Current Cancer Drug Targets

ISSN: 1568-0096

Current Cancer Drug Targets
Volume 8, Number 4, June 2008

Contents



S100A8 and S100A9 Overexpression Is Associated with Poor Pathological Parameters in Invasive Ductal Carcinoma of the Breast Pp. 243-252
Kazumori Arai, Sachiko Takano, Takumi Teratani, Yasuhiro Ito, Toshihiro Yamada and Ryushi Nozawa
[Abstract]


Cancer Neovascularization and Proinflammatory Microenvironments Pp. 253-265
Mitsuko Furuya and Yoshikazu Yonemitsu
[Abstract]


Targeting Cancer and Neuropathy with Histone Deacetylase Inhibitors: Two Birds with One Stone? Pp. 266-274
V. Rodriguez-Menendez, L. Tremolizzo and G. Cavaletti
[Abstract]


The Inhibitor of Growth (ING) Gene Family: Potential Role in Cancer Therapy Pp. 275-284
Mehmet Gunduz, Esra Gunduz, Rosario S. Rivera and Hitoshi Nagatsuka
[Abstract]


Skeletal Muscle in Cancer Cachexia: The Ideal Target of Drug Therapy Pp. 285-298
Maurizio Bossola, Fabio Pacelli, Antonio Tortorelli, Fausto Rosa and Giovan Battista Doglietto
[Abstract]


Regulators of Chemokine Receptor Activity as Promising Anticancer Therapeutics Pp. 299-340
Konstantin V. Balakin, Yan A. Ivanenkov, Sergey E. Tkachenko, Alex S. Kiselyov and Alexandre V. Ivachtchenko
[Abstract]




Abstracts


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S100A8 and S100A9 Overexpression Is Associated with Poor Pathological Parameters in Invasive Ductal Carcinoma of the Breast
Kazumori Arai, Sachiko Takano, Takumi Teratani, Yasuhiro Ito, Toshihiro Yamada and Ryushi Nozawa

S100 protein A8 and A9 naturally form a stable heterocomplex. Recently, we have proved that S100A9 overexpression in various adenocarcinomas is associated with poor tumor differentiation. In this study, we examined the relationship between the expression of each protein and the pathological parameters that reflect the aggressiveness of carcinoma, in invasive ductal carcinoma (IDC) of the breast. Serial paraffin-embedded tissue sections from 101 IDC cases were immunostained with respective monoclonal antibodies, and the results were as follows: 1) A positive correlation of immunoreactivity between S100A8 and S100A9 was noticed (r=0.873 and P<0.0001); 2) The percentage of S100A9-positive tumor cells was higher than that of S100A8-positive tumor cells (P<0.001), and S100A8 alone was not detected in any case; 3) Overlap between S100A8 and S100A9 staining patterns was found in the corresponding tissue areas, but S100A9 positivity was also observed in S100A8-negative tumor cells; 4) The immunopositivity for each protein also correlated with the mitotic activity, MIB-1 index, HER2 overexpression, node metastasis, and poor pT categories and pStage (P<0.05); 5) Co-expression of both proteins was associated with poor tumor differentiation, vessel invasion, node metastasis, and poor pStage (P<0.05). Furthermore, co-expression of the proteins was also observed in MCF-7 cells, and it was suggested that the immunolocalization is related with cell cycle. Our conclusions are as follows: 1) It is suggested that S100A8 is S100A9-dependently expressed and acquires the protein stability by S100A8/A9 heterocomplex formation; 2) S100A8 and S100A9 overexpression should be considered marker of poor prognosis in IDC.


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Cancer Neovascularization and Proinflammatory Microenvironments
Mitsuko Furuya and Yoshikazu Yonemitsu

Tumor neovascularization plays critical roles for the development, progression and metastasis of cancers via utilizing blood flow to supply nutrients and oxygen. Recent cumulative information on biology of tumor neovascularization from both laboratory and clinical studies has opened us to develop new therapeutic approaches to treat malignancies by controlling angiogenic activities; i.e., a humanized monoclonal antibody bevacizumab specifically targeting VEGF (vascular endothelial growth factor), as well as several tyrosine kinase inhibitors targeting VEGF-related pathways. It is obvious that VEGF is a key molecule for tumor neovascularization, however, strategies targeting VEGF may be a milestone and not a goal for antiangiogenic approach, because it has been elucidated the complexity of cancer microenvironments that mediate neovascularization and blood-borne metastasis. Specific subsets of chemoattractants recruit hematopoietic cells from the BM (bone marrow) that support tumor neovascularization in the primary lesion, and these mobilized cells are suggested to participate in pre-metastatic niche formation for circulating tumor cells. To establish safe and effective antiangiogenic therapies, it is important to understand the cross-communication between tumors and hosts that medi-ate proinflammatory milieu of both primary and metastatic lesions. This review discusses special features of tumor angio-genic vessels and their microenvironments, and in addition, recent topics including contribution of BM-derived cells, special mesenchymal cells and their chemoattractants that activate tumor vascular beds are summarized.


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Targeting Cancer and Neuropathy with Histone Deacetylase Inhibitors: Two Birds with One Stone?
V. Rodriguez-Menendez, L. Tremolizzo and G. Cavaletti

Histone deacetylase inhibitors (HDACi) belong to a novel class of drugs able to act on the epigenome, indirectly remodeling the spatial conformation of the chromatin: by increasing histone acetylation these drugs ultimately promote the detachment of the DNA from the nucleosome octamer, therefore allowing the access of transcription factors to the double helix. Such a mechanism of action is of particular interest in the field of cancer treatment, considering the reactivation of silenced tumor suppressor genes as an important target at which aiming; indeed, it is currently believed that dysregulation of the epigenome plays a major role in cancer. Interestingly, some of the compounds belonging to the HDACi family have also additional therapeutic properties, as in the case of valproate that may ameliorate neuropathic pain in animal models and in patients. Conceivably, this is a remarkable observation, since peripheral neuropathy is a potentially severe side effect of several classes of anticancer agents, such as platinum-derived drugs, antitubulins or protesome inhibitors, limiting an effective treatment of the underlying cancer. Based on these data, in this review we will argue that, with respect to other nowadays available anticancer agents, HDACi might offer the advantage not only to target the neoplastic disorder, but also to prevent peripheral neuropathies, possibly displaying a complementary mechanism of action.


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The Inhibitor of Growth (ING) Gene Family: Potential Role in Cancer Therapy
Mehmet Gunduz, Esra Gunduz, Rosario S. Rivera and Hitoshi Nagatsuka

The discovery of ING1 gene paved the way to the identification of other ING members (ING2-5) and their isoforms associated with cell cycle, apoptosis and senescence. The ING family has been an emerging putative tumor suppressor gene (TSG) in which the major mechanism is through interaction with the determinants of chromatin function and gene-specific transcription factors. The regulatory mechanism highly involves the conserved plant homeodomain (PHD), which binds to histones in a methylation-sensitive manner, suggesting that ING proteins may contribute to the maintenance of the epigenetic code. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although ING proteins have the same PHD motif, the variation in the N-terminal dictates the differences in tumor the suppressive ability of ING in various tumors. Inactivation of the normal function is achieved through allelic loss of genomic regions containing the ING gene, alteration in the ING promoter region, variation of mRNA splicing efficacy or reduced mRNA stability. It is most probably the apparent combination of these aberrant mechanisms that resulted in reduced availability of functional ING protein. In cancer cells, ING transcript levels are often suppressed but the genes are rarely mutated. The mechanism of suppression of ING expression may have to do with the abnormally high methylation levels of the ING gene promoter, which have been correlated with low transcript levels. Emerging evidence on the function of ING and related regulatory mechanisms strongly points to ING as a candidate TSG and therefore a potential target in the molecular therapy of some types of tumor.


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Skeletal Muscle in Cancer Cachexia: The Ideal Target of Drug Therapy
Maurizio Bossola, Fabio Pacelli, Antonio Tortorelli, Fausto Rosa and Giovan Battista Doglietto

Cancer cachexia is a debilitating and life-threatening syndrome that accounts for at least 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients.

The loss of lean body mass is the main characteristic of cancer cachexia and the principal cause of function impairment, fatigue and respiratory complications. It is the result of an imbalance between protein synthesis and protein degradation, the mechanisms underlying such alteration being multiple and partially known.

Current therapy of cancer cachexia continues to be extremely poor. However, in the last decade, the attention has focused just on the skeletal muscle, as a potential target of therapy, with the aim to discover drugs capable to inhibit the catabolic processes and to stimulate the anabolic pathways.

The skeletal muscle has been faced at different levels such as the mediators (cytokines and tumor-derived factors), the receptors (TNF-α  and androgen receptors), the proteolytic pathways (calpains and ubiquitin-proteasome), the intracellullar signalling pathways (NF-kB, AP-1, FOXO, PKR), and the negative modulators of muscle growth/hypertrophy (myostatin, GSK3-β).

Most of the drugs that have been tested have shown to be effective, at least in experimental models of cancer cachexia. It remains to define their safety, tolerance and efficacy in humans through large, adequate, clinical trials. However, the impression is that there is a light at the back of the tunnel.


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Regulators of Chemokine Receptor Activity as Promising Anticancer Therapeutics
Konstantin V. Balakin, Yan A. Ivanenkov, Sergey E. Tkachenko, Alex S. Kiselyov and Alexandre V. Ivachtchenko

Chemokines are a family of small proteins inducing directed cell migration via specific chemokine receptors, which play important roles in a variety of biological and pathological processes. Their respective ligands act as proinflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors, and also have a role in pathological conditions that require neovascularization. Therapeutic strategies based on modulation of chemokine receptor pathways were reported to be promising clinical strategies in the treatment of inflammatory diseases and viral infections. Recent studies have been also demonstrated that chemokines and chemokine receptors are produced by many different cell types, including tumor cells. Overexpression of many chemokine and chemokine receptors in tumor cells suggests that they are crucial regulators of the levels of tumor infiltrating leukocytes implicated in the tumorigenesis of multiple human cancers. In the tumor microenvironment they control a variety of biological activities, such as production and deposition of collagen, activation of matrix-digesting enzymes, stimulation of cell growth, inhibition of apoptosis and promotion of neo-angiogenesis and metastasis. In this review we elucidate key aspects of chemokine signaling as well as clinically relevant strategies to modulation of chemokine receptor activity in the treatment of cancer with emphasis on small-molecule agents. We also elucidate various research strategies which were found to be useful in the design of chemokine receptor targeted therapeutics.