript received June 24, 1999, accepted August 27, 1999.

Reprint requests and correspondence: Dr. R. Preston Mason, Director, Membrane Biophysics Laboratory, Allegheny General Hospital, 320 E. North Avenue, 2ST, Pittsburgh, Pennsylvania 15212-4772
mason{at}pgh.auhs.edu


   Abstract
Top
 Abstract
Overview
 Discussion
 References
 
Calcium channel blockers (CCBs) represent a chemically and pharmacologically diverse group of agents that are widely used for the treatment of hypertension and angina. A small number of retrospective, observational analyses have raised concern about a potential causal link between CCB use and an increased risk for cancer development. Despite the absence of cancer findings in extensive preclinical studies, it has been proposed that CCBs may work differently in humans by interfering with apoptosis, leading to an increased potential for abnormal cell proliferation and tumor growth. This biologic hypothesis has attracted considerable attention in the medical community but has not been critically evaluated. An analysis of the basic and clinical literature was conducted to examine biologic relationships among cell Ca2+ modulation, apoptosis, and cancer. In addition to a comprehensive review of the cellular and animal data, the results of large observational studies were included in this analysis. Results of this review demonstrated that the effects of CCBs on apoptosis are complex as both increases and decreases in intracellular Ca2+ have been linked to this form of programmed cell death. Most studies show that an effect (either positive or negative) of CCBs on apoptosis requires doses in the supra-pharmacologic range, and are therefore not clinically relevant. Results of large and methodologically robust observational studies fail to provide support for the hypothesis that CCB use is associated with an increased susceptibility for cancer incidence. A comprehensive analysis of the basic and clinical evidence does not support a causal relationship between the therapeutic use of CCBs and an increased incidence of cancer development as a result of interfering with apoptosis.

Abbreviations and Acronyms
  Ca2+ = calcium
  CCB = calcium channel blocker
  RR = relative risk
  TUNEL = terminal deoxynucleotide transferase-mediated dUTP-biotin nick end labeling


   Overview
Top
 Abstract
 Overview
Discussion
 References
 
With the introduction of specific L-type calcium channel blockers (CCBs) for the treatment of hypertension and angina, the effects of these compounds on the development and spread of cancer have been carefully investigated over the past two decades. Results of these studies have provided important insights into the biologic relationship between cell calcium (Ca2+) regulation and mechanisms of proliferation. The objective of this review was to critically evaluate the hypothesis that CCB use is associated with increased carcinogenic potential by interfering with cellular apoptosis, an important form of programmed cell death. This analysis was based on a comprehensive review of cellular, animal, and human evidence on this subject. At the cellular level, the demonstrated effects of CCBs and Ca2+ on apoptosis are complex as both increases and decreases in intracellular Ca2+ can be linked to apoptosis. Although CCBs inhibit apoptosis in certain nontransformed cell lines at supra-pharmacologic concentrations, a number of independent reports have shown that CCBs promote apoptosis in transformed cell lines, leading to a reduction in tumor development. Extensive preclinical animal studies have failed to demonstrate a link between extended CCB use and increased rates of neoplasia or developmental defects. The animal safety data are validated, in turn, by an analysis of a number of large and methodologically sound clinical investigations. Thus, a critical and objective review of the basic and clinical evidence does not support the hypothesis that CCB use is associated with an increased risk for cancer development as a result of interfering with apoptosis.


   Discussion
Top
 Abstract
 Overview
 Discussion
References
 
Apoptosis: A complex biologic process.   In the past decade, considerable scientific attention has been directed to the cellular regulation of apoptosis, a form of programmed cell death associated with embryogenesis and tissue turnover. In biologic systems, apoptosis is a genetically regulated, energy-dependent process that effects cell death and removal in an efficient manner (1). During animal development, apoptosis is required for the efficient modeling and development of tissue derived from the early blastocyst. Apoptosis is especially critical to the proper formation of the emerging central nervous system; during development, as many as 50% of cells that form the nervous system die before full maturation as a result of programmed cell death. In the adult organism, the regulation of normal tissue mass is controlled by a balanced production of growth and death factors that regulate mitosis and apoptosis, respectively.

As a mechanism of cell death, apoptosis is very distinct from necrosis: whereas apoptosis is a deliberate process modulated by specific genetic pathways, necrosis can be considered accidental, as when a toxin blocks cellular functions necessary for survival (2). Morphologically, the cell undergoing apoptosis is characterized by a reduction in cell volume, while the chromatin becomes pyknotic and condensed into delineated fragments associated with the nuclear envelope. Nuclear condensation during apoptosis can be detected by microscopy approaches, especially confocal laser scanning microscopy. The nuclear chromatin in the apoptotic cell then condenses, typically followed by a loss of the nuclear membrane and fragmentation of the nuclear DNA into discrete, 180 to 200-bp fragments (3). When run on a gel, the fragments are distributed in a periodic fashion, referred to as "DNA laddering." The DNA breaks associated with apoptosis can be visualized by microscopy following terminal deoxynucleotide transferase-mediated dUTP-biotin nick end labeling (TUNEL) and in situ end labeling (4). TUNEL approaches are commonly used in combination with other techniques (microscopy, gel electrophoresis) to demonstrate apoptosis, because necrotic cells have also been shown, at times, to stain with this technique (5). In addition to DNA fragmentation, apoptosis is characterized by condensation of the cytoplasm, elimination of microvilli, and cell-surface blebbing. In the latter stages of apoptosis, prominent surface protrusions eventually separate and form sealed plasma membrane vesicles; the entire cell is thus reduced to microscopic bodies of various size and content that are efficiently eliminated by parenchymal cells and mononuclear phagocytes without generally triggering an immunologic response. Thus, apoptosis is very distinct from necrosis, as reviewed in Table 1.


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  		Table 1 Apoptosis and Necrosis: Two Distinct Mechanisms of Cell Death

 
Although apoptosis contributes to both tissue development and maintenance, it is also clear that abnormal regulation of this process can be highly deleterious. Apoptosis at an inappropriate time or place, or in excessive or insufficient amounts, leads to impaired cellular plasticity and, ultimately, aberrant tissue structure and function. In this context, excessive apoptotic cell death has been observed in association with cardiovascular, neurological and immune diseases (2,6–8). In the cardiovascular system, excessive apoptosis has been associated with the pathogenesis of heart failure, coronary artery disease, hypertension and arrhythmogenic right ventricular dysplasia. Abnormal apoptosis has also been observed in animal models of ischemia-reperfusion injury, atherosclerosis, hypoxia, rapid ventricular pacing, pressure-induced cardiac overload, and myocardial infarction (6,7,9–25) (Table 2). The development of pharmacologic agents that can inhibit abnormal cell loss by apoptosis may hold important promise for the treatment of cardiovascular disease and is the subject of intense investigation.


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  		Table 2 Evidence for Apoptosis in Cardiovascular Disease

 
Effects of cell Ca2+ modulation on apoptotic cell death.   The ubiquitous role of Ca2+ in cell biology would lead one to suspect that it could have some effect on the complex process of apoptosis. It is difficult to predict a priori, however, how changes in any single pathway will ultimately affect the plethora of Ca2+-regulated cell mechanisms. In fact, both increases and decreases in cellular Ca2+ levels have been shown to promote apoptotic cell death (26–33). In general, the prevailing view is that elevations in intracellular Ca2+ may be one of the key signals leading to the promotion of apoptosis. Specifically, a link between elevations in Ca2+ levels and apoptosis suggests that this ion can activate key cation-dependent endonucleases required for the enzymatic cleavage of nuclear chromatin into small, discrete fragments (26). An alternative hypothesis is that elevated Ca2+ levels can alter the conformation of nuclear chromatin in a manner that makes it more accessible to endonuclease cleavage. However, apoptosis may still occur even in the absence of internucleosomal DNA (34,35).

A search for the intracellular source of Ca2+ that is involved in the activation of nuclear enzymes during apoptosis has been carefully examined at the cellular level. An increase in Ca2+ levels within the cell nucleus preceding DNA fragmentation can be attributed to a selective increase in Ca2+ permeability through nuclear pores and/or upregulation of Ca2+ transport from perinuclear pools (36). This observation argues that the increase in nuclear Ca2+ levels is the result of intracellular Ca2+ mobilization, as opposed to transmembrane influx via voltage-sensitive Ca2+ channels regulated by CCBs (28). A detailed discussion on the intracellular source of Ca2+ that may be involved in apoptosis has been previously covered by Nicotera et al. (36).

Complex effects of CCBs on apoptosis.   With the advent of pharmacologic modulators of L-type CCBs, there has been considerable interest over the past two decades in the effects of these agents on apoptosis and cell proliferation (37). Several investigators have hypothesized that CCB use is associated with an increased risk for tumor development by reducing the levels of intracellular Ca2+ (38–40), a potential signal for cellular apoptosis (26,41–43). This basic assumption, however, is directly contradicted by the findings of a number of laboratories, demonstrating that an elevation in cytoplasmic Ca2+ is not required for either the activation of DNA endonucleases or apoptosis itself (27,30,44,45); apoptosis can be reproducibly initiated by a decrease in cytyoplasmic Ca2+ levels (27–33). Although not fully understood, it has been proposed that low Ca2+ levels prevent cation-mediated charge neutralization of DNA, resulting in the stimulation of apoptosis. In fact, chelators of intracellular Ca2+ and the calmodulin inhibitor W-7 have been shown to effectively accelerate the rate of apoptosis in neutrophils (46). Under cellular conditions characterized by a deficiency in cytoplasmic Ca2+, cells can be rescued from apoptotic cell death with the use of Ca2+ ionophores or Ca2+ channel agonists (31,33). This lack of an apparent requirement for elevated Ca2+ levels in the cytoplasm during apoptosis suggests that the activation of cation-sensitive DNA endonucleases may require only very low levels of Ca2+ or may not even be an essential process (27). This observation could help to rationalize why CCBs have inconsistent effects on apoptosis (Tables 3 and 4).


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  		Table 3 CCBs Promote Cellular Apoptosis in Cancer Cells, Leading to a Reduction in Growth

 

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  		Table 4 Contradictory Effects of CCBs on Apoptosis in Noncancerous Cells

 
A review of the literature indicates that the effects of CCBs on mechanisms of apoptosis are both Ca2+-dependent and -independent. A number of separate reports have shown that the addition of CCBs directly promote apoptosis in both transformed and nontransformed cell models (29–32,47–55), highlighting the fact that the role of these agents in this process is difficult to predict (Tables 3 and 4). Inhibition of apoptosis by CCBs has been also reported, but only in noncancerous systems, and this effect did not lead to tumor development (Table 4). In every study on this subject, the antiapoptotic effects of CCBs were beneficial, as in the case of blocking the apoptotic destruction of pancreatic beta-cells (50) and endothelial cells (55,56). In most reports, the CCB concentrations necessary to modulate rates of apoptosis (either positively or negatively) were as much as 1,000-fold higher than normal pharmacologic levels, as in the case of prostatic glandular cells (41). Although scientifically intriguing, such high levels of CCBs would not be found among patients that use these agents for the treatment of hypertension and angina.

At supra-pharmacologic CCB levels, one can only speculate about the mechanism of action by which these agents interfere with the process of apoptosis. Several studies report that CCB modulation of apoptosis is entirely independent of pharmacologic manipulation of Ca2+-flux through membrane channels (29,30,51); the ability of CCBs to influence apoptosis at these elevated levels could be attributed to interactions with intracellular kinases and membrane transport proteins. Thus, the basic assumption that pharmacologic levels of CCBs inhibit apoptosis by interfering with cell Ca2+ homeostasis and, hence, increase an organism’s carcinogenic potential is not supported by the scientific literature. By contrast, substantial support exists for the opposite to be true: CCBs can promote apoptosis in transformed cells, especially when administered in combination with chemotherapeutic agents, resulting in the inhibition of abnormal cell proliferation (29–32,47–55) (Tables 3 and 5).


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  		Table 5 CCBs Inhibit Cancer Growth in Cellular and Animal Models

 
Activity of CCBs in experimental models of cancer.   Calcium channel blockers bind to membrane-bound, L-type voltage-sensitive channels in vascular smooth muscle cells at very low concentrations (low nanomolar levels) in a remarkably specific and reversible manner (57–59). At low pharmacologic levels, CCBs have no apparent effects on other ion channels or intracellular transduction pathways. Indeed, if CCBs contribute to tumor development by interfering with Ca2+-mediated apoptosis, then one would expect to see increased cancer rates with CCB use in tissues enriched with these Ca2+ channels, such as blood vessels or skeletal muscle. Increases in cancer have not been reported in these areas, however, even at elevated levels administered over an extended period of time (60,61).

Contrary to contributing to tumor development, a number of laboratories have demonstrated that CCBs may be effective in blocking abnormal cell proliferation when used either alone or as adjunctive therapy with standard chemotherapeutic agents (29,48,62–74), as shown in Table 5. A summary of the established mechanisms by which CCBs may interfere with carcinogenesis is reviewed in Table 6. In many cases, the beneficial mechanism of action for these agents, especially in drug-resistant tumors, appears to be entirely independent of Ca2+ channel modulation (29,75–77). The lipophilic CCB verapamil, in particular, has been shown to be effective in improving the efficacy of agents used to treat certain cancers as a result of interfering with the function of the membrane-bound MDR1 protein (78–80). In addition, the antitumor activity of the dihydropyridine CCB nifedipine was demonstrated in human glioblastoma cells. When used in combination with cisplatin, nifedipine inhibited tumor growth by inducing apoptosis (29).


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  		Table 6 Effects of CCBs on Mechanisms of Carcinogenesis

 
The benefit of CCBs in models of cancer is also due to the fact that the Ca2+ ion itself has an important role as a mitogenic signal that stimulates abnormal cell growth (63,64,70,72,81,82). For this reason, CCBs alone can be effective in the treatment of certain types of tumors by maintaining normal Ca2+ homeostasis. In a breast cancer system, for example, it was reported that representative CCBs (diltiazem, amlodipine, and verapamil) were very effective in blocking the growth of human breast cancer cells in a concentration-dependent manner (63). In parallel animal studies, CCBs dramatically inhibited tumor growth as compared to controls, by reducing excessive cell Ca2+ levels linked to abnormal cell growth (63). As these effects were observed using pharmacologic levels of the drugs, the authors of that study suggest that CCBs may be useful in the treatment of certain Ca2+-dependent neoplasias, such as breast cancer (63). Moreover, CCBs have been shown to be effective in blocking proliferation of nontransformed cell lines following mitogenic stimulation, an observation that also has therapeutic implications in the pathogenesis of hypertension and atherosclerosis (83–86). Finally, the antioxidant activity of certain CCBs may also interfere with abnormal cell proliferation mechanisms (87–92). Well-known antioxidants such as vitamin E have been shown to be successful inhibitors of cancer growth, presumably by interfering with oxy-radical-mediated cell damage (93–96). Similarly, electron-rich dihydropyridine CCBs are very effective as "chain-breaking" antioxidants, especially analogs that have high affinity for the cell membrane (97).

Beyond cellular systems of investigation, the effects of CCBs on tumor development have been extensively and systematically evaluated in well-defined animal models, as required by government regulatory agencies. The whole animal represents a fully integrated system in which to evaluate the potentially complex and multifactorial effects of these compounds on cancer development. In addition to reproducing human physiologic processes, animal studies also provide the opportunity to evaluate CCB activity at supra-pharmacologic doses. Results of these studies demonstrated that CCB used neither increased rates of mutagenesis nor affected the frequency of tumor development in the animals, even when administered during the entire life span (60,61). Animal genotoxicity animal studies are consistent with large observational studies that have failed to demonstrate a consistent increase in overall risk for cancer among hypertensive patients using CCBs (98–115).

CCB effects on cancer incidence in human studies.   A retrospective analysis by Pahor et al. (116) raised concern about a potential link between CCB use and an increased susceptibility to cancer. Although the authors of that study acknowledged methodologic limitations with the study, their results have nonetheless raised significant concern in the medical community and the general public as a result of widespread media reports. This concern has stimulated a careful analysis of the clinical data related to this question, as reviewed in Table 7. The overwhelming majority of observational analyses failed to find an increased risk for cancer in association with CCB use (98–112,114,115). An exception is the report by Pahor and colleagues (116) that compared, in retrospective fashion, cancer incidence in 202 elderly patients on CCBs only (primarily short-acting agents) to 424 subjects on beta-blockers only. The reason for this anomalous finding may be due to several methodologic limitations (106,117–119), including:


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  		Table 7 Effect of CCB Use on Human Cancer Incidence

 
By contrast, a much larger study by Jick et al. (106) demonstrated no correlation between CCB dose or time of exposure with measured changes in cancer incidence among patients, including elderly subjects. These clinical findings serve to undermine a causative role for CCBs in cancer development. Similar in design to the study by Pahor et al. (116), Jick et al. (106) compared hypertensive patients who were using CCBs only (n = 751) to those on either beta-blockers (n = 938) or ACE inhibitors (n = 507). However, the Jick et al. study had several methodologic advantages over the previous analysis, including a much larger number of cancer cases (n = 446) and multiple study-drug exposure assessments, beginning at least four years prior to any diagnosis of cancer. Using a nested case-control analysis, the relative risk (RR) estimate for users of the highest doses of CCBs for the longest period in the study was low, 0.70 (95% CI: 0.24 to 2.1) (106). Overall, the RR of incidence for CCBs was inversely related to time of drug use; hypertensive patients who used CCBs for the longest time period in the study (at least four years) had a lower risk for cancer than did those taking the drug for less than one year (106). The lack of any correlation between drug use or time of exposure and carcinogenic potential argues persuasively against a cause-and-effect role for CCBs in cancer. In addition to an analysis of overall cancer incidence, the effects of CCBs on site-specific cancers, such as breast or prostate cancer, have also been carefully assessed, and the majority of these studies failed to support a causal relationship (Table 8).


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  		Table 8 Effect of CCB Use on Tissue-Specific Cancer Incidence

 
Any increase in rates of cancer associated with the use of antihypertensive medications may be attributed to the effects of hypertension, as opposed to any specific pharmacologic therapy (119,120). In support of this hypothesis, it is has been reported that other widely used antihypertensive medications, including beta-blockers and diuretics, have been linked to an increased risk for malignancy (114,121–130) (Table 9). Curiously, these studies did not attract nearly the same attention by the medical community as did the small number of negative reports related to CCBs. In general, changes in cancer rates associated with the use of these other antihypertensive agents were attributed to chance, and therefore dismissed. Nonetheless, these findings suggest that further study is needed into the biologic contribution of hypertension itself to mechanisms of cancer development (119,120).


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  		Table 9 Studies Linking the Use of Other Antihypertensive Agents to an Increased Risk for Cancer

 
Conclusions.   A biologic hypothesis that links CCB use to an increased risk for cancer as a result of interfering with apoptosis is not supported by the scientific literature. Over the past two decades, the role of Ca2+ in cellular apoptosis has been carefully investigated. Studies have shown that the effect of Ca2+ on apoptosis is complex: both increases and decreases in the levels of this ubiquitous ion have been associated with increases in apoptosis. With the development of pharmacologic modulators of L-type calcium channel modulators, intensive investigations have been pursued concerning their specific effects on apoptosis. Results of these analyses have been highly variable, depending on the experimental model and dose of drug utilized. Most studies have shown that an effect (either positive or negative) of these agents on apoptosis requires drug doses in the supra-pharmacologic range, and are therefore not relevant to the clinical use of these compounds. Safety of these agents with respect to cancer incidence has also been demonstrated in extensive preclinical animal studies and large clinical analyses. Thus, a comprehensive assessment of the cellular, animal, and human evidence indicates that use of CCBs would not be expected to increase the risk for cancer development by interfering with apoptosis. The World Health Organization (WHO) and the International Society of Hypertension reached a similar conclusion (131). A liaison committee from these groups stated, "The available evidence from observational studies does not provide good evidence of an adverse effect of calcium antagonists on cancer risk" (WHO 1997) (131).


   Acknowledgments
 
The author wishes to express his appreciation to Pamela E. Mason, M.S., for valuable discussions related to this manuscript. The author also acknowledges the excellent assistance of Carrie M. Blawas, B.S., in the preparation of this study.


   Footnotes
 
R.P. Mason acknowledges research support from a Nathan Shock Award (NIA/NIH) and PPG HL22633 (NHLBI/NIH).


   References
Top
 Abstract
 Overview
 Discussion
 References
 

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