Begell House Inc.
Onco Therapeutics
OT
2694-4642
4
1
2013
Preface: Practical Molecular Targets for Suppression of Cancer
v-vii
10.1615/ForumImmunDisTher.2013008329
Kazuo
Umezawa
Department of Molecular Target Medicine Screening Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
It is a preface from the guest editor
Growth Factor Signaling Regulates Breast Cancer Stem Cells
1-10
10.1615/ForumImmunDisTher.2013008345
Noriko
Gotoh
Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Ishikawa, 920-1192 Japan
cancer stem cells
breast cancer
(HER) epidermal growth factor receptor
mammosphere
cancer stem cell niche
ErbB
Accumulating evidence suggests that cancer stem cells−which make up only a small proportion of heterogeneous tumor cells−possess a greater ability to maintain tumor formation than other tumor cell types. Although the concept of cancer stem cells greatly impacts cancer biology and evokes a reconsideration of cancer treatment, the molecular mechanisms involved in the contribution of cancer stem cells to tumorigenesis remain obscure. We found that heregulin (HRG), a ligand for HER3/ErbB3, induced tumor sphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced tumor sphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI-3 kinase). Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSC-enriched populations, was induced by HRG through the activation of the PI3K/NF-κB pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain tumor sphere formation through a PI3K/NF-κB pathway in human breast cancer.
Current Molecular Targeting of Lymphomas
11-23
10.1615/ForumImmunDisTher.2013008322
Ryouichi
Horie
1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan
lymphomas
signal transduction
molecular target
oncogene addiction
apoptosis
A typical discrepancy exists between the classification of and treatment strategies for lymphomas. The identification of key molecules in subtypes of lymphomas and the development of molecular targeted strategies will fill this gap. Pathological characteristics might be the consequence of deregulated molecular patterns in lymphomas. Therefore, exploration of addictive molecules based on the pathological classification might be an efficient way to establish molecular targeted therapy for lymphomas. The chromosomal translocation characterizing the subtypes of lymphomas and molecular characteristics for each subtype may suggest a molecular biological approach to identifying addictive molecules to be targeted. This review highlights the potential molecular targets in oncogenic signaling pathways in lymphomas.
Current Molecular Targets for Urological Cancer
25-32
10.1615/ForumImmunDisTher.2013008313
Yutaka
Horiguchi
Department of Urology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 160-0023 Tokyo, Japan
cancer stem cell
molecular target
NF-κB
urological cancer
Clinically advanced stages of urological cancers are currently treated with conventional surgery, radiation, and chemotherapy. As for molecular targets, multiple kinase inhibitors (MKIs) and mammalian target of rapamycin (mTOR) inhibitors have already been introduced to treat advanced metastatic renal cell carcinoma, which is refractory to cytokine therapies such as interferon-α and interleukin-2. In recent trends in cancer research, the translation of basic science into clinical application has been accelerated. In this review, new molecular targets, such as MKIs, mTOR inhibitors, along with the phosphatidylinositol 3-kinase (PI3K)/ Akt signaling pathway, vascular endothelial growth factor (VEGF), and NF-κB, as well as conventional COX inhibitors, are overviewed. As the putative source of cancer oncogenesis, cancer stem cells (CSCs) have been highlighted in recent research. Current understandings of CSCs in urologic oncology are also discussed.
Apoptosis as a Practical Target for Identifying Anticancer Agents of Marine Origin
33-41
10.1615/ForumImmunDisTher.2013008307
Osamu
Ohno
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan
Toshiaki
Teruya
Faculty of Education, University of Ryukyus, 1 Senbaru, Nishihara, Okinawa 901-0213, Japan
Kiyotake
Suenaga
Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan
Daisuke
Uemura
Department of Chemistry, Faculty of Science, Kanagawa University, 2946 Tsuchiya, Hiratsuka 259-1293, Japan
anticancer drug
apoptosis
marine organism
bisebromoamide
biselyngbyaside
Natural products and their synthetic analogs are widely used as anticancer drugs. Many anticancer drugs originated from cytotoxic compounds, and most have been shown to induce apoptosis in cancer cells. Based on the variety of their modes of action, the identification of new cytotoxic compounds may lead to the discovery of new types of drugs. Recently, much attention has been given to the metabolites of marine organisms due to their strong cytotoxicity. For example, eribulin mesylate, a synthetic analog of halichondrin B isolated from H. okadai Kadota, has been developed as an anticancer drug. Novel cytotoxic substances, such as halichonines, bisebromoamides, and biselyngbyasides, have been isolated from marine organisms as apoptosis-inducing agents. All of these compounds may possess therapeutic potential, and thus, efforts to identify new apoptosis-inducing agents of marine origin may contribute to the discovery of new pharmaceuticals.
Molecular Targets for Suppression of Metastasis: Recent Cellular Observations
43-51
10.1615/ForumImmunDisTher.2013008306
Siro
Simizu
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan
Yuki
Niwa
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan
molecular target
metastasis
invasion
migration
nuclear factor κB (NF-κB)
CXCL12/CXCR4
K+ channel
heparanase
glycosylation
Cancer metastasis is regulated by many factors. In this review article, we introduce novel molecular targets for the suppression of cancer metastasis. Dehydroxymethylepoxyquinomicin (DHMEQ) is a specific inhibitor of NF-κB that inhibits many types of cancer cell growth in vivo. Recently, DHMEQ was reported to suppress cell invasion in an ovarian cancer cell line due to the deregulation of the autocrine system of CXCL12/ CXCR4. An ATP-sensitive K+ channel blocker, glybenclamide, has been reported to suppress PDGF secretion, thereby inhibiting cell migration in ovarian cancer. Other emerging molecular targets are glycosaminoglycan (GAG)-degrading enzymes, such as heparanase and hyaluronidases. These inhibitors have been shown to suppress cancer cell metastasis both in vitro and in vivo. We previously reported the important role of protein glycosylation for metastasis-related protein functions. Thus, we hypothesize that NF-κB, K+ channels, GAG-degrading enzymes, and protein glycosylation may be useful targets for suppression of metastasis.
Modulation of Tumor–Stromal Cell Interactions: A New Anti-Tumor Strategy Targeting the Tumor Microenvironment
53-62
10.1615/ForumImmunDisTher.2013008317
Manabu
Kawada
Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Shizuoka, Japan
Shuichi
Sakamoto
Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Shizuoka, Japan
Akio
Nomoto
Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Shizuoka, Japan
tumor-stromal cell interactions
tumor microenvironment
anti-tumor drug
natural compound
Tumor tissues are composed of tumor cells as well as the surrounding stroma. The stroma consists of various kinds of cells and the extracellular matrix that together form the tumor microenvironment. Among them, stromal cells (fibroblast-like cells) can regulate the growth of tumor cells positively or negatively through the tumor–stromal cell interactions (TSIs). TSIs are mediated by secreted factors or direct adhesion. Thus, the growth of tumor cells may be able to be suppressed by modulation of TSIs. In this review, we introduce new strategies targeting the tumor microenvironment, especially TSIs. Molecular targets in TSIs and small molecule compounds that can modulate TSIs are discussed.
Peritoneal NF-κB as a Possible Molecular Target for Suppression of Various Cancers and Inflammation
63-77
10.1615/ForumImmunDisTher.2013008314
Kazuo
Umezawa
Department of Molecular Target Medicine Screening Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
nuclear factor-kappaB (NF-kB)
peritoneal cavity
dehydroxymethylepoxyquinomicin (DHMEQ)
Rel family proteins
cancer
inflammation
NF-κB is a transcription factor that promotes the expression of many inflammatory cytokines and apoptosis inhibitory proteins. We have designed a new NF-κB inhibitor, dehydroxymethyl-epoxyquinomicin (DHMEQ), which directly binds to a specific cysteine residue of the Rel family of proteins to inhibit their DNAbinding activity. DHMEQ has shown potent anti-inflammatory and anticancer activities in many animal models. In the course of in vivo research on DHMEQ, I have developed a new concept regarding the role of peritoneal NF-κB in inflammation or cancer. So far, DHMEQ has been administered mainly into the peritoneal cavity of animals to suppress peripheral inflammation and cancer. According to the limited distribution of DHMEQ in the peritoneal cavity, it is likely that NF-κB in the peritoneal cells is the main target of DHMEQ. The inflammatory cells in the peritoneal cavity appear important for the regulation of peripheral inflammation and tumor growth. Thus, NF-κB of the peritoneal cells may be a practical molecular target for suppression of cancer growth.
Roles Each of Snail, Yin Yang 1, and RKIP in the Regulation of Tumor Cells Chemo- Immuno-Resistance to Apoptosis
79-92
10.1615/ForumImmunDisTher.2013008299
Benjamin
Bonavida
Department of Microbiology, Immunology, &
Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
Ali R.
Jazirehi
Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center; and Department of Surgery, University of California, Los Angeles, California, USA
Mario I.
Vega
Oncology Research Unit, Oncology Hospital Siglo XXI National Medical Center IMSS, Mexico City, Mexico; Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, David Geffen School of
Medicine, University of California, Los Angeles
Sara
Huerta-Yepez
Hospital Infantil de México Federico Gomez
Stavroula
Baritaki
Center for Systems Biomedicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Snail
Raf kinase inhibitor protein (RKIP)
Yin Yang 1 (YY1)
resistance
cancer
The current anti-cancer therapeutic armamentarium consists of surgery, chemotherapy, radiation, hormonal therapy, immunotherapy, and combinations thereof. Initial treatments usually result in objective clinical responses with prolongation of overall survival (OS) and progression-free survival (PFS) in a large subset of the treated patients. However, at the onset, a subset of patients does not respond, and another subset initially responds but experiences relapses and recurrences. These latter subsets of patients develop a state of crossresistance to a variety of unrelated therapies. Therefore, there is an urgent need to first unravel the underlying mechanisms of resistance and associated gene products that regulate the cross-resistance. Such gene products represent potential therapeutic targets as well as potential prognostic/diagnostic biomarkers. In this context, we have identified three interrelated gene products involved in resistance, namely, Snail, YY1, and RKIP that are components of the dysregulated NF-κB/Snail/YY1/RKIP loop in many cancers. In this review, we discuss the roles each of Snail, YY1, and RKIP in the regulation of tumor cell resistance to chemo- and immunotherapies. Because these gene products have also been shown to be involved in the regulation of the EMT phenotype and metastasis, we hypothesize that targeting any of these gene products can simultaneously inhibit tumor cell
resistance and metastasis.