Natural killer activity against cultured human neural tumor and fetal brain cells

Ten human neural tumor lines and three established from normal human brain were analyzed for sensitivities to natural killer (NK) cytolysis. Compared to MOLT-4, fetal brain cells were sensitive, but those from adult brain and eight of ten neural tumor cell lines demonstrated marked NK resistance. The frequencies of target-binding cells (TBC) and single-cell lysis of glioma cells bound within tumor cell conjugates demonstrated that the resistance of two lines was explained either by a decrease in the frequencies of TBC or reduced ability of bound NK cells to lyse the tumor cell conjugates. A third resistant line demonstrated decreases in both TBC and tumor cell conjugate lysis. Two glioma lines with less NK resistance had greater frequencies of TBC or conjugate lysis than the resistant lines. Thus, NK resistance can result from decreased recognition of targets, diminished NK lysis of bound targets, or a combination of both.     

Novel combination of Celecoxib and proteasome inhibitor MG132 provides synergistic antiproliferative and proapoptotic effects in human liver tumor cells

Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Celecoxib (Celebrex®) exhibits antitumor effects in human HCC cells, and its mechanism of action is mediated either by its ability to inhibit cyclooxygenase 2 (COX-2) or by a number of various other COX-2 independent effects. Proteasome inhibitors (PIs) can exert cell growth inhibitory and apoptotic effects in different tumor cell types, including HCC cells. The present study examined the interaction between celecoxib and the PI MG132 in two human liver tumor cell lines HepG2 and HA22T/VGH. Our data showed that each inhibitor reduced proliferation and induced apoptosis in a dose-dependent manner in both cell lines. Moreover, the combination of celecoxib with MG132 synergistically inhibited cell viability and increased apoptosis, as documented by caspase 3 and 7 activation, PARP cleavage, and down-regulation of Bcl-2. Celecoxib and MG132, both alone and synergistically in combination, induced expression of the endoplasmic reticulum (ER) stress genes ATF4, CHOP, TRB3 and promoted the splicing of XBP1 mRNA. Knockdown of TRB3 mRNA expression by small interference RNA significantly decreased combination-induced cell death in HA22T/VGH cells, whereas it increased combination-induced cell death in HepG2 cells, suggesting that activation of the ER stress response might have either a detrimental or a protective role in liver tumor cell survival. In conclusion, our data indicate that combination treatment with celecoxib and MG132 resulted in synergistic antiproliferative and proapoptotic effects against liver cancer cells, providing a rational basis for the clinical use of this combination in the treatment of liver cancer.     

New titanocene derivatives with high antiproliferative activity against breast cancer cells

The synthesis and characterization of some new titanocene-complexes, having a ethenyl-phenoxide or a benzyl group as substituents of the cyclopentadienyl rings, are reported. The synthesized compounds have been evaluated for their cytotoxic potential against two human breast cancer cell lines, that is: MCF7 and SkBr3. Most of these compounds have shown significant cytotoxic effects, compared to cisplatin, in MTT-based cell tests.     

Studies on quinones. Part 42: Synthesis of furylquinone and hydroquinones with antiproliferative activity against human tumor cell lines

The preparation of furyl-1,4-quinone and hydroquinones by reaction of 2-furaldehyde N,N-dimethylhydrazone with benzo- and naphthoquinones is reported. Access to furylnaphthoquinones from unactivated quinones requires acid-induced conditions, however oxidative coupling reactions of activated quinones proceed under neutral conditions. The in vitro cytotoxic activity of the prepared compounds against a panel of three human cancer cell lines has been studied. Most of the furyl-1,4-quinones exhibited good antiproliferative activity (GI(50)=6.5-33.5microm) against the MCF-7, NCI-H460, and SF-268 (CNS cancer) cell lines chosen for testing.     

Ajugalide-B (ATMA) is an anoikis-inducing agent from Ajuga taiwanensis with antiproliferative activity against tumor cells in vitro

Ajuga taiwanensis is widely used for the treatment of hepatitis and hepatoma in Taiwanese folk medicine. However, its bioactive components and mechanism of action are unclear. Herein, ajugalide-B (ATMA), a neoclerodane diterpenoid isolated from Ajuga taiwanensis, is reported to exhibit high anti-proliferative activity against tumor cell lines from various tissues. These results demonstrate that ATMA disrupts the focal adhesion complex by decreasing phosphorylation of paxillin and focal adhesion kinase (FAK). As a result, anoikis, a specific type of apoptosis caused by detachment of cells, is triggered by activation of caspase-8 in A549 cells. Furthermore, ATMA also blocks anchorage-independent growth and cell migration and, therefore, ATMA may serve as a lead compound for the developing of anti-cancer therapeuties with anoikis-inducing properties.     

Phenyl-substituted aminomethylene-bisphosphonates inhibit human P5C reductase and show antiproliferative activity against proline-hyperproducing tumour cells

In certain cancers, such as breast, prostate and some lung and skin cancers, the gene for the enzyme catalysing the second and last step in proline synthesis, δ¹-pyrroline-5-carboxylate (P5C) reductase, has been found upregulated. This leads to a higher proline content that exacerbates the effects of the so-called proline-P5C cycle, with tumour cells effectively using this method to increase cell survival. If a method of reducing or inhibiting P5C reductase could be discovered, it would provide new means of treating cancer. To address this point, the effect of some phenyl-substituted derivatives of aminomethylene-bisphosphonic acid, previously found to interfere with the catalytic activity of plant and bacterial P5C reductases, was evaluated in vitro on the human isoform 1 (PYCR1), expressed in E. coli and affinity purified. The 3.5-dibromophenyl- and 3.5-dichlorophenyl-derivatives showed a remarkable effectiveness, with IC₅₀ values lower than 1 µM and a mechanism of competitive type against both P5C and NADPH. The actual occurrence in vivo of enzyme inhibition was assessed on myelogenous erythroleukemic K562 and epithelial breast cancer MDA-MB-231 cell lines, whose growth was progressively impaired by concentrations of the dibromo derivative ranging from 10⁻⁶ to 10⁻⁴M. Interestingly, growth inhibition was not relieved by the exogenous supply of proline, suggesting that the effect relies on the interference with the proline-P5C cycle, and not on proline starvation.     

In silico identification of novel EGFR inhibitors with antiproliferative activity against cancer cells

Inhibition of the epidermal growth factor receptor (EGFR) tyrosine kinase activity by small molecules has proved effective for the treatment of cancer. To the best of our knowledge, the crystal structure of EGFR has been used for the first time to identify novel inhibitor chemotypes by docking-based in silico screening of a large virtual chemical library followed up by experimental validation. We identified several compounds with antiproliferative effects on cancer cells. Amongst them, a C(4)-N(1)-substituted pyrazolo[3,4-d]pyrimidine MSK-039 (39) was discovered as a low-micromolar inhibitor of EGFR tyrosine kinase activity. The predicted binding mode of 39 opens a new avenue toward the optimization of novel chemical entities to develop potent and selective inhibitors of EGFR signaling.     

Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines

New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity.     

Aminoquinoline derivatives with antiproliferative activity against melanoma cell line

The synthesis of a novel series of aminoquinoline derivatives 1a–p and their antiproliferative activities against A375 human melanoma cell line were described. Most compounds showed superior antiproliferative activities to Sorafenib as a reference compound. Among them, quinolinyloxymethylphenyl compounds 1k and 1l exhibited potent activities (IC₅₀ = 0.77 and 0.79 μM, respectively) and excellent selectivity against melanoma and fibroblast cell lines.     

Chilean propolis: antioxidant activity and antiproliferative action in human tumor cell lines

Propolis, a natural product derived from plant resins collected by honeybees, has been used for thousands of years in traditional medicine all over the world. The composition of the propolis depends upon the vegetation of the area from where it was collected and on the bee species. In this study, we investigated the antioxidant activity of a propolis sample, provided by NATURANDES-CHILE, collected in a temperate region of central Chile. In addition, this natural compound was tested for its antiproliferative capacity on KB (human mouth epidermoid carcinoma cells), Caco-2 (colon adenocarcinoma cells) and DU-145 (androgen-insensitive prostate cancer cells) human tumor cell lines. Results showed that this Chilean propolis sample exhibits interesting biological properties, correlated with its chemical composition and expressed by its capacity to scavenge free radicals and to inhibit tumor cell growth.     

Structure–activity relationships of diverse annonaceous acetogenins against human tumor cells

Twelve annonaceous acetogenins (ACGs) with different stereochemical structures and configuration were selected to test for their inhibitions on the growth of Hela, SMMC-7541, SGC-7901, MCF-7 and A-5408 tumor cell lines using MTT method. This was the first to simultaneously investigate effects of structural factors of stereochemical structures and configuration on cytotoxicities with structure–activity relationship. The present study showed that cytotoxic selectivities of ACGs with threo/trans/threo/trans/erythro stereochemical arrangement were gently more active than those with threo/trans/threo/trans/threo stereochemical arrangement, and ACGs with cis THF ring partly produced notable cytotoxic selectivities. Furthermore, ACGs with S configuration at C-24 exhibited gently more cytotoxic selectivities potency than those with R configuration at C-24.     

Evaluation of chemical constituents from Glehnia littoralis for antiproliferative activity against HT-29 human colon cancer cells

In order to investigate the potential of Glehnia littoralis as a cancer chemopreventive food, antiproliferative effects of both its crude extracts and solvent-partitioned fractions (n-hexane, 85% aq. MeOH, n-BuOH, and water) were evaluated in HT-29 human colon cancer cells. Its crude extracts and solvent-partitioned fractions exhibited dose-dependent inhibitory effects on the cell proliferation. Especially, n-hexane and 85% aq. MeOH fractions exhibited a high antiproliferative effect, induced apoptosis as determined by 4,6-diamidino-2-phenylindole (DAPI) staining, and reduced mRNA expression of Bcl-2, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS). Systematic separation of n-hexane and 85% aq. MeOH fractions by diverse chromatographic methods led to the isolation of furanocoumarins (1–4) and polyacetylene alcohols (5–7). All compounds exhibited dose-dependent inhibitory effects on the cell proliferation. These results indicated that potent inhibitory activity of G. littoralis on proliferation of cancer cells can be significantly traceable to furanocoumarines and polyacetylenic alcohols contained in G. littoralis.     

Novel potent dual inhibitors of CK2 and Pim kinases with antiproliferative activity against cancer cells

A novel family of potent dual inhibitors of CK2 and the Pim kinases was discovered by modifying the scaffolds of tricyclic Pim inhibitors. Several analogs were active at single digit nanomolar IC(50) values against CK2 and the Pim isoforms Pim-1 and Pim-2. The molecules displayed antiproliferative activity in various cell phenotypes in the low micromolar and submicromolar range, providing an excellent starting point for further drug discovery optimization.     

N-Aryltriazole ribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer

Novel N-aryltriazole nucleosides were synthesized via Cu-mediated C–N cross-coupling reaction starting with 3-aminotriazole ribonucleoside and various boronic acids. Two of them exhibited potent apoptosis-related antiproliferative activity against the drug-resistant pancreatic cancer cell line MiaPaCa-2, with an increased potency compared to gemcitabine, the reference treatment for pancreatic cancer. A preliminary SAR study suggests that the appended N-aryl moiety and the substituent at its para-position, as well as the ribose sugar component, contribute considerably to the observed antiproliferative activity.     

Screening and fractionation of plant extracts with antiproliferative activity on human peripheral blood mononuclear cells

Three hundred and thirteen extracts from 136 Brazilian plant species belonging to 36 families were tested for their suppressive activity on phytohemaglutinin (PHA) stimulated proliferation of human peripheral blood mononuclear cells (PBMC). The proliferation was evaluated by the amount of [3H]-thymidine incorporated by the cells. Twenty extracts inhibited or strongly reduced the proliferation in a dose-dependent manner at doses between 10 and 100 micro g/ml. Three of these extracts appeared to be non-toxic to lymphocytes, according to the trypan blue permeability assay and visual inspection using optical microscopy. Bioassay-guided fractionation of Alomia myriadenia extract showed that myriadenolide, a labdane diterpene known to occur in this species, could account for the observed activity of the crude extract. Using a similar protocol, an active fraction of the extract from Gaylussacia brasiliensis was obtained. Analysis of the 1H and 13C NMR spectra of this fraction indicates the presence of an acetylated triterpene whose characterization is underway. The extract of Himatanthus obovatus is currently under investigation.     

Antiproliferative activity of dmoPTA-Ru(II) complexes against human solid tumor cells

The biological evaluation of new Ru(II) complexes carrying dmoPTA (dmoPTA = 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) ligands is reported. The results on the biological activity revealed that the organometallic complexes are active against all cell lines with GI₅₀ values in the range 1.1-2.6 μM. When compared to the standard anticancer drug cisplatin, the bimetallic Ru(II) complexes showed a greater activity profile. The cell cycle analysis revealed that the new compounds induced arrest in G₁ phase. Contrary to cisplatin, these Ru(II) complexes do not interact with DNA. This result suggests that DNA might not be the key pharmacological target.     

Synthesis of quinolinylaminopyrimidines and quinazolinylmethylaminopyrimidines with antiproliferative activity against melanoma cell line

Abstract

Synthesis of a new series of quinolinylaminopyrimidines 1a–k and quinazolinylmethylaminopyrimidines 2a–i containing aminoquinoline and aminoquinazoline as hinge regions is described. Their in vitro antiproliferative activities against A375P human melanoma cell line were tested. Among them, compounds 1h and 1k exhibited the highest antiproliferative activities against A375P cell line with IC₅₀ values in sub-micromolar scale. Compounds 1i, 2b and 2g showed similar potency against A375P to Sorafenib as a reference compound. The representative compound 1h showed high, dose-dependent inhibition of MEK and ERK kinases.