Current Cancer Drug Targets - Volume 7, Issue 4, 2007

Cancer development is recognized as a multi-stage phenomenon consisting of initiation, promotion and progression stages. The rate-limiting steps in multistage carcinogenesis are now thought to reside during the period of tumor promotion and progression. Exposure to tumor promoters results in activation of transcription factors, and regulation of their target genes through signal transduction pathways, which have been characterized as tumor promotion and progression stages. Therefore, one of the most difficult challenges for scientists in the cancer research field is addressing fundamental questions concerning the response of mammalian cells to carcinogens at the level of transcription factors and protein kinases both in vitro and in vivo. Elucidation of carcinogeninduced signal transduction pathways leading to the activation of transcription factors by which gene expression is mediated will therefore, not only define the central scientific hunt in cancer biology and open an unprecedented window into the nature of cancer, but will also be necessary for cancer prevention and therapy as well. Chemoprevention can be defined as the use of substances that interfere with the process of cancer development. Since cancer is a multifactor disease that requires the modulation of multiple pathways, chemoprevention could target multiple targets. These targets include transcription factors, kinase cascades leading to activation, as well as downstream target genes of those transcription factors. Although substantial progress has been made in elucidating signal transduction pathways leading to the activation of transcription factors induced by carcinogens, further advances are needed to identify molecular targets for effective use of chemopreventive agents. This special issue describes the most recent progress made in this field. The PI3K/Akt signaling pathway is a relative early event involved in the mediation of the activation of its downstream transcription factors. Growing evidence demonstrates that dysregulation of this pathway is critical for the carcinogenic effect upon environmental carcinogen exposure. The first review article provided by Dr. Huang and his colleague summarizes the PI3K/Akt pathway, its downstream regulated transcriptional factors, and the dysregulation of this pathway in carcinogenesis, as well as the chemoprevention strategies targeting those components. The transcription factor activator protein-1 (AP-1) plays a pivotal role in inflammation and tumorigenesis, which has been supported in research both in vitro and in vivo. AP-1 could also act as a link between chronic inflammation and tumor development. The second review by Drs. Matthews, Colburn and Young has addressed the AP-1 family proteins, its relation to inflammation and cancer development, and as targets for chemoprevention. More than 1,000,000 cases of non-melanoma skin cancer (NMSC) are diagnosed in the Unites States each year. Solar radiation has been described as an important etiological factor in the development of NMSC. Damage of cells induced by ultraviolet B (UVB) light at the DNA level and molecular level initiates the activation of transcription factor pathways, which in turn, regulate the expression of a number of genes termed the “UV response genes”. Nuclear factor-κB (NF-κB) and AP-1 are two important transcription factors that are responsible for the regulation of those response genes. The review from Dr. Bowden's group has extensively discussed the advances made in this research area. Ionizing radiation (IR) is another environmental carcinogenic factor. Dr. Li's review article has focused on recent findings related to the relationship between ATM and NF-κB in response to IR, and the association of ATM with the NF-κB subunit p65 in adaptive radiation response as well. Nuclear factor of activated T cells (NFAT) is another important family of transcription factors which have important roles in various cell functions. In the last a few years, there has been increasing evidence relating NFAT family proteins to carcinogenesis, even though various members may have different roles...

The PI3K/Akt signalling pathway and its downstream transcription factors have been intensively studied for their role in cell proliferation, survival, cycle control, as well as other cellular functions. There is growing evidence showing that dysregulation of this pathway also plays an essential role in cancer development. The overexpression or permanent activation of RTKs and GPCRs, as well as the exposure to environmental carcinogens cause constant activation of PI3K/Akt. On the other hand, PI3K/Akt themselves can also become hyperactivated due to gene amplification or PTEN inactivation. Consequently, the targets downstream of PI3K/Akt can be abnormally activated, which promote proliferation and survival of cancer cells in carcinogenesis. Among these targets we find that the NFκB and AP-1 are the most interesting. Therefore, methods and compounds aiming to inhibit the altered components of this pathway can simultaneously prevent the proliferation of tumor cells and sensitize them toward apoptosis. To this regard, the natural compounds from vegetables and fruits with high affinity and non toxicity to target the PI3K/Akt pathway and prevent cancer are attractive.

The transcription factor activator protein 1 (AP-1) plays a pivotal role in tumorigenesis. AP-1 activity is increased in multiple human tumor types. Inhibitors of AP-1 have been shown to block tumor promotion, transformation, progression and invasion. Chronic inflammation and tumor development are linked. AP-1 may act, in part, by perpetuating the inflammatory signal. AP-1 is a recognized molecular target of many antioxidant and anti-inflammatory chemopreventive compounds. This review focuses on the AP-1 family proteins as targets for chemoprevention.

Prolonged and repeated exposure of the skin to ultraviolet light (UV) leads not only to aging of the skin but also increases the incidence of non-melanoma skin cancer (NMSC). Damage of cells induced by ultraviolet B (UVB) light both at the DNA level and molecular level initiates the activation of transcription factor pathways, which in turn regulate the expression of a number of genes termed the “UV response genes”. Two such transcription factor families that are activated in this way are those of the nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) families. These two transcription factor families have been identified to be involved in the processes of cell proliferation, cell differentiation and cell survival and therefore play important roles in tumorigenesis. The study of these two transcription factor pathways and the cross-talk between them in response to UVB exposure may help with the development of new chemopreventive strategies for the prevention of UVB-induced skin carcinogenesis.

Ionizing radiation (IR) plays a key role in both areas of carcinogenesis and anticancer radiotherapy. The ATM (ataxia-telangiectasia mutated) protein, a sensor to IR and other DNA-damaging agents, activates a wide variety of effectors involved in multiple signaling pathways, cell cycle checkpoints, DNA repair and apoptosis. Accumulated evidence also indicates that the transcription factor NF-κB (nuclear factor-kappaB) plays a critical role in cellular protection against a variety of genotoxic agents including IR, and inhibition of NF-κB leads to radiosensitization in radioresistant cancer cells. NF-κB was found to be defective in cells from patients with A-T (ataxia-telangiectasia) who are highly sensitive to DNA damage induced by IR and UV lights. Cells derived from A-T individuals are hypersensitive to killing by IR. Both ATM and NF-κB deficiencies result in increased sensitivity to DNA double strand breaks. Therefore, identification of the molecular linkage between the kinase ATM and NF-κB signaling in tumor response to therapeutic IR will lead to a better understanding of cellular response to IR, and will promise novel molecular targets for therapy-associated tumor resistance. This review article focuses on recent findings related to the relationship between ATM and NF-κB in response to IR. Also, the association of ATM with the NF-κB subunit p65 in adaptive radiation response, recently observed in our lab, is also discussed.

The nuclear factor of activated T cells (NFAT) family proteins are transcription factors that regulate the expression of a variety of target genes with or without forming complexes with other transcription factors. Although NFAT proteins have been extensively investigated and characterized in immune systems, their role in carcinogenesis are far from being understood. We, to our knowledge, are first to determine the potential involvement of the NFAT pathway in cell responses to carcinogen exposure. Experimental evidence accumulated from our studies indicate the critical role of NFAT3 in some carcinogen-induced cell transformation and tumorigenicity. Moreover, NFAT proteins have been found to be involved in cell cycle regulation, cell differentiation, cell survival, angiogenesis, and tumor cell invasion and metastasis. In the meantime, NFAT inhibitors are being developed with the ultimate aim to specifically switch off NFAT signaling without side effects. This review comprehensively reviews the results from the most recent studies, and also discusses some difficulties in current studies. To validate whether NFAT can be a promising target for chemoprevention, more research has to be done to further detail the roles of NFAT and to differentiate the functions of different members of this protein family in future studies.

With increasing incidence of cancer at most of the sites, and growing economic burden and associated psychological and emotional trauma, it is becoming clearer that more efforts are needed for cancer cure. Since most of the chemotherapeutic drugs are non-selective because they are also toxic to the normal cells, new and improved strategies are needed that selectively target the killing of cancer cells. Since aberrant activation of numerous signaling pathways is a key element of cancer cell survival and growth, blocking all of them is not that practical, which leads to the step where most of them commonly converge; the transcription factors. Recent research efforts, therefore, are also directed on targeting the activity and activation of transcription factors, which ultimately control the expression of genes that are involved in almost all aspects of cell biology. One class of agents that is becoming increasingly successful, not only in targeting signaling cascades, but also transcription factors is phytochemicals present in diet and those consumed as supplement. The added advantage with these agents is that they are mostly non-toxic when compared to chemotherapeutic agents. This review focuses on the efficacy of various phytochemicals in targeting transcription factors such as AR, Sp1, STATs, E2F, Egr1, c-Myc, HIF-1α, NF-κB, AP-1, ETS2, GLI and p53 in the context of prostate cancer intervention.

The 90 kDa heat shock proteins (Hsp90) are proving to be an excellent target for the development of novel anticancer agents designed to selectively block the growth and proliferation of tumor cells. Since Hsp90 is a molecular chaperone and is responsible for folding numerous oncogenic proteins, its inhibition represents a novel approach toward the simultaneous disruption of multiple signaling cascades. This review summarizes recent literature implicating Hsp90 as a key facilitator for the maturation of proteins represented in all six hallmarks of cancer: 1) growth signal self-sufficiency, 2) anti-growth signal insensitivity, 3) evasion of apoptosis, 4) unlimited replicative potential, 5) metastasis and tissue invasion, and 6) sustained angiogenesis. Also described are recent advances towards the development of novel Hsp90 inhibitors via structure-based drug design that have contributed to the number of compounds undergoing clinical development.

The development and progression of cancer is marked by the acquisition of specific genetic hallmarks that endow tumour cells with a survival advantage over their normal tissue counterparts. In the process, tumours frequently develop resistance to radiotherapy and chemotherapy, and acquire the ability to evade the host immune response. Cancer gene therapy (CGT) represents an ideal therapeutic tool to target one or more of these underlying genetic abnormalities, and restore some form of order, to the otherwise autonomous and discordant microenvironment of the tumour. Most of the current research in CGT is aimed at its development as a novel form of targeted therapy that can be combined with other treatment modalities such as radiotherapy and chemotherapy. CGT may be integrated into radical chemoradiotherapy regimens, with the rationale of optimising the therapeutic index, through selective enhancement of radiosensitivity and cytotoxicity in tumour compared to normal tissues. CGT strategies have been developed that are aimed at enhancing the radiosensitivity of tissues by targeting angiogenesis, silencing abnormal cellular signalling, restoration of apoptosis, and promotion of immune detection and destruction of tumour cells. In addition, cytotoxic approaches such as virus directed enzyme prodrug therapy (VDEPT), genetic radionuclide therapy (GRANT) and oncolytic viral therapy have been combined with radiation to augment the cumulative tumour cell kill and overall therapeutic effect. In this article, we discuss various CGT strategies that have been investigated in combination with radiation. All the available preclinical and clinical evidence is reviewed with special emphasis on strategies that have already found their way into the clinic, or those with significant translational potential for the future.