Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance to multiple chemotherapeutic agents is a common clinical problem which can arise during cancer treatment. Drug resistance often involves overexpression of the multidrug resistance MDR1 gene, encoding P-glycoprotein (P-gp), a 170-kDa glycoprotein belonging to the ATP-binding cassette superfamily of membrane transporters. We have recently demonstrated apoptosis-induced, caspase-3-dependent P-gp cleavage in human T-lymphoblastoid CEM-R VBL100 cells. However, P-gp contain many aspartate residues which could be targeted by caspases other than caspase-3. To test whether other caspases could cleave P-gp in vivo, we investigated the fate of P-gp during roscovitine- and sangivamycin- induced apoptosis in MCF7 human breast cancer cells, as they lack functional caspase-3. MCF7 cells were stably transfected with human cDNA encoding P-gp. P-gp was cleaved in vitro by purified recombinant caspase-3, -6 and -7. However, P-gp cleavage was not detected in vivo in MCF7 cells induced to undergoing apoptosis by either roscovitine or sangivamycin, despite activation of both caspase-6 and -7. Interestingly, P-gp overexpressing MCF7 cells were more sensitive to either roscovitine or sangivamycin than wild-type cells, suggesting a novel potential therapeutic strategy against P-gp overexpressing cells. Taken together, our results support the concept that caspase-3 is the only caspase responsible for in vivo cleavage of P-gp and also highlight small molecules which could be effective in treating P-gp overexpressing cancers.
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PMID:The cyclin-dependent kinase inhibitor roscovitine and the nucleoside analog sangivamycin induce apoptosis in caspase-3 deficient breast cancer cells independent of caspase mediated P-glycoprotein cleavage: implications for therapy of drug resistant breast cancers. 1934 73

Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G(0)-G(1) phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3beta. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth.
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PMID:Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. 1935 20

Mitomycin C (MMC) is an active antineoplastic agent and is suggested to induce apoptosis in a caspase- dependent manner in human gastric, bladder, and breast cancer cells. In this study, the death mode of human cervical cancer cells (HeLa) induced by MMC and the cellular localization of MMC-induced P-glycoprotein (P-gp) were investigated. The results of caspase-3 activity, Annexin V binding, and DNA fragmentation suggested that the degree of caspase-dependent apoptosis induced by MMC was in a dose-, but not time-dependent, manner. Further, in low-dose (0.0299 microM) and long-term (2 months) treatment with MMC, P-gp is itself extruded from the cells and colocalized with nuclear DNA and the overexpression was achieved.
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PMID:Apoptotic death mode of mitomycin C-treated HeLa cells and cellular localization of mitomycin C-induced P-glycoprotein. 1951 52

Drug resistance in breast cancer remains a major cause for the failure of chemotherapy. Glucosylceramide synthase (GCS) plays an important role in multidrug resistance (MDR) in breast cancer. P-glycoprotein (P-gp) also confers a cross-resistance of many unrelated drugs. In this study, we studied the MDR effect and potential mechanisms of breast cancer after constructing permanent breast cancer cell lines with GCS knockout by using recombinant vectors targeting GCS (pSUPER-GCSshRNAs). The GCSshRNA stably transfected cells were successfully established and significant lower levels of GCS mRNA and protein expression were confirmed. In in vitro experiments, the GCSshRNA stably transfected cells showed a significantly reduced level of MDR1 and P-gp expression and decreased drug efflux ability. Reduced level of GCS expression conveyed a significant reversal of drug resistance by MTT assay and increased caspase-3 activity. In in vivo experiments by using nude mice with xenograft tumors, a significant inhibition of tumor growth was observed after comparing with the control group. Furthermore, enhanced response of chemotherapy was acquired by reduced expression of GCS as well as MDR1 in vivo. In conclusion, GCSshRNA could efficiently suppress GCS and MDR1 expression in vitro and in vivo and these findings may be used as one of the methods to reverse MDR in breast cancer.
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PMID:Targeting glucosylceramide synthase downregulates expression of the multidrug resistance gene MDR1 and sensitizes breast carcinoma cells to anticancer drugs. 1969 66

Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy. We evaluated the effect of daunorubicin (DNR)-loaded magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) on K562-n/VCR cells in vivo. K562-n and its MDR counterpart K562-n/VCR cell were inoculated into nude mice subcutaneously. The mice were randomly divided into four groups: group A received normal saline, group B received DNR, group C received MNPs-Fe3O4, and group D received DNR-loaded MNPs-Fe3O4. For K562-n/VCR tumor, the weight was markedly lower in group D than that in groups A, B, and C. The transcriptions of Mdr-1 and Bcl-2 gene were significantly lower in group D than those in groups A, B, and C. The expression of Bcl-2 was lower in group D than those in groups A, B, and C, but there was no difference in the expression of P-glycoprotein. The transcriptions and expressions of Bax and caspase-3 in group D were increased significantly when compared with groups A, B, and C. In conclusion, DNR-loaded MNPs-Fe3O4 can overcome MDR in vivo.
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PMID:Daunorubicin-loaded magnetic nanoparticles of Fe3O4 overcome multidrug resistance and induce apoptosis of K562-n/VCR cells in vivo. 1991 66

5-Bromotetrandrine (BrTet) was shown to overcome multi-drug resistance (MDR) in vitro and in vivo by inhibiting the overexpression and efflux function of P-glycoprotein in our previous study. The purpose of the present study was to evaluate the effect of BrTet on the sensitivity of doxorubicin (Dox) induced apoptosis in intrinsic resistant human hepatic cancer Bel7402 cells. The cells were treated with non-toxic concentrations of BrTet (1 microM, 2 microM, 4 microM) or the positive control drug verapamil (Vrp) (10 microM) for 24h followed by a low dose Dox (3 microM) for 24 h. The results showed that BrTet pretreatment followed by Dox led to typical apoptotic characters as indicated by morphologic changes, DNA fragmentation and changes in cell cycle, while the same dose of BrTet, Vrp and Dox alone did not induce apoptosis in Bel7402 cells. In addition, the pretreatment of BrTet or Vrp followed by Dox induced activation of caspase-3, release of cytochrome c and AIF from mitochondria into cytosol, loss of mitochondrial transmembrane potential (DeltaPsi(m)) and elevation of Bax/Bcl-2 ratio, with no effect on activation of caspase-8 and the expression of Fas/FasL. In conclusion, BrTet pretreatment enhanced the sensitivity of Dox to induce apoptosis by causing loss of DeltaPsi(m) and elevating the ratio of Bax/Bcl-2, eventually activated mitochondrial apoptotic pathway. These findings further support the potential of BrTet to be used in clinical trail of cancer treatment.
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PMID:5-Bromotetrandrine enhances the sensitivity of doxorubicin-induced apoptosis in intrinsic resistant human hepatic cancer Bel7402 cells. 1996 32

Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1H-pyrrole-2,5-dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway.
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PMID:YQ36: a novel bisindolylmaleimide analogue induces KB/VCR cell death. 2006 25

Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one of the principal mechanisms by which tumor cells escape the cell death induced by chemotherapeutic agents. In our previous study, we demonstrated that KBH-A42 [N-hydroxy-3-(2-oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a synthetic histone deacetylase inhibitor, effectively inhibited the growth of several human cancer cell lines. In this study, we attempted to determine whether KBH-A42 was also capable of inhibiting the growth of multidrug-resistant cells. Doxorubicin dose-dependently inhibited the growth of P-gp-negative K562 human leukemia cells, but did not show substantial inhibition on the growth of P-gp-positive K562/ADR cells even at 10 microM, the highest concentration of KBH-A42 used, which increased the acetylation of histones in these leukemia cells, dose-dependently and effectively inhibited the cell growth, regardless of the presence of P-gp in the cells. KBH-A42 mediated G0/G1 cell cycle arrest, probably as the result of the down-regulation of CDK2, CDK4 and CDK6 and the up-regulation of p21WAF1. When the expression of p21WAF1 was ablated by a specific siRNA, the inhibition of cell growth by KBH-A42 was partly reduced in both cell lines. In addition to the cell cycle arrest, KBH-A42 also induced apoptosis in these cells, which was accompanied by the activation of caspases, including caspase-9, caspase-8 and caspase-3. The pan-caspase inhibitor, Z-VAD-fmk, partially blocked the cell death induced by KBH-A42. These results indicate that KBH-A42 induces cell cycle arrest and apoptosis via the up-regulation of p21WAF1 and caspase activation, respectively, regardless of the presence of P-gp in the leukemia cells.
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PMID:KBH-A42, a histone deacetylase inhibitor, inhibits the growth of doxorubicin-resistant leukemia cells expressing P-glycoprotein. 2012 23

Multidrug resistance (MDR) is one of important issues to cause the chemotherapy failure against cancers including gynecological malignancies. Despite some MDR reversal evidences of natural compounds including quinidine and cinchonine, there are no reports on MDR reversal activity of hydrocinchonine with its analogues quinidine and cinchonine especially in uterine sarcoma cells. Thus, in the current study, we comparatively investigated the potent efficacy of hydrocinchonine and its analogues quinidine and cinchonine as MDR-reversal agents for combined therapy with antitumor agent paclitaxel (TAX). Hydrocinchonine, cinchonine, and quinidine significantly increased the cytotoxicity of TAX in P-glycoprotein (gp)-positive MES-SA/DX5, but not in the P-gp-negative MES-SA cells at nontoxic concentrations by 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyltetrazolium bromide (MTT) assay. Rhodamine assay also revealed that hydrocinchonine, cinchonine, and quinidine effectively enhanced the accumulation of a P-gp substrate, rhodamine in TAX-treated MES-SA/DX5 cells compared with TAX-treated control. In addition, hydrocinchonine, cinchonine, and quinidine effectively cleaved poly (ADP-ribose) polymerase (PARP), activated caspase-3, and downregulated P-gp expression as well as increased sub-G1 apoptotic portion in TAX-treated MES-SA/DX5 cells. Taken together, hydrocinchonine exerted MDR reversal activity and synergistic apoptotic effect with TAX in MES-SA/DX5 cells almost comparable with quinidine and cinchonine as a potent MDR-reversal and combined therapy agent with TAX.
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PMID:Hydrocinchonine, cinchonine, and quinidine potentiate paclitaxel-induced cytotoxicity and apoptosis via multidrug resistance reversal in MES-SA/DX5 uterine sarcoma cells. 2019 46

P-Glycoprotein (Pgp) overexpression and alterations in p53 oncogene expression are known to affect chemotherapeutic efficacy in the treatment of human hepatocellular carcinoma (HCC). The present study has demonstrated the anti-HCC potential of cryptotanshinone (1), dihydrotanshinone (2), tanshinone I (3), and tanshinone IIA (4), the active lipophilic constituents of Salvia miltiorrhiza, using MTT and caspase-3 activity assays and poly(ADP-ribose) polymerase cleavage in HepG2, Hep3B, and PLC/PRF/5 cells. THLE-3, a normal human immortalized liver cell line, was used to demonstrate the selective growth inhibitory effect of 3 for a HCC cell line. Compound 1 suppressed doxorubicin efflux, a process mediated by P-glycoprotein, in a Pgp-overexpressed HepG2 subclone (R-HepG2 cells). Despite its moderate cytostatic and pro-apoptotic effects and minimal influence on doxorubicin efflux, 4 provided the best synergism with doxorubicin as determined by the Combination Index, the Loewe additivity model, and the Bliss independence criterion.
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PMID:Cytotoxic effects of tanshinones from Salvia miltiorrhiza on doxorubicin-resistant human liver cancer cells. 2045 78


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