dihydropyridines and Liver-Neoplasms

Three groups of synthetic lipids are chosen for studies: (1) 1,4-dihydropyridines (1,4-DHPs) containing two cationic moieties and their analogues; (2) 3,4-dihydro-2(1

Topics: Animals; Carcinoma, Hepatocellular; Cell Proliferation; Dihydropyridines; Fibrosarcoma; Humans; Liver Neoplasms; Lung Diseases; Mice; Molecular Structure; NIH 3T3 Cells; Pyridones; Tumor Cells, Cultured; Vinyl Compounds

A novel method for preparation of a new class of dihydropyridine thioglycosides and their corresponding dehydrogenated forms, via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides has been studied. The evaluation of antiproliferative activity against HepG-2 cell lines (liver carcinoma cell lines) of the dihydropyridine thioglycosides and pyridine thioglycosides revealed that many of the thioglycosides have interesting antitumor activities specifically 5c, 5g, 5l, 5o, 5p, 7a, 7i, 7p, 8b, 8f, 8s, and 8v.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Dihydropyridines; Drug Design; Hep G2 Cells; Humans; Liver Neoplasms; Molecular Structure; Oxidation-Reduction; Structure-Activity Relationship; Thioglycosides

A convenient synthesis of a novel series of dihydropyridine and pyridine thioglycosides was developed. The evaluation of anti-proliferative activity against HepG-2 cell lines (liver carcinoma cell lines) shows that most of the compounds have antitumor activity, especially 5b, 5f, 5j, 5n, 7b, 7f, 7j, 7n, 8b, 8f, and 8j. The results of molecular docking reveal that these compounds have high binding affinity by hydrogen bond formation with the binding pocket of thymidylate synthase dihydrofolate reductase (TS-DHFR).

Topics: Antineoplastic Agents; Cell Proliferation; Dihydropyridines; Drug Design; Hep G2 Cells; Humans; Liver; Liver Neoplasms; Molecular Docking Simulation; Multienzyme Complexes; Protein Binding; Pyridines; Tetrahydrofolate Dehydrogenase; Thioglycosides; Thymidylate Synthase

Mallory-Denk bodies (MDBs) are found in the liver of patients with alcoholic and chronic nonalcoholic liver disease, and hepatocellular carcinoma (HCC). Diethyl 1,4-dihydro-2,4,6,-trimethyl-3,5-pyridinedicarboxylate (DDC) is used as a model to induce the formation of MDBs in mouse liver. Previous studies in this laboratory showed that DDC induced epigenetic modifications in DNA and histones. The combination of these modifications changes the phenotype of the MDB forming hepatocytes, as indicated by the marker FAT10. These epigenetic modifications are partially prevented by adding to the diet S-adenosylmethionine (SAMe) or betaine, both methyl donors. The expression of three imprinted ncRNA genes was found to change in MDB forming hepatocytes, which is the subject of this report. NcRNA expression was quantitated by real-time PCR and RNA FISH in liver sections. Microarray analysis showed that the expression of three ncRNAs was regulated by DDC: up regulation of H19, antisense Igf2r (AIR), and down regulation of GTL2 (also called MEG3). S-adenosylmethionine (SAMe) feeding prevented these changes. Betaine, another methyl group donor, prevented only H19 and AIR up regulation induced by DDC, on microarrays. The results of the SAMe and betaine groups were confirmed by real-time PCR, except for AIR expression. After 1 month of drug withdrawal, the expression of the three ncRNAs tended toward control levels of expression. Liver tumors that developed also showed up regulation of H19 and AIR. The RNA FISH approach showed that the MDB forming cells' phenotype changed the level of expression of AIR, H19 and GTL2, compared to the surrounding cells. Furthermore, over expression of H19 and AIR was demonstrated in tumors formed in mice withdrawn for 9 months. The dysregulation of ncRNA in MDB forming liver cells has been observed for the first time in drug-primed mice associated with liver preneoplastic foci and tumors.

Topics: Animals; Betaine; Biomarkers, Tumor; Diet; Dihydropyridines; Gene Expression Profiling; Gene Expression Regulation; Humans; In Situ Hybridization, Fluorescence; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C3H; Microarray Analysis; Proteins; RNA, Long Noncoding; RNA, Untranslated; Transcription Factors

We have previously shown that a series of N-alkylated 1,4-dihydropyridines potentiate the therapeutic efficacy of vincristine in vincristine-resistant P388 leukemia. The purpose of this study was to investigate the ability of one of the compounds, AC394, and its enantiomers to potentiate the antitumor activity of adriamycin against colon cancer cells in vitro and in vivo.. The effects of AC394 on potentiation of adriamycin cytotoxicity and enhancement of its accumulation were evaluated using colon 26, HCT-15 and MCF-7 cells. Furthermore, the activities of AC394 and its enantiomers were compared. We also studied the combined effects of (+)-AC394 and adriamycin on subcutaneously (s.c.)-implanted and liver metastasis tumor models.. AC394 potentiated the cytotoxicity of adriamycin and enhanced its accumulation in colon cancer cells (colon 26 and HCT-15), which are known to express P-GP (P-glycoprotein) intrinsically. Enhancement of adriamycin accumulation by AC394 was found in s.c.-implanted colon 26 cells in vivo. Although both enantiomers of AC394 showed equal activity in vitro, (+)-AC394 was more effective than (-)-AC394 given orally. (-)-AC394 was found to be cleared more rapidly from the plasma than (+)-AC394. Thus, (+)-AC394 was evaluated for further study. Administration of (+)-AC394 significantly potentiated the antitumor activities of adriamycin in human colon cancer HCT-15 cells implanted s.c. Furthermore, in the liver metastasis model using colon 26 cells, a model completely resistant to adriamycin, the combination therapy of adriamycin with (+)-AC394 produced superior antitumor effects over adriamycin alone.. A newly synthesized N-alkylated 1,4-dihydropyridine derivative, (+)-AC394, showed superior effects on the potentiation of adriamycin antitumor and antimetastatic activities in vivo. These results suggest that this combination may have therapeutic efficacy not only against primary colon cancers but also against metastatic liver cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Colon; Colonic Neoplasms; Dihydropyridines; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Liver Neoplasms; Mice; Mice, Nude; Tumor Cells, Cultured

Virally-induced hepatocellular carcinomas (HCC) are intrinsically resistant to cancer chemotherapy partly due to increased expression of p-glycoprotein (pgp). In this study, we determined that pgp expressed in woodchuck HCC had binding properties were similar to the drug resistant human pgp. Pgp drug binding properties were characterized by photoaffinity labeling with the calcium channel blocker [3H]azidopine (AZD). AZD bound pgp in HCC but not in non-tumor liver samples, and binding was confirmed by competition with Adriamycin (IC50 = 10 microM) and actinomycin D (IC50 = 1 microM). In summary, WHV-induced HCC overexpress a pgp which binds anticancer drugs suggesting a common pathway for drug resistance.

Topics: Affinity Labels; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Binding, Competitive; Carcinoma, Hepatocellular; Dihydropyridines; Doxorubicin; Liver Neoplasms; Marmota