Current Cancer Drug Targets - Volume 11, Issue 4, 2011

The renin-angiotensin system (RAS) plays a critical role in the regulation of the cardiovascular system, and the RAS is present in various local organ systems. A retrospective cohort study raised the possibility of protection against cancer by the use of angiotensin converting enzyme (ACE) inhibitors. It has been reported that angiotensin II (Ang-II) is implicated in the development or invasion of several kinds of cancer tissue. There has recently been clinical evidence supporting the involvement of Ang-II in carcinogenesis. Continuously, several studies concerning the association between antihypertensive medication and cancer risk have been reported. This special issue of CCDT aims to provide an overview of important aspects on the cutting edge of RAS in cancer. Gallagher et al. focus on studies examining the RAS in pulmonary cancers and whether clinical intervention in this pathway may serve as an effective chemotherapeutic or chemopreventive modality for lung cancer. Ino et al. present the role of the RAS in the progression of gynecologic cancers and the clinical potential of blocking the RAS as a promising strategy for treatment. The review by Leung et al. appraises the current research progress on the role of the RAS in pancreatic cancer, and discusses the potential for developing drugs to target the RAS for treatment of pancreatic cancer. Ruiter et al. summarize the insertion/deletion polymorphism in the ACE gene in association with the risk of cancer and consequently on its potential role as therapeutic drug target in cancer. Yoshiji et al. concentrate upon the possible application of widely available agents, ACE inhibitor and/or angiotensin-II type I receptor blocker (ARB) against hepatocellular carcinoma as alternative agents in clinical practice. Uemura et al. present a potential role of the RAS in various aspects of prostate cancer, and useful treatment or chemoprevention by using ARBs for prostate cancer.

Lung cancer is a leading cause of death in both men and women, with over 1,000,000 new cases diagnosed worldwide annually and a 5-year survival rate of only 14%, a figure that has improved little in the past thirty years. This poor prognosis suggests a need for novel approaches for the treatment and prevention of lung cancer. The reninangiotensin system is an established, primary regulator of blood pressure, homeostasis, and natriuresis; however, compelling evidence indicates that the angiotensin peptides also play a role in cell proliferation and inflammation. Angiotensin II is a vasoconstrictor, a mitogen, and an angiogenic factor, while angiotensin-(1-7) has vasodilator, antiproliferative, and anti-angiogenic properties. This review focuses on studies examining the renin-angiotensin system in pulmonary cancers and whether clinical intervention of this pathway may serve as an effective chemotherapeutic and/or chemopreventive modality for lung cancer.

Recent studies have shown an activation of the local renin-angiotensin system (RAS) in various tumor tissues, including the abundant generation of angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and the upregulation of angiotensin II type 1 receptor (AT1R) expression. Thus, considerable attention has been paid not only to the role of the RAS in cancer progression, but also to the blockade of RAS as a new approach to the treatment of human cancer. There is increasing evidence that the Ang II-AT1R pathway is involved in tumor growth, angiogenesis and metastasis in various experimental animal models, suggesting the therapeutic potential of an ACE inhibitor and AT1R blocker. In addition, specific Ang II-degrading enzymes are also expressed in tumors and play a regulatory role in tumor cell proliferation and invasion. This review focuses on the role of the RAS in the progression of gynecologic cancers, such as cervical cancer, endometrial cancer, ovarian cancer, and gestational choriocarcinoma. We present here the clinical potential of blocking the RAS as a novel and promising strategy for the treatment of gynecologic cancers.

Angiotensin II (Ang II), a main effector peptide of the renin-angiotensin system (RAS), mediates a hormonal action in the maintenance of blood pressure and electrolyte levels, and thus fluid homeostasis. Ang II also mediates paracrine, autocrine and/or intracrine actions in the control of various specific functions of diverse tissue organs. In the pancreas, Ang II exerts a growth promoting, angiogenic influence via the mediation of angiotensin II type 1 receptor (AT1R). Recent studies have implicated inappropriate activation of the local RAS in pancreatic cancer, including upregulation of AT1R and the angiotensin-converting enzyme (ACE), which consequently enhance Ang II-induced tumour activity. In addition to acting in a classical antihypertensive capacity, RAS blockers (AT1R blockers or ACE inhibitors) may yield protective effects against pancreatic cancer, a highly aggressive malignancy that is intrinsically resistant to radiotherapy and chemotherapy. Substantial experimental data from studies using cell and animal models of pancreatic cancer support the notion that RAS regulates tumour growth, angiogenesis, and metastasis; and a convergence of such findings suggests that pharmacological RAS blockade could have therapeutic potential in the management of pancreatic cancer. This review critically appraises the current research progress on the role of RAS in pancreatic cancer, and discusses the potential for developing drugs that target RAS for treatment of pancreatic cancer.

The renin-angiotensin system (RAS) plays an important role in the regulation of the cardiovascular system. In addition to RAS enzymes in plasma, the RAS is present in various local organ systems. Moreover, local expression of the RAS has been shown in various malignant cells. In 1990, an insertion/deletion (I/D) polymorphism in the ACE gene was discovered, accounting for half of the variance of the serum ACE enzyme levels. Serum ACE concentrations were significantly higher in homozygotes with the shorter deletion allele (DD) than in heterozygotes (ID) or in homozygotes with the longer insertion allele (II). Since 2000, twentyfour studies have been published hypothesizing an association between the ACE I/D polymorphism and cancer risk. This review focuses on the insertion/deletion polymorphism in the ACE gene in association with the risk of cancer and consequently on its potential role as therapeutic drug target in cancer. Furthermore a meta-analysis of the published studies was performed. Fourteen statistically non-significant studies were found, as well as ten studies with a statistically significant finding. The results of the meta-analyses performed were not consistent. However, both methods (one based on the Fisher p-value, and one on inverse variance weighted meta-analysis), indicated a (nearly) statistically significantly decreased risk in carriers of the II genotype in comparison to the DD genotype with regard to risk of prostate cancer and risk of (postmenopausal) breast cancer. Nevertheless, results show a large variation and are often contradictory. As this may be partly explained by a lack of power, genotyping techniques, and choice of study population, it is expected that future studies will shed more light on these associations.

Angiogenesis is a complex and critical process essential for supporting the growth of hepatocellular carcinoma (HCC) as well as hepatocarcinogenesis. Recent studies have revealed that renin-angiotensin system (RAS) is involved in many types of cancer including HCC. Some studies have proven that suppression of angiotensin-II (AT-II) by a clinically used angiotensin-converting enzyme inhibitor (ACE-I) significantly attenuated the HCC growth and hepatocarcinogenesis along with down-regulation of a potent angiogenic factor; namely, the vascular endothelial growth factor (VEGF). When used in combination with the clinical available drugs such as interferon (IFN) and vitamin K (VK), ACE-I exerted more potent anti-tumor activities as compared with either single agent in addition to suppression of the intra-tumoral angiogenesis both in experimental models and clinical practice. It is well known that AT-II plays an important role in the insulin resistance (IR), and IR is reportedly involved in the progression of HCC. The combination of ACE-I and branched-chain amino acids (BCAA) exerted a marked chemopreventive effect against HCC under the condition of IR. In addition to AT-II, aldosterone (Ald), which plays a role in the downstream of AT-II, is also involved in the HCC development, and a clinically used selective Ald blocker (SAB) significantly suppressed the HCC growth and hepatocarcinogenesis. Since ACE-I, IFN, VK, BCAA, and SAB are already in widespread clinical use without any serious adverse effects, they may represent a potential new strategy for cancer therapy and chemoprevention against HCC especially in combination with other angiostatic agents.

Angiotensin II (Ang-II) plays a role not only as a vasoconstrictor in controlling blood pressure and electrolyte and fluid homeostasis, but also as a mitogenic factor through the Ang-II type-1 (AT1) receptor in cardiovascular cells. Since a low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors has been reported, the molecular mechanisms of the renin-angiotensin system (RAS) in cancer cells have been elucidated. Interestingly, there is increasing evidence that the RAS is implicated in the development of prostate cancer. As previously reported, AT1 receptor blockers (ARBs), a class of antihypertensive agent, have the potential to inhibit the growth of prostate cancer cells and tumors through the AT1 receptor. This review highlights that the RAS plays a potential role in various aspects of prostate cancer, and ARBs could be useful for treatment of prostate cancer or its chemoprevention.

Patients with inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are at increased risk of developing colon cancer, confirming that chronic inflammation predisposes to development of tumors. Moreover, it appears that colon cancers that do not develop as a complication of inflammatory bowel disease are also driven by inflammation, because it has been shown that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the mortality from sporadic colon cancer and results in regression of adenomas in familial adenomatous polyposis (FAP) patients, who inherit a mutation in the Apc gene. Colorectal cancer therefore represents a paradigm for the link between inflammation and cancer. Inflammation is driven by soluble factors, cytokines and chemokines, which can be produced by tumor cells themselves or, more often, by the cells recruited to the tumor microenvironment. Inflammatory cytokines and chemokines promote growth of tumor cells, perturb their differentiation, and support the survival of cancer cells. Tumor cells become addicted to inflammatory stroma, suggesting that the tumor microenvironment represents an attractive target for preventive and therapeutic strategies. Proinflammatory cytokines, such as TNFα, IL-6 and IL-1β, or transcription factors that are required for signaling by these cytokines, including NF-κB and STATs, are indeed emerging as potential targets for anticancer therapy. TNFα antagonists are in phase I/II clinical trials and have been shown to be well tolerated in patients with solid tumors, and IL-1β antagonists that ameliorate several inflammatory disorders characterized by excessive IL-1β production, will likely follow. Therefore, development of drugs that normalize the tumor microenvironment or interrupt the crosstalk between tumor and the tumor microenvironment is an important approach to the management of cancer.

In addition to the currently available conventional therapeutic modalities i.e. chemotherapy, radiotherapy and surgery, there is a desperate need for more effective and less toxic therapies for head and neck malignancies. Chemotherapy alone shows high toxicity and a low survival rate. In some cases, malignant cells develop resistance to a particular drug and to combat this, a variety of approaches like intra-arterial therapy, induction chemotherapy, immunotherapy, photodynamic therapy as well as targeted molecular therapy have recently been employed. Techniques like intra-arterial and induction chemotherapy have showed some improvement in survival rate. Immununotherapy is in the experimental stages while photodynamic therapy is being clinically applied, but because of its side effects it is not very popular. Utilizing specific molecular targets with their inhibitors (like inhibitors of EGFR and VEGF); either alone or in combination with conventional therapy, may improve the survival rate of these patients. Blocking the signaling pathway (P13k/Akt/mTOR), with or without chemotherapy, may also overcome the problem of drug resistance. These modalities hold the promise of being more selective - harming fewer normal cells, reducing side effects and improving the quality of life. The various options and novel strategies currently available to the treating physician are critically examined in this review.

This review attempts to provide a broad overview of the changes in the cellular redox environment in breast cancer cells. The regulatory power of the redox environment lies in its capacity to control the growth behavior, spread, and differentiation. Neoplastic cells adapt to a wide variety of environmental conditions, including persistent oxidative stress and genomic instability by shifting their redox environment to more reductive conditions, which in its turn triggers upregulation of various redox sensitive prosurvival pathways. This review also examines the interactions between prosurvival signaling pathways, metallothioneins, and hydrogen peroxide generating dual oxidase, and presents a hypothesis to explain their relevance for therapeutic response.

Kinases are enzymes that are involved in a wide-range of cellular targets such as cell proliferation, metabolism, survival and apoptosis. Aberrations in the activity of the kinases have been linked to many human diseases such as diabetes, inflammation and cancer. The discovery of more than 518 kinases encoded by the human genome has spurred the development of rapid screening techniques for potential drugs against these enzymes and these have been identified as interesting targets for medicinal chemistry programs, especially in cancer therapy. On the other hand, sulfur and selenium have been increasingly recognized as essential elements in biology and medicine. Converging data from epidemiological and clinical studies have highlighted these elements as effective chemopreventive agents, particularly against various types of cancer (prostate, lung, breast, leukemia, colon, skin, lymphome, thyroid, pancreas, liver). These elements act through a wide range of potential mechanisms where one identified signal pathway event is kinase modulation, which is common for the two elements and emerges as a valid target. The kinases modulated by sulfur and selenium derivatives include MAP, ERK, JNK, Akt, Cdc2, Cyclin B1 and Cdc25c amongst others. Although both of the elements in question are in the same group in the periodic table and have similar biochemistries, there are relevant differences related to redox potentials, stabilities, oxidation states and anticancer activity. Literature data suggest that the replacement of sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs. In view of the multi-target kinase mechanisms in preventing cellular transformation, as well as the differences and similarities between them, in this review we focus on the development of new structures that contain selenium and/or sulfur and discuss our understanding of the regulation of antitumoral effects with emphasis on kinase modulation activity and its implications in cancer.

Both the nonreceptor tyrosine kinase Src and the receptors for transforming growth factor (TGF)-β (TβRI, TβRII) play major roles during tumorigenesis by regulating cell growth, migration/invasion and metastasis. The common Src family kinase inhibitors PP2 and PP1 effectively block Src activity in vitro and in vivo, however, they may exert nonspecific effects on other kinases. In this study, we have evaluated PP2 and PP1 for their ability to inhibit TGFβ1-mediated responses in the TGF-β-responsive pancreatic adenocarcinoma cell line Panc1. We show that PP2 and PP1 but not the more specific Src inhibitor SU6656 effectively relieved TGF-β1-induced growth arrest and p21WAF1 induction, while basal growth was enhanced by PP2 and PP1, and suppressed by SU6656. PP2 and PP1 but not SU6656 also suppressed TGF-β1-induced epithelial-to-mesenchymal transition (EMT) as evidenced by their ability to inhibit downregulation of the epithelial marker E-cadherin, and upregulation of the EMT-associated transcription factor Slug. Likewise, PP2 and PP1 but not SU6656 effectively blocked TGF-β1-induced activation of Smad2 and p38 MAPK and partially suppressed Smad activation and transcriptional activity on TGF-β/Smad-responsive reporters of a kinase-active TβRI mutant ectopically expressed in Panc1 cells. Interestingly, PP2 and PP1 strongly inhibited recombinant TβRI in an in vitro kinase assay, with PP1 being more potent and PP2 being nearly as potent as the established TβRI inhibitor SB431542. PP2 but not PP1 also weakly inhibited the TβRII kinase. Together, these data provide evidence that PP2 and PP1 are powerful inhibitors of TβR function that can block TGF-β/Smad signaling in a Src-unrelated fashion. Both agents may be useful as dual TGF-β/Src inhibitors in experimental therapeutics of late stage metastatic disease.