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

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

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

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

PURPOSE: Traditional chemotherapy is the main adjuvant therapy for the treatment of non-small cell lung cancer (NSCLC). However, the emergence of multi-drug resistance (MDR) has greatly restricted the curative effect of chemotherapy. Therefore, it is necessary to find a method to treat MDR NSCLC clinically. It is worth investigating whether NSCLCs that are resistant to traditional chemotherapy can be effectively treated with tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: The expression of P-glycoprotein (P-gp) and lung resistance-related protein (LRP) was detected by immunohistochemistry, and mutations in EGFR (exons 19 and 21) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (exon 2) were detected by high-resolution melting analysis (HRMA) of surgical NSCLC specimens from 127 patients who did not undergo traditional chemotherapy or radiotherapy. A Pearson chi-square test was performed to analyze the correlations between the expression of P-gp and LRP and mutations in EGFR and KRAS. RESULTS: The expression frequencies of P-gp and LRP were significantly higher in adenocarcinomas from non-smoking patients; the expression frequency of LRP was significantly higher in cancer tissue from female patients. The frequency of EGFR mutations was significantly higher in well to moderately differentiated adenocarcinomas from non-smoking female patients. The frequency of EGFR mutations in the cancers that expressed P-gp, LRP, or both P-gp and LRP was significantly higher than that in cancers that did not express P-gp or LRP. CONCLUSION: NSCLCs expressing P-gp/LRP bear the EGFR mutation in exon 19 or 21 easily.
Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung/*genetics/surgery ; Exons/*genetics ; Female ; Humans ; Lung Neoplasms/*genetics/pathology/surgery ; Middle Aged ; Mutation ; P-Glycoprotein/*genetics ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins/*genetics ; Proto-Oncogene Proteins p21(ras) ; Receptor, Epidermal Growth Factor/*genetics ; Treatment Outcome ; Vault Ribonucleoprotein Particles/*genetics ; ras Proteins/*genetics

The prognostic significance of multidrug resistance (MDR) gene expression is controversial. We investigated whether multidrug resistance gene 1 (MDR1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) mRNA expression are associated with outcomes in acute leukemia patients. At diagnosis we examined MDR1, MRP and LRP mRNA expression in bone marrow samples from 71 acute leukemia patients (39 myeloid, 32 lymphoblastic) using nested RT-PCR. The expression of each of these genes was then expressed as a ratio in relation to beta-actin gene expression, and the three genes were categorized as being either 0, 1+, 2+ or 3+. MDR1, MRP and LRP mRNA expression was detected in 23.9%, 83.1% and 45.1 %, respectively. LRP mRNA expression was significantly associated with resistance to induction chemotherapy in acute leukemia patients, and in the AML proportion (p=0.02 and p=0.03, respectively). MRP and high MDR1 mRNA expression was associated with poorer 2-yr survival (p=0.049 and p=0.04, respectively). Patients expressing both MRP and LRP mRNA had poorer outcomes and had worse 2-yr survival. The present data suggest that MDR expression affects complete remission and survival rates in acute leukemia patients. Thus, determination of MDR gene expression at diagnosis appears likely to provide useful prognostic information for acute leukemia patients.
Vault Ribonucleoprotein Particles/*genetics ; Survival Rate ; RNA, Neoplasm/genetics ; RNA, Messenger/genetics ; Prognosis ; Neoplasm Proteins/*genetics ; Multidrug Resistance-Associated Proteins/*genetics ; Middle Aged ; Male ; Leukemia, Myelocytic, Acute/drug therapy/genetics/mortality ; Leukemia, Lymphocytic, Acute/drug therapy/genetics/mortality ; Leukemia/drug therapy/*genetics/mortality ; Infant ; Humans ; *Genes, MDR ; Gene Expression ; Female ; Child, Preschool ; Child ; Base Sequence ; Aged ; Adult ; Adolescent

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce drug transporter genes such as the ATP-binding cassette G member 2 (ABCG2), which contributes to multidrug resistance. We investigated the effect of TCDD pretreatment on drug transporters induction from cancer cells of various origins. Cell viabilities after treatment of cisplatin were measured to evaluate acquiring cisplatin resistance by TCDD. Acquring cisplatin resistance was found only in cisplatin senstivie cancer cells including gastric SNU601, colon LS180, brain CRT-MG and lymphoma Jurkat cells which showed a significant increase in cell viability after combined treatment with TCDD and cisplatin. High increase of ABCG2 gene expression was found in SNU601 and LS180 cells with a mild increase in the expression of the ABCC3, ABCC5,and SLC29A2 genes in SNU601 cells, and of major vault protein (MVP) in LS180 cells. The AhR inhibitor kaempferol suppressed the upregulation of ABCG2 expression and reversed the TCDD-induced increase in cell viability in LS180 cells. However, in CRT-MG cells, other transporter genes including ABCC1, ABCC5, ABCA3, ABCA2, ABCB4, ABCG1, and SLC29A1 were up-regulated. These findings suggested the acquiring cisplatin resistance by TCDD associated with cancer cell-type-specific induction of drug transporters.
ATP-Binding Cassette Transporters/genetics/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; Drug Resistance, Neoplasm/drug effects ; Equilibrative-Nucleoside Transporter 2/genetics/metabolism ; Humans ; Jurkat Cells ; K562 Cells ; Kaempferols/pharmacology ; Multidrug Resistance-Associated Proteins/genetics/metabolism ; Neoplasm Proteins/genetics/*metabolism ; RNA, Messenger/metabolism ; Receptors, Aryl Hydrocarbon/metabolism ; Tetrachlorodibenzodioxin/*pharmacology ; Up-Regulation/*drug effects ; Vault Ribonucleoprotein Particles/genetics/metabolism