Iron as a target of chemoprevention for longevity in humans

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.     

Iron as a target of chemoprevention for longevity in humans

Abstract

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.     

Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention

Trans-cinnamaldehyde (CA) and its analogs 2-hydroxycinnamaldehyde and 2-benzoyloxycinnamaldehyde have been reported to possess antitumor activity. CA is also a known Nrf2 activator. In this study, a series of ortho-substituted cinnamaldehyde analogs was synthesized and screened for antiproliferative and thioredoxin reductase (TrxR)-inhibitory activities. Whereas CA was weakly cytotoxic and TrxR inhibiting, hydroxy and benzoyloxy substitutions resulted in analogs with enhanced antiproliferative activity paralleling increased potency in TrxR inactivation. A novel analog, 5-fluoro-2-hydroxycinnamaldehyde, was identified as exhibiting the strongest antitumor effect (GI₅₀ 1.6 μM in HCT 116 cells) and TrxR inhibition (IC₅₀ 7 μM, 1 h incubation with recombinant TrxR). CA and its 2-hydroxy- and 2-benzoyloxy-substituted analogs possessed dual TrxR-inhibitory and Nrf2-inducing effects, both attributed to an active Michael acceptor pharmacophore. At lethal concentrations, TrxR-inhibitory potencies correlated with the compounds' antiproliferative activities. The penultimate C-terminal selenocysteine residue was shown to be a possible target. Conversely, at sublethal concentrations, these agents induced an adaptive antioxidant response through Nrf2-mediated upregulation of phase II enzymes, including TrxR induction. We conclude from the results obtained that TrxR inactivation contributes at least partly to cinnamaldehyde cytotoxicity. These Michael acceptor molecules can potentially be exploited for use in different concentrations in chemotherapeutic and chemopreventive strategies.     

Mitochondria: A novel target for the chemoprevention of cancer

The mitochondria have emerged as a novel target for anticancer chemotherapy. This tenet is based on the observations that several conventional and experimental chemotherapeutic agents promote the permeabilization of mitochondrial membranes in cancerous cells to initiate the release of apoptogenic mitochondrial proteins. This ability to engage mitochondrial-mediated apoptosis directly using chemotherapy may be responsible for overcoming aberrant apoptosis regulatory mechanisms commonly encountered in cancerous cells. Interestingly, several putative cancer chemopreventive agents also possess the ability to trigger apoptosis in transformed, premalignant, or malignant cells in vitro via mitochondrial membrane permeabilization. This process may occur through the regulation of Bcl-2 family members, or by the induction of the mitochondrial permeability transition. Thus, by exploiting endogenous mitochondrial-mediated apoptosis-inducing mechanisms, certain chemopreventive agents may be able to block the progression of premalignant cells to malignant cells or the dissemination of malignant cells to distant organ sites as means of modulating carcinogenesis in vivo. This review will examine cancer chemoprevention with respect to apoptosis, carcinogenesis, and the proapoptotic activity of various chemopreventive agents observed in vitro. In doing so, I will construct a paradigm supporting the notion that the mitochondria are a novel target for the chemoprevention of cancer.     

Connexins as targets for cancer chemoprevention and chemotherapy

Cells within a tissue continuously interact to coordinate normal tissue functions and maintain homeostasis. Gap junctional communication (GJC), mediated by the connexin protein family, allows this type of intercellular crosstalk resulting in synchronized and cooperative tissue behavior such as cardiac contraction. In cancer, loss of these types of cell:cell interactions has been shown to facilitate tumorigenesis and enable the autonomous cell behavior associated with transformed cells. Indeed, many human tumor lines demonstrate deficient or aberrant GJC and/or loss of connexin expression. Restoration of exogenous connexin expression/GJC function is correlated with increased cell growth control both in vitro and in vivo. In support of this growth regulatory hypothesis, decreased connexin expression has been observed in situ in early human neoplasia of various organs. Additionally, genetically engineered mice lacking particular connexins (Connexins 32 or 43) exhibit increased susceptibility to radiation and chemically-induced liver and/or lung tumorigenesis. These studies strongly suggest that connexins and GJC serve a tumor suppressor role. Consistent with this proposed role, in a model cell culture system, retinoids and carotenoids up-regulate Connexin43 (Cx43) expression in direct proportion to their ability to suppress carcinogen-induced neoplastic transformation. Here, we discuss the important role of connexins and GJC in tumorigenesis and suggest the possibility of connexins as potential anti-oncogenic targets for chemoprevention and/or chemotherapy.     

MYCN as a target for cancer immunotherapy

MYCN is a potential target for cancer immunotherapy by virtue of its overexpression in numerous human malignancies and its functional role in tumour progression. Here we show limited expression of MYCN in normal human tissues indicating that anti-MYCN immune responses are unlikely to cross react with self tissues. An HLA-A2 restricted ten amino acid peptide epitope from MYCN, VILKKATEYV, was used to stimulate cytotoxic T cell lines from the peripheral blood of normal blood donors, and from a patient with MYCN amplified neuroblastoma. Strong and specific activity was seen against each MYCN overexpressing cell line and against autologous tumour cells. We generated two CTL clones capable of killing cells pulsed with as low as 0.5 nM of VIL peptide. Therefore strong and specific immune responses against MYCN expressing tumours are possible in patients with the most common HLA class 1 type in the Caucasian population.     

K-ras as a target for cancer therapy

The central role K-, H- and N-Ras play in regulating diverse cellular pathways important for cell growth, differentiation and survival is well established. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is common in human tumors. Of the Ras proteins, K-ras is the most frequently mutated and is therefore an attractive target for cancer therapy. The complexity of K-ras signaling presents many opportunities for therapeutic targeting. A number of different approaches aimed at abrogating K-ras activity have been explored in clinical trials. Several of the therapeutic agents tested have demonstrated clinical activity, supporting ongoing development of K-ras targeted therapies. However, many of the agents currently being evaluated have multiple targets and their antitumor effects may not be due to K-Ras inhibition. To date, no selective, specific inhibitor of K-ras is available for routine clinical use. In this review, we will summarize the structure and function of K-ras with attention to its role in tumorigenesis and discuss the successes and failures of the various strategies designed to therapeutically target this important oncogene.     

Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer

The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone(?)). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC(50) of 80 μM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer.     

Nrf2 as a target for prevention of age‐related and diabetic cataracts by against oxidative stress

Cataract is one of the most important causes of blindness worldwide, with age‐related cataract being the most common one. Agents preventing cataract formation are urgently required. Substantial evidences point out aggravated oxidative stress as a vital factor for cataract formation. Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2)/Kelch‐like erythroid‐cell‐derived protein with CNC homology (ECH)‐associated protein 1 (Keap1) system is considered as one of the main cellular defense mechanisms against oxidative stresses. This review discusses the role of Nrf2 pathway in the prevention of cataracts and highlights that Nrf2 suppressors may augment oxidative stress of the lens, and Nrf2 inducers may decrease the oxidative stress and prevent the cataract formation. Thus, Nrf2 may serve as a promising therapeutic target for cataract treatment.     

肺癌化学预防和治疗的新途径——COX-2

肺癌的发生包含基因突变、凋亡受阻、增殖失控、转移侵袭、血管生成等一系列过程.表皮细胞向间叶细胞化生是癌变的一个重要过程,它的发生是由于人体内解除控制的炎症反应,从而导致细胞免疫的削弱和恶性肿瘤的发生.基于肿瘤细胞存在免疫抑制性,如何提高人体的免疫反应成为我们研究的重点.环氧合酶-2(COX-2)及其下游信号转导可能成为肺癌的化学预防和治疗的途径.COX-2抑制剂作为肺癌患者化疗的辅助用药和预防支气管肺癌发生的作用等大量临床实验正在进行.随着对炎症反应和肺癌发生的分子机制的认识,我们发现了新的药物来逆转或阻止突变,为肺癌的化学预防和治疗提供了方向.     

Use of transgenic mice as models for prostate cancer chemoprevention

Prostate cancer is a long latency type of tumor that usually develops in men older than 50 years of age. Prostate epithelial neoplasia (PIN), the initial malignant lesion, progresses to invasive carcinoma over the course of years. Because of the particular features of prostate carcinogenesis, this type of tumor may represent a paradigm for cancer prevention. Several clinical trials have evaluated the effect of different compounds on prostate tumor development, including finasteride, selenium, vitamin E, and carotenes. Although some results are promising, no conclusive data have been achieved as to recommend any of these compounds as preventive agents. Results from some trials, such as SELECT, where supplementation of selenium and/or vitamin-E was used, have been rather disappointing. However, many novel chemopreventive agents that target different cancer-related pathways are being developed lately. Appropriate animal models (in particular, genetically modified mice) are being used to assess the efficacy of these novel compounds. The transgenic adenocarcinoma of the mouse prostate (TRAMP) model has been validated as an accurate model to test a variety of preventive agents. Genistein, alpha-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib, and green tea polyphenols have been shown to prevent prostate cancer development in TRAMP mice. In conclusion, new chemopreventive compounds which are effective in animal models are likely to be tested soon in clinical trials, with the final goal of reducing prostate cancer incidence in men.     

Omics underpins novel clues on VDR chemoprevention target in breast cancer

Breast cancer is the commonest form of female malignancy among women in Western countries. The advent of genomic technologies has enhanced the diagnosis and the biological classification of such pathology. It has been demonstrated that cancer takes many years to be fully established. This long dormancy could represent a potential window for intervening with chemoprevention studies. Cancer chemoprevention is by definition the use of natural, synthetic, or biological chemical agents to reverse, suppress, or delay the genetic or other alterations that culminate in the appearance of the tumor phenotype. An important step for the success of chemoprevention is the identification of molecularly targeted agents to prevent cancer development. Currently, only two chemoprevention agents, raloxifene and tamoxifen, are used in clinical practice to prevent breast cancer. In this review, we will mainly focus on: (1) the application of genomic technologies for the identification and validation of molecular targets for chemoprevention; (2) the role of vitamin D and its cognate receptor VDR (vitamin D receptor) as a model for the molecularly targeted chemoprevention of breast cancer.     

Reliability and validity of a histologic score as a marker for skin cancer chemoprevention studies

OBJECTIVE: To develop a reliable and valid scoring system for grading skin biopsies from actinic keratosis (AK) and sun-damaged skin for use in evaluating the efficacy of skin cancer chemopreventive agents. STUDY DESIGN: A panel of dermatopathologists developed histologic criteria and diagnostic definitions for the progression of lesions from early AK to AK. The criteria were then applied to a sample of 335 histologic slides from an ongoing chemoprevention study. A 10% sample of 35 slides was reread in order to assess intrarater reliability. RESULTS: Six of the 7 criteria demonstrated high reliability (> 85%). The total histologic score, calculated using the 6 criteria, was found to significantly differentiate between (blinded) biopsy location (normal, pre-AK, AK and adjacent to squamous cell carcinoma) and histologic diagnosis (normal, pre- or early AK, AK and squamous cell carcinoma). CONCLUSION: The total histologic score, having demonstrated reliability on repeated readings and validity in its association with biopsy location and histologic score, is a reliable and valid end point for judging the efficacy of agents in skin cancer chemoprevention studies. Additional interrater reliability tests utilizing larger test sets and a rigorous statistical design should be undertaken to establish its portability.     

Wee1 kinase as a target for cancer therapy

Wee1, a protein kinase, regulates the G₂ checkpoint in response to DNA damage. Preclinical studies have elucidated the role of wee1 in DNA damage repair and the stabilization of replication forks, supporting the validity of wee1 inhibition as a viable therapeutic target in cancer. MK-1775, a selective and potent small-molecule inhibitor of wee1, is under clinical development as a potentiator of DNA damage caused by cytotoxic chemotherapies. We present a review of the role of wee1 in the cell cycle and DNA replication and summarize the clinical development to date of this novel class of anticancer agents.