Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of multidrug resistance (MDR) modulators, termed chemosensitizers, have been identified from a variety of chemicals, but most have been proven to be clinically toxic. Low concentrations of the pleuromutilin-derived semi-synthetic antibiotic tiamulin (0.1 to 10 microM) sensitized the three highly resistant P-glycoprotein (Pgp)-overexpressing tumor cell lines P388 (murine lymphoid leukemia), AS30-D (rat hepatoma), CEM (human lymphoblastic leukemia), and the barely resistant AS30-D/S cell lines to several MDR-related anticancer drugs. Flow cytometric analysis showed that tiamulin significantly increased the intracellular accumulation of daunomycin. When compared to reference modulating agents such as verapamil and cyclosporin A, tiamulin proved to be 1.1 to 8.3 times more efficient in sensitizing the resistant cell lines. Moreover, when given i.p. (1.6 microg/mg body weight), tiamulin increased the survival rate of adriamycin-treated mice bearing the P388/ADR25 tumor line by 29%. In the presence of an anticancer drug, tiamulin inhibited both ATPase and drug transport activities of Pgp in plasma membranes from tumor cells. Tiamulin is thus a potent chemosensitizer that antagonizes the Pgp-mediated chemoresistance in many tumor cell lines expressing the MDR phenotype at different levels and displays no toxic effects on contractile tissues at active doses, therefore providing the promise for potential clinical applications.
 ...
PMID:In vitro and in vivo reversal of cancer cell multidrug resistance by the semi-synthetic antibiotic tiamulin. 980 34

Overexpression of the trans-membrane drug efflux pump P-glycoprotein is one of the major mechanisms by which cancer cells develop multidrug resistance. We demonstrated previously that noncytotoxic doses of various genotoxic chemicals, particularly DNA cross-linking agents, preferentially altered expression of inducible genes. These effects occurred principally at the transcriptional level and were closely correlated temporally with DNA damage. Because the mdr1 gene coding for P-glycoprotein has been reported to be highly inducible, we were interested in the effects of genotoxic cancer chemotherapy agents on its expression. We report that the DNA cross-linking agent mitomycin C significantly suppressed mRNA and protein expression of P-glycoprotein and decreased the rate of drug efflux. Mitomycin C pretreatment also significantly increased the sensitivity of cancer cells to subsequent killing by the P-glycoprotein substrate doxorubicin, decreasing the ED50 by 5- to 10-fold. Suppression of P-glycoprotein expression was also observed with subtoxic doses of the DNA cross-linking agents cisplatin, BMS181174, and chromium(VI). These effects occurred in both human and rodent cell lines; in cell lines derived from colon, breast, leukemia, neuroblastoma, and hepatoma tumors; and under both monolayer and "spheroid" culture conditions. These results suggest the basis for novel clinical cancer chemotherapy regimens aimed at drug-resistant tumors, in which a sub-chemotherapeutic dose of a DNA cross-linking agent is used to modulate the multidrug resistance phenotype prior to treatment with a second cytotoxic agent.
 ...
PMID:Suppression of P-glycoprotein expression and multidrug resistance by DNA cross-linking agents. 981 17

We previously showed that combined neoadjuvant doxorubicin (DOX) treatment and orthotopic liver transplantation produced a 3-year tumor-free survival rate of 54% in stage II-IVa nonresectable hepatocellular carcinomas (HCCs). These patients received posttransplant immunosuppressive doses of cyclosporin A (CsA). CsA has been shown to modify the function of a membrane P-glycoprotein (Pgp) whose overexpression is associated with a multidrug-resistant (MDR1) phenotype. This study utilized HCC cell lines to characterize the in vitro chemomodulatory properties of CsA as found in posttransplant patient plasma to consider the hypothesis that CsA may prolong posttransplant survival by enhancing the therapeutic efficacy of DOX against multidrug-resistant hepatoma cells. We characterized Pgp expression in the HCC lines Hep3B, Hep G2, and SK-HEP-1 by immunohistochemistry and the reverse transcription-polymerase chain reaction. The combined cytotoxicity of DOX + CsA was examined by [3H]thymidine uptake and flow cytometric drug-retention assays. Pgp expression was assessed further after prolonged (10-day) treatment with CsA. Hep3B and Hep G2 cells expressed low to moderate levels of Pgp. The effective DOX dose required for inhibiting MDR1(+) Hep3B and Hep G2 cell proliferation by 50% (DOX IC50) was 44.5 ng/ml and 43.5 microgram/ml, as compared with 10.7 ng/ml for Pgp-negative SK-HEP-1 cells. Optimal concentrations of CsA (0.8 micrometer) lowered DOX IC50 for Hep3B cells and Hep G2 cells by 6-fold and 4-fold, respectively. Similarly, plasma from patients containing immunosuppressive levels of CsA lowered DOX IC50 of the MDR1(+) Hep G2 cells by up to 4-fold. Prolonged exposure to CsA did not affect its chemosensitizing capacity or Pgp expression of HCC cells. PSC-833, a nonimmunosuppressive analogue of CsA, was equally effective in reducing the DOX IC50 of MDR1(+) HCC cells. CsA and PSC-833 increased drug retention by approximately 75%, but did not significantly affect hepatoma cell viability or Pgp expression. Pharmacological concentrations of cyclosporin analogues, including one nonimmunosuppressive form, enhance DOX cytotoxicity of MDR1(+) HCC cells by modulating drug retention. CsA as found in posttransplant patient plasma enhanced DOX cytotoxicity to human MDR1(+) hepatoma cells in vitro, albeit at less than optimal chemosensitizing concentrations. Prolonged exposure to CsA did not affect its chemosensitizing properties or block Pgp expression of HCC cells. These findings support our hypothesis that in vivo immunosuppressive levels of CsA may enhance DOX chemotherapeutic efficacy on MDR1(+) HCC cells.
 ...
PMID:Chemosensitization of human hepatocellular carcinoma cells with cyclosporin A in post-liver transplant patient plasma. 981

A murine model in which to study multiple drug resistance in human hepatocellular carcinoma was developed. PRF/PLC/5 hepatoma cells (Alex 0) and an induced multidrug resistant clone (Alex 0.5) were injected intrasplenically into severe combined immunodeficiency mice. In 70% of injected mice, hepatoma cells engrafted in the liver and grew as intrahepatic metastasis. Since Alex cells contain an integrated hepatitis B virus genome and secrete hepatitis B surface antigen (HBsAg), the serum HBsAg concentration in tumor-bearing mice was used to quantitate tumor burden. Tumor wet weight determined at necropsy was directly proportional to the serum HBsAg concentration. In Alex 0 cells, IC50s for doxorubicin, vinblastine, and cis-platinum were 0.35 microM, 0.029 microM, and 3.70 microM, respectively. Alex 0.5 cells were 25-, 14-, and 1.4-fold more resistant to doxorubicin, vinblastine, and cis-platinum, respectively. Immunoblotting of Alex 0 cell membranes with an anti-P-glycoprotein antibody (C219) revealed small amounts of P-glycoprotein, whereas Alex 0.5 membranes overexpressed the protein. Concurrent exposure to verapamil (10 microM) sensitized both cell lines to the cytotoxic action of vinblastine and doxorubicin but had no effect on the cytotoxicity of cis-platinum. Mice bearing intrahepatic xenografts derived from Alex 0 and 0.5 cells had no response to treatment with i.v. vinblastine or doxorubicin, as was anticipated from in vitro drug testing. Addition of verapamil to vinblastine treatment did not improve the success of in vivo chemotherapy. Immunotherapy with a human anti-P-glycoprotein antibody (MRK16) suppressed the in vivo growth of tumors derived from both cell lines. The effect was most pronounced in mice bearing Alex 0.5 tumors. Immunoblotting of tumors which initially responded to MRK16 therapy, but subsequently relapsed, revealed a marked decrease in P-glycoprotein expression when compared to results in tumors that were untreated or treated with vinblastine or control antibody. In summary, we have developed an intrahepatic tumor xenograft model of human hepatocellular carcinoma in mice that permits noninvasive serial quantification of tumor burden by determination of serum HBsAg levels and demonstrated a positive response to immunotherapy with anti-P-glycoprotein antibodies.
 ...
PMID:Establishment and serial quantification of intrahepatic xenografts of human hepatocellular carcinoma in severe combined immunodeficiency mice, and development of therapeutic strategies to overcome multidrug resistance. 981 20

The innate drug resistance of human hepatocellular carcinoma (HCC) Bel7402 cell line was studied in vitro. MTT assay showed that Bel7402 cells were innately resistant to doxorubicin (Dox), and even more resistant to vincristine (VCR). This resistance could be effectively reversed by verapamil (Ver), one of the classical multidrug resistance (MDR) modulating agents. However, the differences in 5-fluorouracil (5-FU) toxicity between these two cell lines is much less and the resistance of Bel7402 cells could only be slightly reversed by Ver, which may be experimental noise. Immunocytochemical staining using anti-p-glycoprotein monoclonal antibody JSB-1 indicated that the expression of the P-glycoprotein (P-gp) in the innate Bel7402 cells was elevated compared with the sensitive KB cells. The accumulation of Dox in innate resistant Bel7402 cells was 50.7% lower than that in sensitive KB cells by using spectrofluometric analyses, and the accumulation of Dox increased 1.6 fold in Bel7402 cells in the presence of Ver. The susceptibility of Dox-induced apoptosis was also increased in the presence of Ver by using flow cytometric assay and DNA fragmentation quantitative assay as well as by Hoechst 33258 staining. It appears that the innate Bel7402 cells might be useful in screening new antitumour drugs or new chemosensitisers which could overcome the innate or acquired resistant mechanism, and the toxicity and reversal effects with 5-FU are different from those known to be P-gp substrates such as VCR, Dox, and taxol.
 ...
PMID:The study of innate drug resistance of human hepatocellular carcinoma Bel7402 cell line. 1007 27

In the previous study we have found that Djungarian hamster fibroblasts with high levels of multidrug resistance (MDR) (colchicine-resistance index RI of 1000 to 42000) produce soluble factor(s) communicating MDR to the drug-sensitive cells of the same species by elevating the functional activity of P-glycoprotein (Pgp). Here we have shown that these cells can influence human tumor cells in the same fashion. Rat hepatoma McA RH7777 cells and their colchicine-resistant derivatives are shown to produce a factor with similar effects (induction of MDR and Pgp functional activity in the drug-sensitive cells). These effects seem to depend on the drug resistance level of the donor cells. Our results show that induction of the Pgp-mediated MDR is not species-specific and the tumor cells with intrinsic MDR (arising from the tissue with a high level of Pgp expression) can produce a factor(s) communicating this type of drug resistance to the sensitive cells.
 ...
PMID:Induction of P-glycoprotein functional activity and multidrug resistance by a soluble factor(s) produced by some mammalian cells. 1036 65

The constitutive and induced activities of cytochrome P-4501A isoforms in hepatoma McA 7777 sublines with different levels of colchicine (CH) resistance were studied. The higher CH resistance was associated with the elevated functional activity of P-glycoprotein (Pgp). The constitutive level of benzo(a)pyrene hydroxylase and 7-ethoxyresorufin O-deethylase (cytochrome P-4501A-dependent activities) were the same in sublines with different CH resistance levels. However, benzo(a)-anthracene, a cytochrome P-4501A inducing agent, more effectively induced benzo(a)pyrene hydroxylase and 7-ethoxyresorufin O-deethylase activities in sublines with elevated P-glycoprotein activity. The toxicity of benzo(a)pyrene, a compound which is simultaneously a cytochrome P-4501A-inducing agent and a toxic agent activated by cytochrome P-4501A, is more effective in sublines with elevated CH resistance. These results support the suggestion about the coordinated regulation of enzyme systems involved in the defence against various lipophilic xenobiotics. The possibility to overcome the Pgp-mediated MDR of some tumours by using a combination of some drugs including compounds which induce the cytochrome P-4501A isoforms and are activated by them is discussed.
 ...
PMID:Coordinated regulation of P-glycoprotein activity and cytochrome P-4501A induction in sublines of rat hepatoma McA RH7777 cells with different levels of colchicine resistance. 1036 66

The human multidrug resistance gene MDR1 encodes a membrane-bound protein, referred to as P-glycoprotein, that acts as a pump to extrude toxins from cells. The 3' untranslated region (3'UTR) of the human MDR1 mRNA is very AU-rich (70%) and contains AU-rich sequences similar to those shown to confer rapid decay on c-myc, c-fos, and lymphokine mRNAs. We tested the ability of the MDR1 3'UTR to act as an mRNA destabilizing element in the human hepatoma cell line HepG2. The MDR1 mRNA has an intermediate half-life of 8 h in HepG2 cells compared to a half-life of 30 min for c-myc mRNA. The MDR1 mRNA half-life was prolonged to >20 h upon treatment with the protein synthesis inhibitor cycloheximide. We constructed expression vectors containing the human beta-globin coding region with the 3'UTR from either MDR1 or c-myc. The c-myc 3'UTR increased the decay of the chimeric mRNA, but the MDR1 3'UTR had no effect. We tested the ability of MDR1 3'UTR sequences to compete for interaction with AU-binding proteins in cell extracts; MDR1 RNA probes had a fivefold lower affinity for AU-binding proteins that interact with the c-myc AU-rich 3'UTR. Overall, our data suggest that the MDR1 3'UTR does not behave as an active destabilizing element in HepG2 cells.
 ...
PMID:The AU-rich 3' untranslated region of human MDR1 mRNA is an inefficient mRNA destabilizer. 1044 77

To characterize the P-glycoprotein (Pgp) expression in human hepatocellular carcinoma (HCC), we studied 101 cases of HCC treated with surgical resection without prior treatment. Pgp expression was detected immunohistochemically using 2 monoclonal antibodies (C494, C219) and correlated with pathologic features, survival, and p53 expression. Chemotherapy response was analyzed in a separate group of patients with inoperable HCC treated with systemic chemotherapy. Positive immunostaining was seen in 92% and 80% of the tumors with C494 and C219, respectively; bile canalicular type staining was seen in all positive tumors. Pgp expression was less extensive in the tumors than in the corresponding nontumorous liver tissue. Tumor Pgp expression with either antibody had no association with cellular differentiation, aggressive pathologic features, survival, or p53 overexpression. In patients with inoperable HCC, the chemotherapy response was significantly inversely related to Pgp expression with C494 and C219. Pgp was expressed in human HCC but was patchy and less extensive than in the nontumorous tissue. Response to systemic chemotherapy was inversely related to the level of Pgp expression in patients with inoperable tumors. Pgp expression in tumors not treated with chemotherapy was not associated with a more aggressive tumor phenotype or p53 overexpression and did not influence survival.
 ...
PMID:Expression of P-glycoprotein in hepatocellular carcinoma. A determinant of chemotherapy response. 1070 15

The multidrug resistance protein 2 (MRP2, symbol ABCC2) transports anionic conjugates and certain amphiphilic anions across the apical membrane of polarized cells. Human hepatoma Hep G2 cells retain hepatic polarity and form apical vacuoles into which cholephilic substances are secreted. Immunofluorescence microscopy showed that human MRP2 was expressed in the apical vacuole membrane of polarized Hep G2 cells, whereas the isoform MRP3 was localized to the lateral membrane. Expression of both MRP2 and MRP3 was confirmed by immunoblotting and reverse transcription PCR. Fluo 3 secretion into the apical vacuoles was inhibited by cyclosporin A but not by selective inhibitors of multidrug resistance 1 P-glycoprotein. In addition, carboxyfluorescein, rhodamine 123, and the fluorescent bile salt derivatives ursodeoxycholyl-(Nepsilon-nitrobenzoxadiazolyl)-lysine and cholylglycylamido-fluorescein were secreted into the apical vacuoles; the latter two probably via the bile salt export pump. We conclude that MRP2 mediates fluo 3 secretion into the apical vacuoles of polarized Hep G2 cells. Thus the function of human MRP2 and the action of inhibitors can be analyzed by the secretion of fluorescent anions such as fluo 3.
 ...
PMID:MRP2, a human conjugate export pump, is present and transports fluo 3 into apical vacuoles of Hep G2 cells. 1076 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>