Blood Platelets ; drug effects ; metabolism ; Calcium ; blood ; Deoxycholic Acid ; pharmacology ; Humans ; Quinazolines ; pharmacology ; Quinazolinones

Thirteen of 4-anilinoquinazoline derivatives with imine groups at position 6 of quinazoline ring were synthesized and their antitumor activities were evaluated by MTT assay and Western blotting analysis. Among these compounds, 13a-131 were reported first time. The MTT assay was carried out on three human cancer cell lines (A549, HepG2 and SMMC7721) with EGFR highly expressed. Among the tested compounds, 13i and 13j exhibited notable inhibition potency and their IC50 values on three cell lines were equivalent to or less than those of gefitinib. Compound 14, without imine group substituted, displayed excellent inhibitor potency only on A549 cell line. Compounds 14 and 13j were chosen to perform Western blotting analysis on A549. The results showed that both of the compounds could inhibit the expression level of phosphorylated EGFR remarkably. It was concluded that the inhibitor potency of compound 14 was almost equivalent to that of gefitinib and the inhibitor potency of 13j was better than that of gefitinib.
Aniline Compounds ; pharmacology ; Antineoplastic Agents ; pharmacology ; Cell Line, Tumor ; Humans ; Inhibitory Concentration 50 ; Phosphorylation ; Quinazolines ; pharmacology ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors

This study was aimed to investigate the therapeutic effect of two molecular targeted therapeutic drugs, tyrosine kinase inhibitors gefitinib and lapatinib, on JAK2 V617F positive myeloproliferative disorders (MPD). The human leukemia cell line (HEL cell line) carrying JAK2 V617F mutation was treated with gefitinib (0.5, 1, 5, 10, 25 µmol/L) and lapatinib (0.5, 1, 2, 4, 8, 16 µmol/L) respectively. MTT method was used to detect HEL cell proliferation. The apoptotic rate and cell cycle were measured by flow cytometry. The results showed that gefitinib could significantly inhibit the proliferation of HEL cells in a dose-dependent manner, it's correlation coefficients for 24 and 48 h were 0.991 and 0.895 respectively. IC(50) at 48 h was 5.4 µmol/L. Gefitinib could effectively induce apoptosis of HEL cells in a dose-dependent manner (r = 0.896). Otherwise, gefitinib could arrest HEL cells at G(0)/G(1) phase. The inhibitory effect of lapatinib was less than gefitinib, it's IC(50) of inhibiting proliferation of HEL cells was 19.6 µmol/L. It is concluded that both gefitinib and lapatinib can inhibit the proliferation of HEL cells. These two tyrosine kinase inhibitors can be used for researching of targeted therapy of JAK2 V617 positive MPD.
Antineoplastic Agents ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Janus Kinase 2 ; genetics ; Mutation ; Myeloproliferative Disorders ; metabolism ; pathology ; Protein Kinase Inhibitors ; pharmacology ; Quinazolines ; pharmacology

Toxoplasma gondii is the causative agent of toxoplasmosis with symptoms of congenital neurological and ocular diseases and acquired lymphadenitis, retinochoroiditis, and meningoencephalitis. Small molecules which block the activity of protein kinases were tested in in vitro culture of T. gondii to find new therapeutic drugs of safer and more effective than the combined administration of pyrimethamine and sulfadoxine that sometimes provoke lethal Stevens-Johnson syndrome. Among them, Gefitinib and Crizotinib inhibited intracellular growth of T. gondii in HeLa cells by counting the number of T. gondii per parasitophorous vacuolar membrane whereas Sunitinib did not. Gefitinib inhibited the growth of T. gondii in a dose-dependent manner over 5 microM up to the tolerable concentration of HeLa cells and halted the division of the parasite immediately from the time point of treatment. Gefitinib inhibition suggests that tyrosine kinases of EGFR family or other homologous kinases of the parasite itself may be the target to cause the block of T. gondii growth.
Antiprotozoal Agents/*pharmacology ; Dose-Response Relationship, Drug ; Drug Repositioning ; HeLa Cells ; Humans ; Parasitic Sensitivity Tests ; Quinazolines/*pharmacology ; Toxoplasma/*drug effects/*growth & development

OBJECTIVETo determine the effect of the combination of lapatinib with chlorogenic acid on metastasis of breast cancer in mouse model.

METHODSThe classical macrophage M2 polarization model induced by interlukin13in vitro was adopted in the study. Flow cytometric analysis was performed to detect the expression of M2 marker CD206. The transcription of M2-associated genes was measured by RT-PCR. HE staining was used to analyze the metastatic nodes of breast cancer in lungs of MMTV-PyVT mice. Immunostaining analysis was used to detect the expression of related proteins in breast cancer.

RESULTSThe combination of lapatinib and chlorogenic acid inhibited the expression of CD206 induced by IL-13[(42.17%±2.59%) vs (61.15%±7.58%), P<0.05]. The combination more markedly suppressed expression of M2-associated gene Ym1 than lapatinib alone[(0.9±0.1) vs (1.8±0.0), P<0.05]. The combination of lapatinib and chlorogenic acid significantly reduced metastatic nodes in lung[P<0.05], and also significantly decreased the percentage of CD206(+) cells in breast cancer compared to controls[(6.08%±2.60%) vs(29.04%±5.86%), P<0.05].

CONCLUSIONThe combination of lapatinib and chlorogenic acid can effectively inhibit macrophage M2 polarization and metastasis of breast cancer.

Animals ; Chlorogenic Acid ; pharmacology ; Female ; Lung Neoplasms ; drug therapy ; secondary ; Macrophages ; drug effects ; Mammary Neoplasms, Experimental ; drug therapy ; Mice ; Neoplasm Metastasis ; drug therapy ; Quinazolines ; pharmacology

OBJECTIVETo observe the impact of concurrent administration of recombinant human p53 adenovirus (Ad-p53) with EGFR inhibitor gefitinib on breast cancer MDA-MB-468 cells.

METHODSMDA-MB-468 cells were treated with Ad-p53 and/or gefitinib. The effect of Ad-p53 and gefitinib on the growth of MDA-MB-468 cells was evaluated by MTT assay. Cell apoptosis was detected by flow cytometry. Western blot analysis was used to detect the alteration of p53,EGFR, phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and apoptosis-related proteins. Ad-p53 combined with gefitinib was used in vivo to explore their effect on tumor xenograft in nude mice. Immunohistochemistry was used to detect the p53 expression in vivo.

RESULTSThe MTT assay showed a stronger inhibitory effect of gefitinib on MDA-MB-468 cells infected with Ad-p53 than on the control cells. Cell apoptosis assay revealed that the apoptosis rates of MDA-MB-468 cells in vehicle-treated group, Ad-p53 group, gefitinib group, and combination group were 8.5%, 17.4%, 20.5% and 32.6%, respectively. The apoptosis rate of MDA-MB-468 cells in the combination group was higher than that in other groups (P < 0.05, for all) . Western blot analysis revealed that the expression of p53 was significantly up-regulated in the presence of Ad-p53. The combination of Ad-p53 and gefitinib significantly down-regulated p-Akt (S473)(P < 0.01) and up-regulated caspase-9 and cleaved caspase-3 (P < 0.01 for both). Tumor inhibition rates (TIR) in the Ad-p53, gefitinib, and combination groups were 35.7%, 28.7% and 74.4%, respectively. Ad-p53 and gefitinib combination therapy significantly reduced the tumor burden in nude mice (P < 0.05 for all).Immunohistochemistry showed that after intratumoral administration of Ad-p53, wild-type p53 was increased (P < 0.01). p53 expressions in the vehicle-treated, Ad-p53, gefitinib and combination groups were 45.2%, 80.1%, 50.7% and 90.6%, respectively.

CONCLUSIONSWild-type p53 may reverse the sensitivity of MDA-MB-468 cells to gefitinib through down-regulation of the PI3K/Akt pathway. The apoptotic activity induced by this combination treatment might be regulated through caspase cascade.

Adenoviridae ; Animals ; Antineoplastic Agents ; pharmacology ; Apoptosis ; Breast Neoplasms ; Caspase 3 ; Caspase 9 ; Cell Line, Tumor ; Down-Regulation ; Genes, p53 ; Humans ; Mice ; Mice, Nude ; Phosphatidylinositol 3-Kinases ; Quinazolines ; pharmacology

It is now well established that inflammation plays an important role in the development of numerous chronic metabolic diseases including insulin resistance (IR) and type 2 diabetes (T2DM). Skeletal muscle is responsible for 75% of total insulin-dependent glucose uptake; consequently, skeletal muscle IR is considered to be the primary defect of systemic IR development. Our pre- vious study has shown that rutaecarpine (Rut) can benefit blood lipid profile, mitigate inflammation, and improve kidney, liver, pan- creas pathology status of T2DM rats. However, the effects of Rut on inflammatory cytokines in the development of IR-skeletal muscle cells have not been studied. Thus, our objective was to investigate effects of Rut on inflammatory cytokines interleukiri (IL)-1, IL-6 and tumor necrosis factor (TNF)-α in insulin resistant primary skeletal muscle cells (IR-PSMC). Primary cultures of skeletal muscle cells were prepared from 5 neonate SD rats, and the primary rat skeletal muscle cells were identified by cell morphology, effect of ru- taecarpine on cell proliferation by MTT assay. IR-PSMC cells were induced by palmitic acid (PA), the glucose concentration was measured by glucose oxidase and peroxidase (GOD-POD) method. The effects of Rut on inflammatory cytokines IL-1, IL-6 and TNF-α in IR-PSMC cells were tested by enzyme-linked immunosorbent assay (ELISA) kit. The results show that the primary skeletal muscle cells from neonatal rat cultured for 2-4 days, parallel alignment regularly, and cultured for 7 days, cells fused and myotube formed. It was shown that Rut in concentration 0-180. 0 μmol x L(-1) possessed no cytotoxic effect towards cultured primary skeletal muscle cells. However, after 24 h exposure to 0.6 mmol x L(-1) PA, primary skeletal muscle cells were able to induce a state of insulin resistance. The results obtained indicated significant decrease (P < 0.05 to P < 0.001) IL-1, IL-6 and TNF-α production by cultured IR-PSMC cells when incubating 24 hours with Rut, beginning from 20 to 180.0 μmol x L(-1). IL-1, IL-6 and TNF-α in the Rut treated groups were dose-dependently decreased compared with that in the IR-PSMC control group. Our results demonstrated that the Rut promoted glucose consumption and improved insulin resistance possibly through suppression of inflammatory cytokines in the IR-PSMC cells.
Animals ; Cell Proliferation ; drug effects ; Cytokines ; metabolism ; Female ; Glucose ; metabolism ; Indole Alkaloids ; pharmacology ; Inflammation ; metabolism ; Insulin Resistance ; Male ; Muscle, Skeletal ; cytology ; drug effects ; metabolism ; Quinazolines ; pharmacology ; Rats

OBJECTIVETo investigate the killing effect of ZD6474 combined with adriamycin (ADM) on MCF-7 human breast cancer cells.

METHODSThe inhibitory effects of ZD6474 and ADM alone and in combination on the proliferation of MCF-7 cells were assessed by MTT assay. The cell cycle and cell apoptosis were detected by flow cytometry.

RESULTSZD6474 and ADM both significantly inhibited the proliferation of MCF-7 cells, showing a synergistic effect of their reactions in combined use (P<0.05). ZD6474 or ADM alone caused cell cycle arrest at G0/G1 and S phases, respectively. Combined use of the two drugs resulted in significant reduction of the M-phase cell percentage and cell cycle arrest at G0/G1 and S phases. The coadministration of the drugs significantly increased the apoptosis rate of the cells as compared with ZD6474 or ADM treatment alone (P<0.05).

CONCLUSIONSZD6474 and ADM show a synergistic effect in inhibiting the proliferation and inducing apoptosis of MCF-7 cells.

Antibiotics, Antineoplastic ; pharmacology ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Breast Neoplasms ; pathology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Doxorubicin ; pharmacology ; Drug Synergism ; Female ; Humans ; Piperidines ; pharmacology ; Quinazolines ; pharmacology

OBJECTIVEThe aim of the present study is to compare the effects of two alpha1-adrenoceptor antagonist terazosin and alfuzosin together with one alpha-adrenoceptor antagonist phenoxybenzamine on androgen-independent prostate cancer cell lines PC-3 and DU145.

METHODSTwo androgen- independent cell lines, PC-3 and DU145, were used to determine the cell viability, colony-forming ability as well as cell cycle characteristics after exposure to these three drugs.

RESULTSThis study showed that terazosin inhibited not only prostate cancer cell growth but also colony-forming ability, which is the main target of clinical treatment. On the other hand, alfuzosin and phenoxybenzamine have no effect on cell viability and colony forming ability of PC-3 and DU145. In addition, the terazosin inhibits cell growth through G(1) phase cell cycle arrest.

CONCLUSIONThis study provided the evidence that alpha1-adrenoceptor antagonist terazosin may have a therapeutic potential in the treatment of advanced androgen-independent prostate cancer.

Adrenergic alpha-Antagonists ; pharmacology ; Antineoplastic Agents ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Survival ; drug effects ; Dose-Response Relationship, Drug ; Humans ; Male ; Phenoxybenzamine ; pharmacology ; Prazosin ; administration & dosage ; analogs & derivatives ; pharmacology ; Prostatic Neoplasms ; pathology ; Quinazolines ; pharmacology

Human protein tyrosine kinases play an essential role in carcinogenesis and have been recognized as promising drug targets. By the end of 2012, eight small molecule tyrosine kinase inhibitors (TKIs) have been approved by State Food and Drug Administration of China for cancer treatment. In this paper, the pharmacokinetic characteristics (absorption, distribution, metabolism and excretion) and drug-drug interactions of the approved TKIs are reviewed. Overall, these TKIs reach their peak plasma concentrations relatively fast; are extensively distributed and highly protein bound (> 90%); are primarily metabolized by CYP3A4; most are heavily influenced by CYP3A4 inhibitors or inducers except for sorafenib; are mainly excreted with feces and only a minor fraction is eliminated with the urine; and are substrate of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Additionally, many of the TKIs can inhibit some CYP450 enzymes, UGT enzymes, and transporters. Gefitinib, erlotinib, dasatinib, and sunitinib are metabolized to form reactive metabolites capable of covalently binding to biomolecules.
Antineoplastic Agents ; pharmacokinetics ; pharmacology ; Crown Ethers ; pharmacokinetics ; pharmacology ; Cytochrome P-450 Enzyme System ; metabolism ; Dasatinib ; pharmacokinetics ; pharmacology ; Drug Interactions ; Erlotinib Hydrochloride ; pharmacokinetics ; pharmacology ; Glucuronosyltransferase ; metabolism ; Humans ; Imatinib Mesylate ; pharmacokinetics ; pharmacology ; Indoles ; pharmacokinetics ; pharmacology ; Niacinamide ; analogs & derivatives ; pharmacokinetics ; pharmacology ; Phenylurea Compounds ; pharmacokinetics ; pharmacology ; Protein Kinase Inhibitors ; pharmacokinetics ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacokinetics ; pharmacology ; Pyrroles ; pharmacokinetics ; pharmacology ; Quinazolines ; pharmacokinetics ; pharmacology