Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Humans ; Organoplatinum Compounds ; chemical synthesis

In an attempt to develop a new anticancer platinum complex with greater or equivalent antitumor activity but reduced side effects compared with cisplatin (CDDP), a series of new platinum complexes having a glycolate leaving ligand was synthesized. Among them, five complexes were selected for further development on the basis of adequate water solubility, low nephrotoxicity and high antitumor activity in a murine system. The chemosensitivity of these five complexes was examined in MTT assay against two human pulmonary adenocarcinoma cell lines, PC-9 and PC-14, and two human stomach adenocarcinoma cell lines, MKN-45 and KATO III. Their IC50 and relative antitumor activity (RAA) values were compared with those of CDDP and 254-S, a second-generation platinum complex with a glycolate leaving ligand under phase III clinical trial. The lowest mean IC50 value was observed in CDDP, followed by SKI 2034R and SKI 2033R. In this study, the antitumor activity was evaluated in terms of RAA values and SKI 2034R showed the highest RAA value. The order of RAA values was SKI 2034R > CDDP > SKI 2032R > SKI 2033R > SKI 2030R > SKI 2029R > 254-S. Based on the RAA order, we have recommended SKI 2034R as the most promising candidate for further development of a clinically useful platinum complex.
Antineoplastic Agents/*pharmacology ; Cisplatin/pharmacology ; Comparative Study ; Drug Evaluation, Preclinical ; Human ; Organoplatinum Compounds/*pharmacology ; Tumor Cells, Cultured

OBJECTIVETo study the effects of oxaliplatin combined with low-molecular-weight citrus pectin (LCP) on cell proliferation and apoptosis in human colon carcinoma cell line HT29 in vitro.

METHODSEffects of oxaliplatin alone and oxaliplatin combined with LCP on HT29 cells proliferation were determined by MTT. Coefficient of drug interaction (CDI) was calculated. Influence of oxaliplatin alone and oxaliplatin combined with LCP on HT29 cell apoptosis was determined by fluorescence activated cell sorting (FACS). Protein expression change of procaspase-3, 8, 9, PARP was examined by Western blotting.

RESULTSBoth oxaliplatin alone and oxaliplatin combined with LCP could suppress HT29 cell proliferation in both dose- and time-dependent manner. The inhibitory effect of oxaliplatin combined with LCP on HT29 cell proliferation was more significant (P<0.01) with a CDI less than 1. FACS analysis showed that oxaliplatin alone and combination therapy could increase the apoptosis proportion of HT29 cells. After the drug treatment for 6, 24, and 48 hours, the apoptosis rate of oxaliplatin alone group was (9.76±0.47)%, (20.45±0.74)%, (28.70±3.29)%, and apoptotic rate of the combination group was (20.63±0.69)%, (34.35±1.02)%, (49.47±3.04)%, respectively, which was significantly higher as compared to oxaliplatin alone (P<0.01). Both oxaliplatin alone and combination therapy down-regulated expressions of procaspase-3, 9, and PARP protein. Procaspase-3, 9, PARP protein expression in combination group decreased more significantly, while procaspase-8 expression was not significantly different between the two groups.

CONCLUSIONLCP can enhance the ability of oxaliplatin to inhibit cell proliferation and induce apoptosis, which may be associated with the activation of mitochondrial apoptosis pathway.

Apoptosis ; drug effects ; Cell Proliferation ; drug effects ; Colonic Neoplasms ; pathology ; HT29 Cells ; Humans ; Organoplatinum Compounds ; pharmacology ; Pectins ; pharmacology

Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; pathology ; Cell Division ; drug effects ; Cell Line, Tumor ; Humans ; Liver Neoplasms ; pathology ; Organoplatinum Compounds ; pharmacology

OBJECTIVETo investigate the effect of bafilomycin A1 (BAF) on the cell proliferation, invasiveness, apoptosis, and oxaliplatin sensitivity in gastric cancer MGC-803 cells.

METHODSMGC-803 cells were divided into control group, BAF group, oxaliplatin group, and BAFµ oxaliplatin group. MTT assay and plate clone formation assay were used to assess the viability and colony forming ability of the cells after the treatments. The expression of nucleosomes in the cells was examined with ELISA. The cell migration and invasion after the treatments were evaluated. Western blotting was performed to detect the expression of Bcl-2 and Bax in the treated cells, and scanning electron microscopy, immunohistochemistry and Western blotting were employed to to observe the cell autophagy.

RESULTSCompared with the control cells, the cells treated with BAF showed a substantial decrease in autophagosome accumulation with attenuated cell proliferation, migration and invasion. Compared with cells treated with oxaliplatin alone, the cells treated with both BAF and oxaliplatin showed significantly lowered autophagosome accumulation, suppressed cell proliferation, migration and invasion, increased cell apoptosis, increased Bax expression and lowered Bcl-2 expression.

CONCLUSIONBAF can inhibit the proliferation and invasiveness of MGC-803 cells, promote cell apoptosis by inhibiting autophagy, and enhances the sensitivity of the cells to oxaliplatin.

Apoptosis ; Autophagy ; Cell Line, Tumor ; drug effects ; Cell Movement ; Cell Proliferation ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Macrolides ; pharmacology ; Organoplatinum Compounds ; pharmacology ; Stomach Neoplasms ; pathology

BACKGROUNDMonolayer cell culture models are the traditional culture models used for in vitro research of pancreatic carcinoma chemosensitivity. However, these models neglect the interactions between tumor cells and the impact of the tumor microenvironment. Such tumor cell monolayers poorly mimic the solid tumor microenvironment. The present study aimed to investigate the chemosensitivity characteristics of pancreatic cancer cells in a three-dimensional culture system by analyzing the differences in drug sensitivity between a scattered cell culture model and a multicellular spheroid culture model.

METHODSThree pancreatic cancer cell lines (SW1990, ASPC-1 and PCT-3) were cultured in three-dimensional collagen gels as well as in traditional two-dimensional monolayers. The chemosensitivities of the pancreatic carcinoma cells to 5-fluorouracil (5-FU), gemcitabine, and oxaliplatin in vitro were detected by both the Cell Counting Kit-8 test and the collagen gel droplet-embedded culture drug-sensitivity test.

RESULTSIn the two-dimensional culture model, differences in the chemosensitivities of the cloned pancreatic carcinoma cells and scattered cells existed for some concentrations of 5-FU, gemcitabine and oxaliplatin. In the three-dimensional culture model, there were significant differences in the chemosensitivities of the pancreatic cancer cells between the scattered cells and multicellular spheroids (P < 0.05).

CONCLUSIONPancreatic carcinoma cells exhibit multicellular resistance in three-dimensional cultures.

Antineoplastic Agents ; pharmacology ; Cell Culture Techniques ; methods ; Cell Line, Tumor ; Cell Survival ; drug effects ; Deoxycytidine ; analogs & derivatives ; pharmacology ; Fluorouracil ; pharmacology ; Humans ; Organoplatinum Compounds ; pharmacology ; Pancreatic Neoplasms ; drug therapy ; Spheroids, Cellular ; drug effects

BACKGROUNDDicycloplatin is a relatively safe third generation platinum-complex anti-cancer drug. The present study focused on the effects of dicycloplatin on in vitro proliferation and apoptosis of human aortic smooth muscle cells (HASMC) and human aortic endothelial cells (HAEC).

METHODSProliferation of HASMC and HAEC, DNA content, and cellular levels of proliferation- and apoptosis-related proteins were assessed using the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay, flow cytometry and Western blotting assays, respectively.

RESULTSDicycloplatin at 10 ng/ml significantly inhibited HASMC proliferation, however, 10 µg/ml were required to significantly inhibit HAEC proliferation. Cell cycle analysis showed that dicycloplatin was a non-specific inhibitor of the cell cycle. Although dicycloplatin significantly decreased proliferating cell nuclear antigen (PCNA) expression in HASMC at all concentrations tested, it did not significantly affect PCNA expression in HAEC; Bax and p53 protein expression was upregulated in dicycloplatin groups.

CONCLUSIONSDicycloplatin at nanogram concentrations significantly inhibits HASMC proliferation, although the effect is relatively weaker than that of sirolimus. In contrast, the effect of dicycloplatin on inhibition of HAEC proliferation is much less pronounced than that on HASMC. The latter characteristics point to the potential for use of dicycloplatin in drug-eluting stents.

Aorta ; cytology ; Blotting, Western ; Cell Proliferation ; drug effects ; Drug Combinations ; Drug-Eluting Stents ; Endothelial Cells ; cytology ; drug effects ; Flow Cytometry ; Glutamates ; pharmacology ; Humans ; Muscle, Smooth, Vascular ; cytology ; drug effects ; Organoplatinum Compounds ; pharmacology ; Sirolimus ; pharmacology

OBJECTIVETo observe the lethal effect of multidrug resistance gene (MDR1) antisense RNA combined with oxaliplatin and 5-FU on drug-resistant rectal carcinoma cells.

METHODSPC-MDR1 plasmid including MDR1 was constructed with gene cloning techniques. The drug-resistant cancer cells (8348R) were transferred with the plasmids, and the positive neoplasm cells were selected with G418. Green fluorescent protein (GFP) gene was used as a reporting gene to monitor the gene transfer efficiency under the influence of oxaliplatin and 5-FU. The cytotoxicity and therapeutic effects of MDR1 anti-sense RNA combined with oxaliplatin and 5-FU were evaluated by colony-forming rate and MTT assay.

RESULTSA significant decrease of biological activity was observed in 8348R cells transferred with PC-MDR1, cell cycles were blocked in S phase, or in G2/M phase, and apoptosis rate of the cells increased. With treatment of oxaliplatin, the plasmid transfer efficiency in the drug-resistant cancer cells was improved about 18 times. Using an IC(50) dose of oxaliplatin and 5-FU combined with (MDR1) anti-sense RNA, 75 percent of 8348R cells were killed, which was significant higher than that of the control cells.

CONCLUSIONSCombined MDR1 antisense RNA with oxaliplatin and 5-FU has a synergistic effect of killing drug-resistant cancer cells and may be a promising method for treating drug-resistant rectal carcinoma.

Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Combined Modality Therapy ; Drug Synergism ; Fluorouracil ; pharmacology ; Genes, MDR ; genetics ; Genetic Therapy ; Humans ; Organoplatinum Compounds ; pharmacology ; RNA, Antisense ; genetics ; Rectal Neoplasms ; genetics ; pathology ; therapy ; Transfection

Oxaliplatin is a key drug in chemotherapy of colorectal cancer (CRC). However, its efficacy is unsatisfied due to drug resistance of cancer cells. In this study, we tested whether a natural agent, ursolic acid, was able to enhance the efficacy of oxaliplatin for CRC. Four CRC cell lines including SW480, SW620, LoVo, and RKO were used as in vitro models, and a SW620 xenograft mouse model was used in further in vivo study. We found that ursolic acid inhibited proliferation and induced apoptosis of all four cells and enhanced the cytotoxicity of oxaliplatin. This effect was associated with down-regulation of Bcl-xL, Bcl-2, survivin, activation of caspase-3, 8, 9, and inhibition of KRAS expression and BRAF, MEK1/2, ERK1/2, p-38, JNK, AKT, IKKα, IκBα, and p65 phosphorylation of the MAPK, PI3K/AKT, and NF-κB signaling pathways. The two agents also showed synergistic effects against tumor growth in vivo. In addition, ursolic acid restored liver function and body weight of the mice treated with oxaliplatin. Thus, we concluded that ursolic acid could enhance the therapeutic effects of oxaliplatin against CRC both in vitro and in vivo, which offers an effective strategy to minimize the burden of oxaliplatin-induced adverse events and provides the groundwork for a new clinical strategy to treat CRC.
Animals ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Cell Line, Tumor ; Colorectal Neoplasms ; drug therapy ; metabolism ; pathology ; Drug Synergism ; Female ; Humans ; Mice ; Mice, Nude ; Neoplasm Proteins ; metabolism ; Organoplatinum Compounds ; agonists ; pharmacology ; Oxaliplatin ; Triterpenes ; agonists ; pharmacology ; Xenograft Model Antitumor Assays

To search for potential antitumor drugs with potent efficiency and low toxicity, a novel 1,4,7-triazacyclodecane and its platinum (II) complex were synthesized. These compounds were characterized by elemental analysis, IR, 1H NMR, 13C NMR, MS spectra, thermoanalysis and conductivity measurement. Antitumor activity study indicated these compounds had strong antitumor activity in vitro to some extent. Inhibition of human liver tumor of CA was examined by antitumor rate and growth rate, complex C showed inhibition activity on transplanting-tumor growth of CA, 12 mg x kg(-1) was as potent as cisplatin, its ID50 was 853.6 mg x kg(-1).
Animals ; Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Screening Assays, Antitumor ; Female ; Humans ; Inhibitory Concentration 50 ; Liver Neoplasms ; pathology ; Male ; Mice ; Neoplasm Transplantation ; Organoplatinum Compounds ; chemical synthesis ; chemistry ; pharmacology ; Random Allocation