Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 15, Issue 10, 2015

Paraneoplastic pemphigus (PNP) is a debilitating and lethal adult and pediatric autoimmune blistering skin disease that occurs in the setting of a known or occult neoplasm. It is characterized by painful mucosal erosions that are often resistant to therapy. These clinical characteristics, in addition to positive immunohistochemistry findings make the diagnosis of PNP. The ability to recognize and diagnose PNP has dramatically improved in the last two and half decades. However, the mortality remains 75-90% with a mean survival of less than 1 year. The disease typically progresses from localized skin manifestations to multiple organ failure despite treatment with high dose corticosteroids and immunosuppressives. Because PNP has a low incidence and prevalence, information on treatment and management strategies has depended on a limited number of case reports and case series. The rarity of the disease hampers the ability to conduct large-scale clinical trials as well as investigations into the pathophysiology of PNP. In this article, we review clinical presentation, diagnosis, management, treatment, and pathophysiology of PNP.

Oral cancer (OC) is a common and aggressive cancer with poor survival rate. Recent research has investigated in detail the complex network of chemical, viral, and (epi)genetic factors associated with oral carcinogenesis. However, the causal factors that trigger the oral carcinogenesis process and the molecular mechanisms that underlie the tumor progression, and metastasis of OC have not been clarified. The present study analyses the hypothesis that immune reactions following viral infections may crossreact with tumor suppressor action proteins involved in OC. Using proteome databases and epitope catalogue resources together with data derived from an ample scientific-clinical literature, potential peptide crossreactions between HCV, HPV16, EBV, and CMV pathogens and human p53 and CSMD tumor suppressor proteins are detailed. The present study might contribute to understand the molecular basis of oral carcinogenesis and open new therapeutic research perspectives.

Healthy immune repertoire contains a fraction of immunoglobulins that do not possess exquisite antigen specificity but are able to recognize numerous unrelated antigens with similar values of the binding affinity. These antibodies are referred to as polyreactive. Besides natural polyreactive antibodies immune repertoires contain antibodies that acquire polyreactivity post-translationally, upon structural changes in their variable regions. In this article we made an overview of the recent findings about antibody polyreactivity. After introduction of the concept, and description of the origin, functions, and molecular mechanisms of polyreactive antibodies, we discussed their role in autoimmunity, malignancy and infectious diseases. We made a parallel with similar data about antibodies with induced polyreactivity. This review highlights the importance of natural and acquired antibody polyreactivity in immune defense and surveillance and reveals their potential as a new type of therapeutics.

Evidence is reviewed that complementary proteins and peptides form complexes with increased antigencity and/or autoimmunogenicity. Five case studies are highlighted: 1) diphtheria toxin-antitoxin (antibody), which induces immunity to the normally non-antigenic toxin, and autoimmune neuritis; 2) tryptophan peptide of myelin basic protein and muramyl dipeptide (“adjuvant peptide”), which form a complex that induces experimental allergic encephalomyelitis; 3) an insulin and glucagon complex that is far more antigenic than either component individually; 4) various causes of experimental autoimmune myocarditis such as C protein in combination with its antibody, or coxsackie B virus in combination with the coxsackie and adenovirus receptor; 5) influenza A virus haemagglutinin with the outer membrane protein of the Haemophilus influenzae, which increases antigenicity. Several mechanisms cooperate to alter immunogenicity. Complexation alters antigen processing, protecting the components against proteolysis, altering fragmentation and presenting novel antigens to the immune system. Complementary antigens induce complementary adaptive immune responses (complementary antibodies and/or T cell receptors) that produce circulating immune complexes (CIC). CIC stimulate innate immunity. Concurrently, complementary antigens stimulate multiple Toll-like receptors that synergize to over-produce cytokines, which further stimulate adaptive immunity. Thus innate and adaptive immunity form a positive feedback loop. If components of the complex mimic a host protein, then autoimmunity may result. Enhanced antigenicity for production of improved vaccines and/or therapeutic autoimmunity (e.g., against cancer cells) might be achieved by using information from antibody or TCR recognition sites to complement an antigen; by panning for complements in randomized peptide libraries; or using antisense peptide strategies to design complements.

The search for effective methods for detecting cancers at very early stages is currently a top priority of cancer research. While numerous oncogenes have been identified in and associated with human cancers, the last 50 years of molecular and genetic studies have not led to a breakthrough in either the diagnosis or the treatment of cancers. Therefore, the role of oncogenes in carcinogenesis is still unclear, as is their usefulness in the diagnosis of human cancers. In the present review, we discuss the concept of oncogenes and summarize the current approaches for the early detection of human cancers based on antibodies arrays.

The concept according to which unique, rare and common sequences may define immunogenicity, immunopathogenicity and immunotolerance, respectively, is graphically illustrated using a melanoma-associatedantigen, Melan-A/Mart-1, as a model. The final picture is consolidated by experimentally validated data from the scientific literature and may represent a concrete prelude to effective immunotherapies exempt from collateral autoimmune reactions.

Rap2, a member of the GTP-binding proteins, is widely upregulated in many types of tumors. The specific effectors of Rap2 can affect multiple cancer-associated cellular processes, including cytoskeleton reorganization, proliferation, migration, and inflammation. However, the functional role of Rap2 in tumorigenesis and the interplay between different effectors remain to be fully elucidated. A more thorough understanding of the cancer-associated signaling networks of Rap2 is expected to facilitate drug discovery targeting Rap2 for cancer therapy. The present review mainly focused on recent studies on the functional and physical interactions between Rap2 and its effectors. We also speculated on the relevance of these pathways to tumorigenesis.

Four suberoylanilide hydroxamic acid (SAHA) derivatives (N34, N4I, N4B, N24) were designed and synthesized on the basis of our previous studies on N25. Assays for anti-proliferative activity and histone deacetylase (HDAC) activity were performed against human lung cancer (SPC-A-1, LTEP-a-2, NCI-H1650) and normal lung cells (MRC-5), which were compared with those of SAHA. Molecular docking was used to theoretically confirm the receptor-binding ability of N34. Ultimately, N34 was validated as the best HDAC inhibitor candidate. Furthermore, the effects of N34 on the levels of apoptosis- and autophagy-associated proteins caspase-3, caspase-9, Bcl-2 and Beclin-1 in SPC-A-1 cells were evaluated. N34 exerted more evident effects on human lung cancer than the other three SAHA derivatives did.

The formation of a new blood vessel is stimulated by angiogenic factors. Curcumin, which is the active ingredient of the spice plant Curcuma longa L and is used as food and traditional medicine, has shown anticancer effects against different types of cancers. We evaluated the effects of curcumin on angiogenesis/pro-angiogenic factors in a mouse model of human breast cancer. Cell viability was measured by the MTT assay after curcumin treatment in triple-negative breast cancer cells (MDA-MB-231). For the in vivo study, human breast cancer was induced in athymic mice and treated with 300 mg/kg/day of curcumin administered intraperitoneally. Tumor size was measured weekly, and the animals underwent single photon emission computed tomography (SPECT) scanning with Tc-99m tagged VEGF-c to detect the in vivo expression of VEGFR2/3. In addition, the expression of proangiogenic/ growth factors in the tumor extracts was evaluated by a membrane antibody array. Histological analysis was performed to confirm the effect of curcumin on neovascularization. The MTT assay showed that curcumin significantly reduced the cell viability of MDA-MB-231 cells. In breast cancer xenografts, curcumin treatment led to a decrease in tumor volume and cell proliferation (Ki-67) compared with the vehicle treated group. Tc-99m-HYNIC-VEGF-c-SPECT imaging showed decreased uptake to the tumor, which may indicate a lower expression of VEGFR2/3 in curcumin treated tumors; however, a statistically significant difference was not achieved (p>0.05). Additionally, curcumin treatment showed a significantly low level of expression of pro-angiogenic factors (p<0.05) and a decrease in micro-vessel density (vWF) in animals compared with that of vehicle treated tumors. In conclusion, curcumin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.

Deregulation of the PI3K-Akt-mTOR pathway is unanimously pragmatic in a number of tumors. This pathway pedals proliferation, survival, translation, and coupled with tumorassociated endurance. Current efforts focus on the discovery and development of novel inhibitors of this pathway. We have discovered6-(4-phenoxyphenyl)-N-phenylquinolin-4-amine [PQQ] as a potent mTOR inhibitor with IC50 value of 64nM in a cell-based and cell-free mTOR assay. Mechanistically, PQQ was found to be a strong PI3K-Akt-mTOR-p70S6K cascade inhibitor in Human promyelocytic leukemia HL-60 cells. Moreover, it was found to be dual mTORC1 and mTORC2 inhibitor that inhibit the entire mTOR kinase-dependent functions and feedback commencement of PI3K/Akt pathway. PQQ simultaneously induces apoptosis via mitochondrial dependant pathway, which was confirmed through a battery of the assays, e.g. cellular and nuclear microscopy, annexin-V assay, cell cycle analysis and loss of mitochondrial membrane potential. In summary, PQQ discovered as a novel secondgeneration mTOR inhibitor with significant cytotoxic and apoptotic potentials. Thus, it might be a significant lead structure for the development of mTOR-targeted based anti-cancer therapeutics.

4EGI-1 is the prototype of a novel class of anticancer agents targeting translation. Patented drug-like analogue 1 was synthesized and examined for inhibition of translation and cytotoxicity in cancer cells. Unexpectedly, 1 was found inactive in both assays.

Objective: To investigate the antitumor effects of a mitogen-activated protein kinase (MAPK) kinase fusion protein, TAT-OSBP-MKK6E (MAP2K6-FP), and paclitaxel as single agents and in combination against HO8910 human ovarian cancer cells. Methods: We previously synthesized a MAPK kinase-recombinant fusion protein, MAP2K6-FP, that contains three domains: a protein transduction domain TAT, a human ovarian cancer HO8910 cell-specific binding peptide (OSBP), and a potential anti-tumor effector domain MKK6 (E). The HO8910 cells were exposed to MAP2K6-FP, paclitaxel, or both for 24 h. The antiproliferative effects were determined using the Cell Counting Kit-8assay. Antitumor synergy was determined by computing the combinationindex. The in vivo antitumor effects of both drugs as single agents and in combination were tested using HO8910 cells implanted subcutaneously in female BALBC/c nude mice. TUNEL assay, immunohistochemical evaluation, and western blotting were performed to investigate the mechanism of action. Results: A synergistic anti-proliferative effect was observed between MAP2K6-FP and paclitaxel at multiple drug concentrations, resulting in combination indices ranging from 0.3–0.85. In vivo testing against HO8910 cells in a xenograft tumor model indicated that both drugs were effective as single agents and that MAP2K6-FP and paclitaxel in combination had a synergistic antitumor effect. The combination treatmentresulted in significantly alteredcaspase-3, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigenexpression compared to treatment with the single agents (P<0.05). Conclusion: Both MAP2K6-FP and paclitaxel can inhibit cell proliferation and induce apoptosis in ovarian cancer HO8910 cells. Interestingly, the combination of MAP2K6-FP and paclitaxel had a synergistic antitumor effect on HO8910 cells, which induced apoptosis by increasing caspase-3 expression and decreasing VEGF expression.

Objectives: Histone deacetylase inhibitors represent a promising class of potential anticancer agents for the treatment of human malignancies. In this study, the effects of trichostatin A (TSA) on apoptosis, metastasis-associated gene expression, and activation of the Notch pathway in human pancreatic cancer cell lines were investigated. Methods: After treatment with TSA, cell viability and apoptosis were evaluated using the MTT [3-(4,5-dimethylthia-zol-2-yl)-2,5-diphenyltetrazolium bromide] assay, Hoechst 33258 staining, and flow cytometry. Moreover, RT-PCR and western blot analyses were performed to measure the expression levels of apoptosis-associated genes (Bcl-2, Bax, and caspase-3), metastasis-associated genes (E-cadherin, vimentin, and matrix metalloproteinases), and Notch pathway activation (Notch intracellular domain, NICD). The levels of matrix metalloproteinase 2 and NICD were also semi-quantified by immunoassay. Results: Following treatment with TSA for 24 h, PANC-1, SW1990, and MIATACA-2 cells exhibited cell death. The MTT assay revealed that TSA significantly decreased cell viability in a dose-dependent manner in PANC-1 cells. The Hoechst 33258 staining and flow cytometry results evidenced a significant increase in PANC-1 cell apoptosis following TSA treatment. The expression levels of Bax and caspase-3 were increased significantly, whereas Bcl-2 was down-regulated after TSA treatment. In the PANC-1 cells that survived after TSA treatment, the expression levels of vimentin, E-cadherin, and MMP genes were altered by the promotion of potential metastasis and increased expression of NICD. Conclusions: TSA can induce apoptosis of pancreatic cancer cells. In addition, the up-regulation of metastasis-related genes and the activation of the Notch pathway in the survived PANC-1 cells may be associated with a too-low level of TSA or resistance to TSA.

Under the guidance of our previous work, we synthesized 21 new structures of quinazolines (3a~3u) and evaluated their in vitro anticancer activity against A549, HCT116 and MCF-7 cell lines using the MTT method. Most compounds showed good to excellent anticancer activity. In particular, 3o (regarded as erlotinib analogues) has marked anticancer activity against A549, HCT116 and MCF-7 cell lines (IC50s: 4.26, 3.92 and 0.14 μM, respectively) as compared with the standard anticancer drug gefitinib (IC50s: 17.9, 21.55 and 20.68 μM, respectively), and which can be regarded as the best candidate for development of anticancer drugs.

A novel triazole nucleoside analogue was discovered to exhibit potent anticancer activity in prostate cancer cells via down-regulating heat shock factor 1 (HSF1) and related heat shock proteins, along with the consequential inhibition of androgen receptor (AR) expression and transactivation, arresting the cell cycle in AR-governed phase. This triazole nucleoside therefore constitutes a novel structural paradigm and potential drug candidate for prostate cancer through inhibition of HSF1 and AR.