Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 16, Issue 5, 2016

Melanoma prevalently occurs on parts of the body that have been overexposed to the sun. However, it can also originate in the nervous system, eye and mucous membranes. Melanoma has been thought for a long time to arise through a series of genetic mechanisms involving numerous irreversible changes within the human genome. However, recently, “epimutations” have attracted considerable attention owing to their high prevalence rate and reversible nature. These observations opened up new perspectives in the use of epidrugs with the potential for restoring the “correct” control of neoplastic genomes. Here, we focused on the common consensus on genetics and epigenetics in melanoma. We also discussed the clinical applications of regulators of epigenetic enzymes able to revert the epigenetic and metabolic hallmarks of melanoma cells. Such anti-neoplastic agents affect the expression profile of antioncogenes, proto-oncogenes, and microRNAs resulting in enhanced differentiation, apoptosis, and growth inhibition.

In the recent few years, the emergence of heterocyclic ring-containing anti-cancer agents has gained a great deal of attention among medicinal chemists. Among these, azepine-based compounds are particularly becoming attractive recently. In this Focus Review, we highlight the recent advancements in the development of azepine-based anti-cancer compounds since the year 2000.

Recently mutual interactions of chemotherapy and immunotherapy have been widely accepted, and several synergistic mechanisms have been elucidated as well. Although much attention has focused on the combination of DC vaccine and chemotherapy, there are still many problems remaining to be resolved, including the optimal treatment schedule of the novel strategy. In this article, we methodically examined literature about the combination strategy of DC vaccine and conventional chemotherapy. Based on the published preclinical and clinical trials, treatment schedules of the combinational strategy can be classified as three modalities: chemotherapy with subsequent DC vaccine (post-DC therapy); DC vaccine followed by chemotherapy (pre-DC therapy); concurrent DC vaccine with chemotherapy (con-DC therapy).The safety and efficacy of this combinatorial immunotherapy strategy and its potential mechanisms are discussed. Although we could not draw conclusions on optimal treatment schedule, we summarize some tips which may be beneficial to trial design in the future.

Cancer is one of the diseases that seriously threaten to human life worldwide. Up to now, chemotherapy remains to be a critical means of cancer treatment, thus the development of chemotherapeutical drugs has become a top priority. An ion pair high performance liquid chromatography (ion pair RP-HPLC) was established for analyzing intracellular nucleotides of tumor cell lines. In this article, a partial least-squares discriminant analysis (PLS-DA) prediction model of mechanisms of chemotherapeutics was established based on four types of drugs with different mechanisms, including antimetabolic agents, antineoplastic agents that affect protein synthesis, agents directly acting on DNA, and RNA interference agents. Then four anti-tumor agents commonly used in clinical were used to validate the availability of the prediction model. Three natural compounds, including 16- dehydropregnenolone (16-DHP), apigenin (API) and diosgenin (DIO), were reported to display anti-tumor effect with unclear mechanisms. The three components were applied to this prediction model firstly. In conclusion, the recognition model was proved to be accurate and feasible to some degree and might become a promising auxiliary method in the process of chemotherapeutic drugs development.

Oleanolic acid ketones, oximes, lactams and nitriles were obtained. Complete spectral characterizations (IR, 1H NMR, 13C NMR, DEPT and MS) of the synthesized compounds are presented. The derivatives had oxo, hydroxyimino, lactam or nitrile functions at the C-3 position, an esterified or unmodified carboxyl group at the C- 17 location and, in some cases, an additional oxo function at the C-11 position. The new compounds were tested for cytotoxic activity on the HeLa, KB, MCF-7 and Hep-G2 cancer cell lines with the application of MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test. Among the tested compounds, some oximes and all lactams proved to be the most active cytotoxic agents. These triterpenes significantly inhibited the growth of the HeLa, KB, MCF-7 and Hep-G2 cancer cell lines at micromolar concentrations.

Cryptotanshinone (CTS), a natural product isolated from Salvia miltiorrhiza Bunge, demonstrates anticancer effect. Previous reports showed that CTS induced caspase-independent cell death. Here, we reported that CTS induced pro-death autophagy in human lung cancer cells. CTS inhibited the proliferation of A549 cells in a time- and concentration- dependent manner. CTS triggered autophagy as confirmed by monodansylcadaverine staining, transmission electron microscopy analysis, as well as western blot detection of microtubule-associated protein light-chain 3 (LC3). CTS induced intracellular reactive oxygen species (ROS) formation in a concentration- and time-dependent manner, which was reversed by N-acetyl-L-cysteine (NAC), catalase, diphenyleneiodonium (DPI), pyrrolinodimethylthiocarbamate (PDTC), and dicumarol. Furthermore, CTS-induced autophagy was inhibited by NAC, JNK siRNA and SP600125. NAC reversed CTS-induced JNK phosphorylation. NAC, 3-methyladenine (3-MA), and SP600125 partly reversed CTS-induced cell death. In addition, CTS (10 mg/kg) dramatically inhibited tumor growth by 48.3% in A549 xenograft nude mice, which was completely reversed by NAC (50 mg/kg) co-treatment. Our findings showed that CTS induced pro-death autophagy through activating JNK signaling mediated by increasing intracellular ROS production.

Microtubules are composed by α- and β-tubulin polypeptides. α-tubulin undergoes a reversible posttranslational modification whereby the C-terminal tyrosine residue is removed (Glu-tubulin) and re-added (Tyrtubulin). Recent studies have shown that α-tubulin tyrosine residues can be nitrated and the incorporation of NO2Tyr into the C-terminus of Glu-tubulin forms a complex that blocks the tyrosination/detyrosination cycle, an event that can compromise protein/enzyme functions, such as cell division. Since many studies demonstrated that Glu-tubulin levels increase in cancer, the aim of the present study was to investigate the effect of new drugs, fluorazone derivatives (K1-K2-K9-K10-K11), on the proliferation of melanoma cells. Our results demonstrated that these drugs, except for K2, were able to inhibit cellular proliferation without exhibiting cytotoxicity. The anti-proliferative effect was accompanied by the decrease of Glu-tubulin levels and the increase of its nitration. This effect seems to be a consequence of NO2 induction and NO2Tyr ligation to Glu-tubulin. Collectively, these results, showing that the fluorazone derivatives, by promoting NO2Tyr incorporation into α-tubulin, are able to arrest the cycle of detyrosination/tyrosination and to inhibit cell proliferation, offer new perspectives for the possible usage of these drugs, alone or in combination, as non-toxic, anti-proliferative agents in melanoma.

Background: Angiogenesis is an important process facilitating the growth of glioblastoma (GBM). It also has drawn great attention in the treatment of GBM. GBM angiogenesis is closely related to the function of endothelial cells. microRNAs can affect the activities of endothelial 10 cells directly, or indirectly through the interaction of tumor cells and endothelial cells. However, the mechanism underlying the interaction of GBM cells regulated by specific microRNA with endothelial cells and following angiogenesis requires further research. In published articles, microRNA-16 acted as a tumor suppressor in multiple types of cancers including glioma, but the role in glioma angiogenesis has not been well elucidated. Methods: The expression of microRNA-16 was detected in human GBM samples and normal brain tissues. microRNA-16 was transfected to GBM cell line U87 and A172 then the function of endothelial cells co-cultured with U87/A172 (miR-16 or control) were observed in vitro. Expression of VEGF family in vitro and the effect of microRNA-16 on GBM angiogenesis in vivo were also investigated. Results: microRNA-16 is down-regulated in human GBM samples in contrast to the normal brain tissues. Overexpression of microRNA- 16 in the A172 and U87 GBM cell lines inhibited the activities of co-cultured endothelial cells, including proliferation, migration, extension and tubule formation. Further experiments of dual luciferase assays verified microRNA-16 directly targeting Bmi-1. microRNA-16 down-regulated the expression of vascular endothelial growth factor VEGF-A and VEGF- C which were closely related to the angiogenesis of GBM. Moreover, less vascular formed in the section of neoplasm of the microRNA- transduced group than the control group in vivo. Conclusions: Collectively, these findings indicate that loss of microRNA-16 may favor glioma angiogenesis, on the contrary overexpression of microRNA-16 in GBM cells plays a critical role in repressing endothelial function and angiogenesis by targeting Bmi-1. microRNA-16 may be a potential therapeutic agent in the treatment of GBM.

An efficient route towards the synthesis of symmetrical diselenide and seleniumcontaining quinone pseudopeptides via one-pot Ugi and sequential nucleophilic substitution (SN) methodology was developed. Compounds were evaluated for their antimicrobial and anticancer activities and their corresponding antioxidant/pro-oxidant profiles were assesed employing 2,2-diphenyl-1-picrylhydrazyl (DPPH), bleomycin dependent DNA damage and glutathione peroxidase (GPx)-like activity assays. Selenium based quinones were among the most potent cytotoxic compounds with a slight preference for MCF-7 compared to HepG2 cells and good free radical scavenging activity. Furthermore, symmetrical diselenides exhibited the most potent GPx-like activity compared to ebselen. Moreover, compounds 7, 8, 9 and 10 exhibited similar antifungal activity to the antifungal drug clotrimazole with modest activity against the Gram-positive bacterium S. aureus. These results indicate that some of the synthesized organoselenides are redox modulating agent with promising anti-cancer and antifungal potentials.

Background: The inhibition of angiogenesis is a theoretically ideal chemotherapy for cancer, but there remains room for improvement. Most inhibitors of angiogenesis approved to date target vascular endothelial growth factors (VEGFs); however, VEGFs are only one of the many classes of participant in tumor angiogenesis. Because tumor angiogenesis is orchestrated by many components, including growth factors, signal transducers, and effectors, its regulation exhibits redundancy. Curcumin can associate with many proteins, and it reportedly inhibits tumor angiogenesis. Objective: We investigated the ability of a new curcumin analog, GO-Y078, to inhibit tumor angiogenesis. Results: GO-Y078 inhibited human umbilical vascular endothelial cell sprouting. GO-Y078 also induced complete anoikis in vascular endothelial cells. Moreover, GO-Y078 suppressed the migration and invasion of vascular endothelial cells into extracellular matrix proteins. However, expression analysis revealed that GO-Y078 did not suppress molecules involved in VEGF signaling. Rather, GOY078 induced actin disorganization, dissociation of vinculin from actin, and destruction of focal adhesion, resulting in the inhibition of vascular endothelial cell mobility. GO-Y078 also suppressed in-vivo vasculogenesis in Xenopus laevis tadpoles. Conclusion: Actin organization is a common effecter related to vascular endothelial cell mobility in angiogenesis. We demonstrated that GO-Y078 inhibits angiogenesis through actin disorganization.

Moringa oleifera, from the family Moringaceae, is used as a source of vegetable and herbal medicine and in the treatment of various cancers in many African countries, including Kenya. The present study involved the phytochemical analyses of the crude extracts of M.oleifera and biological activities (antioxidant, cytotoxicity and induction of apoptosis in-vitro) of selected isolated compounds. The compounds isolated from the leaves and seeds of the plant were quercetin-3-O-glucoside (1), 4-(β-D-glucopyranosyl-1→4-α-L-rhamnopyranosyloxy)-benzyl isothiocyanate (2), lutein (3), and sitosterol (4). Antioxidant activity of compound 1 was significant when compared to that of the control, while compound 2 showed moderate activity. The cytotoxicity of compounds 1 and 2 were tested in three cell lines, viz. liver hepatocellular carcinoma (HepG2), colon carcinoma (Caco-2) and a non-cancer cell line Human Embryonic Kidney (HEK293), using the MTT cell viability assay and compared against a standard anticancer drug, 5-fluorouracil. Apoptosis studies were carried out using the acridine orange/ethidium bromide dual staining method. The isolated compounds showed selective in vitro cytotoxic and apoptotic activity against human cancer and non-cancer cell lines, respectively. Compound 1 showed significant cytotoxicity against the Caco-2 cell line with an IC50 of 79 μg mL-1 and moderate cytotoxicity against the HepG2 cell line with an IC50 of 150 μg mL-1, while compound 2 showed significant cytotoxicity against the Caco- 2 and HepG2 cell lines with an IC50 of 45 μg mL-1 and 60 μg mL-1, respectively. Comparatively both compounds showed much lower cytotoxicity against the HEK293 cell line with IC50 values of 186 μg mL-1 and 224 μg mL-1, respectively.