Current Cancer Drug Targets - Volume 11, Issue 5, 2011

PTEN is a tumor suppressor gene localized to human chromosome 10q23.31, a genomic region frequently lost in glioblastoma and prostate cancer. The fact that PTEN encodes a lipid phosphatase with specificity towards phosphatidylinositol-3,4,5-triphosphate renders it a gate-keeper of the phosphatidylinositol 3-kinase pathway. Numerous physiological processes have been ascribed to this evolutionarily conserved molecule including proliferation, cell size determination, survival, differentiation, and cell fate specification. Indeed, mutation in PTEN gene is the genetic cause of Cowden Syndrome. Structurally, the 54-kilodalton protein is composed of two major functional domains crucial for catalytic and membrane binding functions. Additional regulatory regions in both amino- and carboxyl-termini further dictate its structural integrity, catalytic activity, and subcellular localization. Extensive characterization of PTEN primary coding sequence has revealed a multitude of post-translational modifications that fine-tune its biochemical properties. These include phosphorylation, ubiquitination, redox modifications, and acetylation. This article aims to provide an indepth review of the diverse post-translational modifications of PTEN, focusing on their biological relevance in both normal and cancer cells. The potential applications to cancer therapy by modulating the post-translational modifications of PTEN will also be discussed.

Cyclooxygenase-2 (COX-2) is a critical enzyme implicated in chronic inflammation-associated cancer development. Our studies have shown that the exposure of Beas-2B cells, a human bronchial epithelial cell line, to lung carcinogenic nickel compounds results in increased COX-2 expression. However, the signaling pathways leading to nickel-induced COX-2 expression are not well understood. In the current study, we found that the exposure of Beas-2B cells to nickel compounds resulted in the activation of both nuclear factor of activated T cell (NFAT) and nuclear factor- κB (NF-κB). The expression of COX-2 induced upon nickel exposure was inhibited by either a NFAT pharmacological inhibitor or the knockdown of NFAT3 by specific siRNA. We further found that the activation of NFAT and NF-κB was dependent on each other. Since our previous studies have shown that NF-κB activation is critical for nickel-induced COX- 2 expression in Beas-2B cells exposed to nickel compounds under same experimental condition, we anticipate that there might be a cross-talk between the activation of NFAT and NF-κB for the COX-2 induction due to nickel exposure in Beas-2B cells. Furthermore, we showed that the scavenging of reactive oxygen species (ROS) by introduction of mitochondrial catalase inhibited the activation of both NFAT and NF-κB, and the induction of COX-2 due to nickel exposure. Taken together, our results defining the evidence showing a key role of the cross-talk between NFAT and NF- κB pathways in regulating nickel-induced COX-2 expression, further provide insight into the understanding of the molecular mechanisms linking nickel exposure to its lung carcinogenic effects.

It is strongly established by numerous studies that oxidative stress-induced inflammation is one of the major causative agents in a variety of cancers. Various factors such as bacterial, viral, parasitic infections, chemical irritants, carcinogens are involved in the initiation of oxidative stress-mediated inflammation. Chronic and persistent inflammation promotes the formation of cancerous tumors. Recent investigations strongly suggest that aldose reductase [AR; AKR1B1], a member of aldo-keto reductase superfamily of proteins, is the mediator of inflammatory signals induced by growth factors, cytokines, chemokines, carcinogens etc. Further, AR reduced product(s) of lipid derived aldehydes and their metabolites such as glutathionyl 1,4-dihydroxynonanol (GS-DHN) have been shown to be involved in the activation of transcription factors such as NF-κB and AP-1 which transcribe the genes of inflammatory cytokines. The increased inflammatory cytokines and growth factors promote cell proliferation, a main feature involved in the tumorigenesis process. Inhibition of AR has been shown to prevent cancer cell growth in vitro and in vivo models. In this review, we have described the possible association between AR with oxidative stress- and inflammation- initiated carcinogenesis. A thorough understanding of the role of AR in the inflammation -associated cancers could lead to the use of AR inhibitors as novel chemotherapeutic agents against cancer.

An innovative approach for cancer therapy implies the use of drugs covalently conjugated to macromolecular carriers that specifically target molecules over-expressed on tumor cells. This drug delivery strategy may allow a controlled release of the drug and a high targeting selectivity on tumor cells, increasing drug cytotoxicity and decreasing its undesirable side effects. We provide in vitro and in vivo preclinical data on the antitumor efficacy of ONCOFID™-S, a new bioconjugate of hyaluronic acid (HA) with SN-38 (the CPT11 active metabolite), that support the validity of the drug delivery strategy implying the use of HA as macromolecular carrier of antineoplastic drugs, an approach based on the over-expression of its target CD44 (the receptor for HA-mediated motility) in a wide variety of cancers. We show that ONCOFID™-S exerts a strong in vitro anti-proliferative activity on CD44 over-expressing rat DHD/K12/trb colon adenocarcinoma cells, as well as on gastric, breast, oesophageal, ovarian and lung human cancer cells, higher than that exerted by unconjugated SN-38. We also demonstrated the in vivo anti-tumor efficacy of locoregional treatment with ONCOFID™-S on two pre-clinical models of colorectal cancer (CRC) in BDIX rats: a) syngeneic model of subcutaneous tumor; b) syngeneic model of metastatic tumor induced by injection of cells into the peritoneal cavity, mimicking the clinical situation of peritoneal carcinomatosis. Specifically, in the latter model ONCOFID™-S is able to dramatically reduce all parameters indicative of a poor prognosis in peritoneal metastatization of CRC without any myelotoxicity or mesothelial inflammation. We propose this CD44-targeted therapeutic strategy for locoregional treatment of peritoneal carcinomatosis from CRC, against which systemic chemotherapy results almost inefficient.

The Serine/Threonine protein kinase B (PKB), which is now called Akt, has well-documented oncogenic potential and pro-survival activities that can counteract apoptosis induced by anti-cancer drugs. The goal of this review is to discuss current evidence that the pro-survival function of Akt can be overridden or converted to a pro-apoptotic function. A brief description of how upstream regulators and downstream effectors of the Akt kinase participate in a network of protection against cell death is presented. This background provides a basis for understanding how specific chemotherapeutic agents and cellular conditions can overcome the Akt pro-survival signal or alter Akt signaling in a way that converts Akt kinase activity to be directly involved in the induction of apoptosis. This pro-apoptotic activity only occurs under specific cellular conditions, since Akt can function as both a survival factor and an apoptotic factor within the same cell type. In some situations, the Akt pro-survival activity was eventually overwhelmed by prolonged treatment with chemotherapeutic agents, or was converted to a pro-apoptotic function upon prolonged hyperactivation of the Akt kinase activity, or by nuclear retention or unbalanced phosphorylation of the Akt protein. Increased levels of intracellular oxidation stimulated Akt activity and were increased by oxidative metabolism resulting from chronic Akt hyperactivity. Downstream effects on mTOR, FoxO3 transcription factors and cdk-2 affected the switch between pro-survival and proapoptotic functions through complex positive- and negative-feedback interactions. Upstream, caveolin-1 stimulated the pro-apoptotic function. Implications of the opposing functions of Akt in cancer therapy are discussed.

The centrosome plays an essential role in cell cycle progression and cell polarity, organizing the microtubule network in interphase and mitosis. During cell division, the centrosome undergoes a series of structural and functional transitions and forms the two poles of the bipolar mitotic spindle. It is the microtubule cytoskeleton that is reorganized to form the two poles, ensuring accurate separation of the two daughter cells. To achieve this a large number of signalling proteins located at the centrosome, undergo precise time-dependent modulation. Protein kinases such as Aurora A, Polo and Neks, trigger and regulate events such as centrosome duplication, maturation and division. These enzymes are also involved in recruiting other proteins in cell division, thus they are likely to mediate the crosstalk between the cell and the centrosome cycle. In its function of microtubule organization, macromolecular complexes also have an important role. Tubulin polymerization confers the structural backbone to cell division, while other proteins may interact with it and/or mediate its recruitment to the centrosome. The interactions of these components regulate centrosome maturation and microtubule growth, essential mechanisms for cell division. Furthermore, dysregulation of this organelle, both at the level of signalling or as a structural element strongly correlates to aberrant proliferation, and the onset of tumours. Therefore, the centrosome represents an attractive target for anti-cancer therapy. Here we review the most important centrosomal proteins and their therapeutic potential. In addition, we summarize the current strategies of intervention and report the present stage of anticancer drug development targeting the centrosome.

The success of current treatment strategies is limited by the development of therapy resistance as evidenced by recurrence of the primary tumor or distant metastasis. Eradication of primary and metastatic disease requires interventions at both the cancer cell and tumor microenvironment levels. In this review, we will discuss mechanisms that are intrinsic to cancer cells, and those that are mediated by the tumor microenvironment as contributors to drug resistance. Mechanisms contributing to multidrug resistance phenotype and the challenges facing molecular targeted therapy are discussed. The DNA damage tolerance pathway confers tolerance to a variety of structurally and functionally unrelated drugs. A rationale for targeting the DNA damage tolerance pathway as a novel tool for overcoming drug resistance is discussed. We have also addressed the need for employing clinically relevant model systems for performing drug sensitivity evaluations. These model systems must take into account the three-dimensional organization and in vivo relationship of tumor with its microenvironment. Such integrative efforts would not only yield a more global understanding of the tumor- and microenvironment-derived mechanisms involved in emergence of drug resistance but would also provide novel therapeutic targets that will disrupt the interactions between the tumor cells and its microenvironment.

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a central role in the process of tumor growth and metastasis. The proliferation of endothelium and formation of new blood vessels further the size of solid tumors. It is expected that blocking angiogenesis will be an efficient therapeutic approach against many tumor types. The key signaling system that regulates proliferation and migration of endothelial cells are vascular endothelium growth factor (VEGF) and their receptors (VEGFR-1, -2 and -3). VEGFR-2, a receptor with higher affinity and greater kinase activity, is more important in the direct regulation of angiogenesis, mitogenic signaling, and permeability-enhancing effects. VEGFRs are expressed at high levels in many types of human solid tumors, including glioma, lung, breast, renal, ovarian and gastrointestinal tract carcinomas. Inhibition of VEGFR has emerged as a potential therapy method for cancers and it has been clinically validated with FDA-approvals of bevacizumab, sorafenib, and suntinib. Consequently, a number of small molecules with VEGFR inhibitory properties have been developed. Many of these have been evaluated as potent inhibitors and some are currently in clinical-trials for various angiogenic related disorders including inflammatory diseases, retinopathies and age related macular degeneration. This review reports various VEGF/VEGFR pathway inhibitors such as small molecules and monoclonal antibodies, along with their reported activities.

The aryl hydrocarbon receptor (AhR) is a ligand activated basic helix-loop-helix transcription factor that binds to environmental poly aromatic hydrocarbons (PAH) and mediates their toxic and carcinogenic responses. There is ample documentation for the role of AhR in PAH-induced carcinogenicity. However, in this report we addressed whether overexpression of AhR alone is sufficient to induce carcinogenic transformation in human mammary epithelial cells (HMEC). Retroviral expression vectors were used to develop a series of stable cell lines expressing varying levels of AhR protein in an immortalized normal HMEC with relatively low endogenous AhR expression. The resulting increase in AhR expression and activity correlated with the development of cellular malignant phenotypes, most significantly epithelial-tomesenchymal transition. Clones overexpressing AhR by more than 3-fold, exhibited a 50% decrease in population doubling time. Cell cycle analysis revealed that this increase in proliferation rates was due to an enhanced cell cycle progression by increasing the percentage of cells transiting into S- and G2/M phases. Cells overexpressing AhR exhibited enhanced motility and migration. Importantly, these cells acquired the ability to invade matrigel matrix, where more than 80% of plated cells invaded the matrigel matrix within 24 h, whereas none of parental or the vector control HMEC were able to invade matrigel. Collectively, these data provide evidence for a direct role of AhR in the progression of breast carcinoma. The results suggest a novel therapeutic target that could be considered for treatment and prevention of breast cancer progression.