OBJECTIVETo explore the pharmacologic effects of Chinese medicine Bushen Huayu Jiedu Compound Recipe (BSHYJDR) in drug-resistance cells of lung cancer.

METHODSHuman lung adenocarcinoma A549/DDP cell strain was selected, serum pharmacology and flow cytometer (FCM) method were adopted, S180 tumor-bearing mice and normal mice were given, through gastrogavage, different doses of a decocted concentration of BSHYJDR. Serum from the abdominal aorta was taken to observe the effect of drug-serum on cisplatin (DDP) concentration, free Ca2+ concentration and the expression of lung drug-resistance protein LRP-56 in A549/DDP cells.

RESULTSCompared with the drug-resistance group, the intracellular DDP concentration in the group taking a high dose and the normal group of Chinese medicine showed significant difference (P<0.05), while no significant difference was found in the low-dose group (P>0.05). Compared with the drug-resistance group, the Ca2+ concentration in cells and the expression of LRP in lung cancer drug-resistance cells A549/DDP of the high-dose group, the low-dose group and the normal group of Chinese medicine were significantly different (all P<0.01), the LRP expression of the normal group was obviously higher than that of the drug-resistance group (P<0.05).

CONCLUSIONIt was indicated that serum containing Chinese medicine BSHYJDR in the tumor-bearing mice and the normal mice had certainly different, tumor-bearing mice serum containing could improve drug concentration in lung cancer drug-resistance cells, prevent the inflow and release of Ca2+, and inhibit the expression of the drug-resistance gene in the lung cancer drug-resistance cells, which might be the mechanism of BSHYJDR in enhancing the efficacy in reversing and inhibiting tumor.

Animals ; Calcium ; metabolism ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Drug Resistance, Neoplasm ; Humans ; Lung Neoplasms ; drug therapy ; pathology ; Medicine, Chinese Traditional ; Mice ; Vault Ribonucleoprotein Particles ; genetics

OBJECTIVETo study the effect of cyclooxygenase -2 selective inhibitor celecoxib on the expression of major vault protein ( MVP) in the brain of rats with status epilepticus and its possible roles in the treatment of refractory epilepsy.

METHODSSixty adult male Sprague-Dawley rats were randomly assigned to blank control (n=16), epilepsy model (n=22) and celecoxib treatment groups (n=22). After the status epilepticus was induced in rats by injecting lithium and pilocarpine, each group had 16 rats enrolled as subjects. Immunohistochemical method and Western blot method were used to detect the expression of MVP in the frontal cortex and hippocampus.

RESULTSThe expression of MVP was significantly higher in the epilepsy model group than in the control group (P<0.01). The expression of MVP in the celecoxib treatment group was significantly decreased compared with the epilepsy model group, but it was still higher than in the control group (P<0.01).

CONCLUSIONSCelecoxib could decrease the expression of MVP in brain tissue of rats with status epilepticus, suggesting that it is promising for the treatment of intractable epilepsy.

Animals ; Blotting, Western ; Brain ; metabolism ; Celecoxib ; pharmacology ; therapeutic use ; Cyclooxygenase 2 Inhibitors ; pharmacology ; Immunohistochemistry ; Male ; Rats ; Rats, Sprague-Dawley ; Status Epilepticus ; drug therapy ; metabolism ; Vault Ribonucleoprotein Particles ; analysis

This study was aimed to detect the glutathione S-transferase-π (GST-π) and lung resistance-related protein (LRP) genes and to investigate their relationship with multidrug resistance (MDR) of patients with acute leukemia (AL). Real-time fluorescent quantitative reverse transcription polymerase chain reaction (RQ-PCR) was used to detect the expression of GST-π and LRP genes in peripheral blood mononuclear cells from 44 AL patients and 27 normal subjects. The results showed that the significant difference in GST-π expression level was found between newly diagnosed patients and complete remission patients and between refractory patients and complete remission patients (P < 0.01), while expression level of LRP genes showed obvious difference (P ≤ 0.01) between newly diagnosed patients and refractory patients and between complete remission patients and refractory patients. Statistical analysis indicated that there was no correlation between GST-π gene and LRP gene. The expression of GST-π and LRP genes was not significantly different in different white blood cell (WBC) count groups and different clinical typing groups (ALL and ANLL). It is concluded that the mechanism of MDR resulting from GST-π and LRP genes is different, thereby combination detection of GST-π and LRP genes demonstrates a larger role for evaluating prognosis of AL patients, as compared with detection of GST-π or LRP gene alone. The WBC count and leukemia typing have no relationship with expression of GST-π and LRP genes.
Acute Disease ; Adolescent ; Adult ; Case-Control Studies ; Drug Resistance, Multiple ; genetics ; Drug Resistance, Neoplasm ; genetics ; Female ; Glutathione S-Transferase pi ; genetics ; Humans ; Leukemia ; genetics ; Male ; Middle Aged ; Polymerase Chain Reaction ; Vault Ribonucleoprotein Particles ; genetics ; Young Adult

BACKGROUNDMultidrug resistance is associated with a poor prognosis in various human cancers. However, the clinical significance of the expression of multidrug resistance-related markers in neuroblastoma is still on debate. In this study, the effect of the expression of p-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance protein (LRP) in neuroblastoma was evaluated.

METHODSThe streptavidin-biotin immunoperoxidase (SP) technique was used to evaluate the expression of P-gp, MRP, and LRP in 70 cases of untreated primary neuroblastoma.

RESULTSThe frequencies of the expression of P-gp, MRP, and LRP were 61.4%, 38.6%, and 24.3%, respectively. A significant positive correlation was observed between P-gp and MRP expression (P=0.001), as well as between LRP and MRP expression (P=0.01). The rates of expression of P-gp and MRP were higher in tumors from patients aged greater than one year old than in tumors from patients aged less than 1 year old at time of diagnosis (P=0.01 and 0.018, respectively). MRP expression in tumors that had metastasized was significantly more frequent than in tumors that had not metastasized (P=0.015). The expression of all tested proteins showed a significant relationship with whether or not the tumor had differentiated (P=0.006, 0.000 or 0.001, respectively). MRP expression was significantly associated with a reduction in both median survival time and 2-year cumulative survival (P=0.02). By contrast, P-gp and MRP expression did not correlate with survival. According to Cox regression analysis, only the co-expression of P-gp and MRP had significant prognostic value (relative hazard, 3.513, P=0.033).

CONCLUSIONSThe intrinsic, multidrug resistance of neuroblastoma involves the combined effects of P-gp, MRP, and LRP. MRP expression may be an important factor determining prognosis in neuroblastoma.

ATP-Binding Cassette, Sub-Family B, Member 1 ; analysis ; Adolescent ; Child ; Child, Preschool ; Drug Resistance, Neoplasm ; Female ; Humans ; Immunohistochemistry ; Infant ; Male ; Multidrug Resistance-Associated Proteins ; analysis ; Neoplasm Proteins ; analysis ; Neuroblastoma ; chemistry ; drug therapy ; pathology ; Prognosis ; Vault Ribonucleoprotein Particles

Acute Disease ; Adolescent ; Child ; Child, Preschool ; Drug Resistance, Multiple ; genetics ; Drug Resistance, Neoplasm ; genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Leukemia ; physiopathology ; Male ; Neoplasm Proteins ; genetics ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Vault Ribonucleoprotein Particles ; genetics

A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs. Several mechanisms may account for this phenomenon, including failure of the cell to undergo apoptosis in response to chemotherapy, or failure of the drug to reach and/or affect its intracellular target. This review focuses on the latter mechanisms, and on intracellular drug transport resistance mechanisms in particular. Expression of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) has generally been reported to correlate with prognosis in acute myeloid leukemia (AML). Additionally, of more controversial, expression of the ABC transporter multidrug resistance protein (MRP) and the vault-transporter lung resistance protein (LRP) have been correlated with the outcome in AML.
ATP Binding Cassette Transporter, Sub-Family B ; physiology ; ATP-Binding Cassette, Sub-Family B, Member 1 ; physiology ; Drug Resistance, Multiple ; genetics ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; genetics ; Neoplasm Proteins ; physiology ; Vault Ribonucleoprotein Particles ; physiology

OBJECTIVE: To explore the relationship among intracellular glutathione S-transferase activity (GST), the expression of lung resistance-related proteins (LRP) in acute leukemia, and its clinical effects. METHODS: The GST activity of bone marrow mononuclear cells and LRP expression in 57 acute leukemia patients were detected by the spectrophotometry assay and immuno-cytochemistry (SABC), respectively. RESULTS: The GST activity of bone marrow mononuclear cells in the acute leukemia group was significantly higher than that of the control group (P < 0.01). The GST activity of mononuclear cells in acute leukemia was positively correlated with the percentage of blast in the bone marrow (r = 0.30, P < 0.05). The GST activity of mononuclear cells in the untreated acute leukemia group was obviously higher than that of the complete remission group (P <0.01). The GST activity in the refractory or relapsed acute leukemia group was significantly higher than that of the complete remission group and untreated leukemia group (P <0.05). In post-chemotherapy 13 of 17 the LRP-positive patients were the non-remission, 12 of the 20 LRP-negative patients were the complete remission. The curative rate of the LRP-positive group was the significantly lower than the LRP-negative group (P < 0.05). The GST activities of non-remission patients in the LRP-positive and LRP-negative group obviously increased. CONCLUSION The increase of GST activity in the bone marrow mononuclear cells is related to the clinical curative effects and the proliferation of blast in acute leukemia. Detection of LRP and GST activities in acute leukemia may have a reference value in judging the leukemia with drug resistance and estimating the prognosis.
Adolescent ; Adult ; Aged ; Bone Marrow Cells ; metabolism ; Child ; Female ; Glutathione Transferase ; metabolism ; Humans ; Leukemia, Myeloid, Acute ; metabolism ; Male ; Middle Aged ; Multidrug Resistance-Associated Proteins ; metabolism ; Neoplasm Proteins ; biosynthesis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; metabolism ; Vault Ribonucleoprotein Particles ; biosynthesis

OBJECTIVETo investigate the role of lung resistance-related protein (LRP) in intrinsic multidrug resistance (MDR) of bladder cancer and detect the relationship of LRP expression with the clinical pathologic parameters.

METHODS66 patients were studied with newly diagnosed primary bladder cancer (T(a) = 12, T(1) = 26, T(2) = 11, T(3) = 10, T(4) = 7; G(1) = 35, G(2) = 19, G(3) = 12). No patient was treated preoperatively with either radiation or chemotherapy. Reverse transcription-polymerase chain reaction (RT-PCR) was performed for measure of mRNA expression for LRP, multidrug-resistance gene 1 (MDR1), and multidrug resist nce-associated protein 1 (MRP1). Expressions of LRP, P53 and P63 proteins were examined by immunohistochemistry staining.

RESULTSLRP mRNA had the highest expression rate (64%, 42/66) among three MDR markers in primary bladder cancers without chemotherapy and its level was significantly higher in normal bladder tissue than in TCC of bladder (t = 2.82, P < 0.01), in low grade than in high grade cancers (t = 4.14, P < 0.01), and in superficial than in invasive cancers (t = 3.58, P < 0.05). LRP mRNA expression showed no correlation with either MDR1 or MRP1, but close correlation with LRP protein level (r = 0.89, P < 0.01). LRP was associated with low-grade (r = 0.81, P < 0.01) and low-stage (r = 0.78, P < 0.05) cancers, but not with tumor suppressor P53 or P63 (P > 0.05).

CONCLUSIONSThe grade and stage-related expression pattern of LRP indicates that it may be a predictive index for intrinsic MDR in bladder cancer. Anti-cancer drugs out of the MDR spectrum of LRP may be more effective for patients with early bladder cancer.

ATP-Binding Cassette, Sub-Family B, Member 1 ; biosynthesis ; genetics ; Adult ; Aged ; Carcinoma, Transitional Cell ; genetics ; metabolism ; pathology ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Multidrug Resistance-Associated Proteins ; biosynthesis ; genetics ; Neoplasm Proteins ; biosynthesis ; genetics ; RNA, Messenger ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Urinary Bladder Neoplasms ; genetics ; metabolism ; pathology ; Vault Ribonucleoprotein Particles ; biosynthesis ; genetics

BACKGROUNDSurvivin, a member of the inhibitor of apoptosis protein (IAP) family, overexpresses in tumor cells and not expresses in terminally differentiated adult tissues. This study aimed to investigate the effects of survivin-specific siRNA on cell proliferation, apoptosis and chemosensitivity to cisplatin in vitro and in vivo and explore the mechanisms about decreasing expression of survivin in reversing cancer cells resistance to chemotherapeutic drug.

METHODSSurvivin-specific siRNA was transfected into A549/DDP cells. The expression of survivin and lung resistance-related protein (LRP) mRNA levels were determined by RT-PCR, chemosensitivity of A549/DDP (cisplatin) cells to cisplatin was determined by MTT assay, and apoptosis and cell cycle were determined by flow cytometry (FCM). The protein expression levels of survivin, LRP, cyclin-D(1), caspase-3 and bcl-2 were determined by Western blotting analyses. The effect of survivin siRNA inhibition on tumor growth was studied in athymic nude mice in vivo.

RESULTSSurvivin-specific siRNA efficiently down-regulated survivin expression. The cell cycle was arrested at G2/M phase, and apoptosis was obviously found. Inhibition of survivin expression could make the IC50 and drug-resistant index of cisplatin decrease, and enhance the cancer cells sensitivity to cisplatin. After transfection by survivin-specific siRNA, expression of LRP and cyclin-D1 were downregulated, caspase-3 expression was upregulated, bcl-2 expression had no obvious change. The animal experiment confirmed knockdown of survivin could inhibit the tumor growth.

CONCLUSIONSSurvivin-specific siRNA can efficiently suppress the expression of survivin, increase apoptosis, inhibit cells proliferation and enhance the chemosensitivity to cisplatin in vitro and in vivo. Suppression of survivin expression helping to reverse drug-resistance may have relationship with downregulation of LRP and upregulation of caspase-3. Anti-tumor strategies based on the inhibition of survivin may be useful in targeting lung adenocarcinomas.

Adenocarcinoma ; drug therapy ; pathology ; Animals ; Apoptosis ; Caspase 3 ; analysis ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Cyclin D1 ; analysis ; Drug Resistance, Neoplasm ; Female ; Humans ; Inhibitor of Apoptosis Proteins ; Lung Neoplasms ; drug therapy ; pathology ; Male ; Mice ; Mice, Inbred BALB C ; Microtubule-Associated Proteins ; antagonists & inhibitors ; genetics ; Proto-Oncogene Proteins c-bcl-2 ; analysis ; RNA, Messenger ; analysis ; RNA, Small Interfering ; genetics ; Vault Ribonucleoprotein Particles ; genetics

OBJECTIVETo observe the base of the interference in correlated biotic active matter obtained multi-drug resistance induced by chemotherapy for different alkaloid, and to supervise the use in clinic to restrain the multi-drug resistant of chemotherapy, and thereby to improve the curative effect.

METHODAfter bestowing subter-dosage unite chemotherapeutant to ascites S180 mouse to set up the mouse models of multi-drug resistance of S180 tumour cell, and giving the mouse matrine, terandrine, oxymatrine and berberine hydrooh loride for 4 weeks, the P170, LRP, TOPOII, Fas and apoposis were determined by flow cytometry.

RESULTMatrine and terandrine could obviously reduce the express of P170, LRP and the activation of TOPOII, and increase the ratio of the express of Fas and the apoposis of drug resistant tumour cell. And at the same time it could obviously reduce the express of intercellular adhesion molecule(CD54).

CONCLUSIONMatrine and terandrine can interfere in MDR which results from chemotherapeutics by the adjustment of correlated biotic active matter, besides, the different degree of alkaloid effect with different configuration.

ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Alkaloids ; isolation & purification ; pharmacology ; Animals ; Apoptosis ; drug effects ; Benzylisoquinolines ; isolation & purification ; pharmacology ; Berberine Alkaloids ; isolation & purification ; pharmacology ; DNA Topoisomerases, Type II ; metabolism ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Female ; Male ; Mice ; Plants, Medicinal ; chemistry ; Quinolizines ; isolation & purification ; pharmacology ; Random Allocation ; Sarcoma 180 ; metabolism ; pathology ; Tumor Cells, Cultured ; Vault Ribonucleoprotein Particles ; metabolism ; fas Receptor ; metabolism