Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular basis of radiotherapy-related multidrug resistance (MDR) is still unclear. Here we report on a study investigating the effect of fractionated irradiation on expression of the MDR-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP), the respective mRNAs, and the functional consequences. Cells of six colon and five breast cancer cell lines were irradiated with a total dose of 27 Gy, five fractions of 1.8 Gy per week. The mRNA expression was measured by quantitative RT-PCR, protein levels and drug sensitivity to cisplatin, doxorubicin and bendamustine were assessed by flow cytometry. Breast cancer cell lines showed enhancement of the mRNAs encoding for P-gp, MRP1 and LRP in comparison to nonirradiated cells. No up-regulation of the three mRNA species was observed in the colon cancer cell lines. After irradiation, three breast cancer cell lines showed an up-regulation of LRP, one line an up-regulation of MRP1, and four lines a small up-regulation of P-gp. In the colon cancer cell lines, radiation induced significant enhancement of all three proteins. In comparison to controls, the irradiated cells lines showed a significant resistance to cisplatin, doxorubicin and bendamustine. This study confirms the prior reports of enhancement of P-gp and MRP1 after irradiation, which is accompanied by a multidrug resistance phenomenon, but in addition proposes a novel mechanism in the appearance of MDR after radiation-induced enhancement of LRP.
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PMID:Fractionated irradiation can induce functionally relevant multidrug resistance gene and protein expression in human tumor cell lines. 1858 50

Pre-clinical studies of multidrug resistance (MDR) usually address severe resistance, yet moderate MDR is already clinically-impeding. The purpose of this study was to characterize moderate drug resistance in human colon cancer, and it's modulation by fluoxetine. In vitro fluoxetine enhanced doxorubicin's cytotoxicity (10-fold), increased doxorubicin's intracellular accumulation (32%) and decreased efflux of intracellular doxorubicin (70%). In vivo, mild treatment with a doxorubicin-fluoxetine combination slowed-down tumor progression significantly (p<0.001 vs. doxorubicin alone), comparable to aggressive treatment with bevacizumab. Collectively, our results suggest that combinations of fluoxetine with chemotherapeutic drugs (P-glycoprotein substrates) are worthy of further pursuit for moderate MDR in the clinic.
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PMID:Treatment of resistant human colon cancer xenografts by a fluoxetine-doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen. 1885 96

The efficacy of doxorubicin in the treatment of cancer is limited by its side effects and by the onset of drug resistance. Reverting such resistance could allow the decrease of the dose necessary to eradicate the tumor, thus diminishing the toxicity of the drug. We transfected doxorubicin-sensitive (HT29) and doxorubicin-resistant (HT29-dx) human colon cancer cells with RhoA small interfering RNA. The subsequent decrease of RhoA protein was associated with the increased sensitivity to doxorubicin in HT29 cells and the complete reversion of doxorubicin resistance in HT29-dx cells. RhoA silencing increased the activation of the nuclear factor-kappaB pathway, inducing the transcription and the activity of nitric oxide synthase. This led to the tyrosine nitration of the multidrug resistance protein 3 transporter (MRP3) and contributed to a reduced doxorubicin efflux. Moreover, RhoA silencing decreased the ATPase activity of P-glycoprotein (Pgp) in HT29 and HT29-dx cells as a consequence of the reduced expression of Pgp. RhoA silencing, by acting as an upstream controller of both MRP3 nitration and Pgp expression, was effective to revert the toxicity and accumulation of doxorubicin in both HT29 and HT29-dx cells. Therefore, we suggest that inactivating RhoA has potential clinical applications and might in the future become part of a gene therapy protocol.
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PMID:RhoA silencing reverts the resistance to doxorubicin in human colon cancer cells. 1892 76

Psychological distress and its ensuing chronic elevation of plasma catecholamines (adrenaline and noradrenaline) lead to poor response of tumors to chemotherapy, and constitute a poor prognostic factor for survival. Colorectal cancer patients suffer from various forms of psychological stress reflected in elevated plasma catecholamines, and their cancer cells express adrenergic receptors. Our objective was to investigate whether adrenergic activation contributes to the chemoresistance of colon cancers, and to explore the signal transduction pathway involved in the activation. The mRNA expression of the ABCB1 gene (previously MDR1) in human colon carcinoma HT-29 cell line was measured after treatment with an adrenergic receptor agonist (adrenaline) and various antagonists (propranolol, prazosin, and yohimbine). The function of P-glycoprotein, the protein product of the ABCB1 gene, was assessed by rhodamine 123 (Rh123)-retention assay, and chemosensitivity was determined by evaluating the cytotoxicity of 5-fluorouracil (5-FU) on the tumor cells. Increased ABCB1 mRNA expression and P-glycoprotein function levels in HT-29 cells by adrenaline was dose-dependent. This was accompanied by promotion of Rh123 efflux, and resistance to the growth-inhibiting effect of 5-FU in the tumor cells. The alpha2-adrenergic receptor antagonist yohimbine completely abolished the induction of ABCB1 mRNA, the stimulatory effect of adrenaline on Rh123 efflux, and the growth-inhibiting effect of 5-FU. The alpha1-adrenergic receptor and beta-adrenergic receptor antagonists did not inhibit the induction of ABCB1. The stimulating effects were coupled with extracellular receptor kinase 1/2 (Erk1/2) phosphorylation, but were not associated with protein kinase A activity. We conclude that adrenaline induces multidrug resistance in colon cancer cells by upregulating ABCB1 gene expression via alpha2-adrenergic receptors, and such effects were associated with the mitogen activated protein kinase (MAPK) pathway.
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PMID:Adrenaline induces chemoresistance in HT-29 colon adenocarcinoma cells. 1938 24

Digoxin and ouabain are cardioactive glycosides, which inhibit the Na+/K+-ATPase pump and in this way they increase the intracellular concentration of cytosolic calcium ([Ca2+](i)). They are also strong inducers of the P-glycoprotein (Pgp), a transmembrane transporter which extrudes several drugs, including anticancer agents like doxorubicin. An increased amount of Pgp limits the absorption of drugs through epithelial cells, thus inducing resistance to chemotherapy. The mechanism by which cardioactive glycosides increase Pgp is not known and in this work we investigated whether digoxin and ouabain elicited the expression of Pgp with a calcium-driven mechanism. In human colon cancer HT29 cells both glycosides increased the [Ca2+](i) and this event was dependent on the calcium influx via the Na+/Ca2+ exchanger. The increased [Ca2+](i) enhanced the activity of the calmodulin kinase II enzyme, which in turn activated the transcription factor hypoxia-inducible factor-1alpha. This one was responsible for the increased expression of Pgp, which actively extruded doxorubicin from the cells and significantly reduced the pro-apoptotic effect of the drug. All the effects of glycosides were prevented by inhibiting the Na+/Ca2+ exchanger or the calmodulin kinase II. This work clarified the molecular mechanisms by which digoxin and oubain induce Pgp and pointed out that the administration of cardioactive glycosides may widely affect the absorption of drugs in colon epithelia. Moreover, our results suggest that the efficacy of chemotherapeutic agent substrates of Pgp may be strongly reduced in patients taking digoxin.
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PMID:Digoxin and ouabain induce P-glycoprotein by activating calmodulin kinase II and hypoxia-inducible factor-1alpha in human colon cancer cells. 1964 9

Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.
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PMID:Drug efflux transporters, MRP1 and BCRP, affect the outcome of hypericin-mediated photodynamic therapy in HT-29 adenocarcinoma cells. 2002 69

In photodynamic therapy (PDT) a tumor-selective photosensitizer is administered and then activated by exposure to a light source of appropriate wavelength. Multidrug resistance (MDR) is largely caused by the drug efflux from the tumor cell by means of P-glycoprotein, resulting in reduced efficacy of the anticancer therapy. This study deals with photodynamic therapy with Photofrin (Ph) on colon cancer cell lines (doxorubicin-sensitive and -resistant). The cells were treated with 15 and 30 microg/mL Ph and then irradiated by a light dose of 3 or 6 J/cm(2) (632.8 nm). After irradiation the cells were incubated for 0, 3 or 18 h. Crucial factors of oxidative stress (thiobarbituric acid reactive substances [TBARS], protein damage, thiazolyl blue tetrazolium bromide [MTT] assay), changes in cytosolic superoxide dismutase (SOD1) activity after photodynamic reaction (PDR), and the intracellular accumulation of photosensitizers in the cells were examined. Moreover, the expressions of glutathione S-transferase (GST)-pi, a marker protein for photochemical toxicity, and secretory phospholipase A(2), a prognostic and diagnostic marker for colon cancers, were determined. After PDR, increases in SOD1 activity and the level of TBARS were observed in both cell lines. The level of protein-associated -SH groups decreased after PDR. Both cell lines demonstrated stronger GST-pi and PLA(2) expression after PDR, especially after 18 h of incubation. The increasing level of reactive oxygen species following the oxidation of sulfhydryl cell groups and lipid peroxidation influence the activity of many transporters and enzymes. The changes in SOD1 activity show that photodynamic action generates oxidative stress in treated cells. Our study presents that PDR caused oxidative alterations in both examined colon adenocarcinoma cell lines. However, the MDR cells reacted more slowly and all oxidative changes occurred in the delay.
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PMID:Oxidative alterations induced in vitro by the photodynamic reaction in doxorubicin-sensitive (LoVo) and -resistant (LoVoDX) colon adenocarcinoma cells. 2040 24

P-glycoprotein (Pgp) is a major ABC transporter responsible for multidrug-resistance (MDR) in cancer chemotherapy. Pre-clinical MDR modulation studies identified promising chemosensitizers, but none are in the clinic yet. Two novel progesterone-derived carbamates (11-carbamic acid N,N-dibenzyl progesterone ester and 11-carbamic acid N,N-dibutyl progesterone ester) were examined as potential chemosensitizers in the Pgp-expressing human colon cancer line HCT-15, applying the classical MDR-drugs paclitaxel and doxorubicin. The major findings were: (1) Pgp was expressed in the HCT-15 cells in both the cell and the nuclear membranes, (2) at the low dose range of 1-5 microM, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold) and (separately) of paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4h) for doxorubicin and 300% (18h) for paclitaxel, (iii) reduced drug efflux from the cell, 2-fold and 4-fold for doxorubicin and for paclitaxel, respectively. Based on detailed kinetic analysis, using liposomes to model paclitaxel diffusion through cell membranes, efflux slowdown can be attributed to reduction in the rate constant of drug diffusion through Pgp, and not to Pgp blockage. Chemosensitization was consistently-better for paclitaxel (cytosol-operating) than for doxorubicin (nuclear-operating) implying linkage between P-glycoprotein localization and loci of drug action. Mapping intracellular locations of MDR-pumps may assist therapeutic strategies.
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PMID:Novel steroid carbamates reverse multidrug-resistance in cancer therapy and show linkage among efficacy, loci of drug action and P-glycoprotein's cellular localization. 2055 61

To treat cancer cells overexpressing P-glycoprotein (P-gp), we propose a new concept using a nanodrug. The nanodrug was prepared from polyethyleneimine (PEI)/all-trans retinoic acid (ATRA) conjugates (PRA) and covered with hyaluronic acid (HA) to control the cytotoxicity of PRA (yielding PRA-H). The size distribution of PRA-H was narrow, with an average particle size of approximately 143 nm. Its superior stability in phosphate-buffered saline (PBS) was verified by monitoring changes in particle size and zeta potential for 24 h, which were negligible. In contrast, PEI-H (not conjugated with ATRA) exhibited a significant change in particle size and zeta potential. Although PRA was highly cytotoxic against HCT-8 and SNU-484 cancer cells, both of which overexpress P-gp, the cytotoxicity was significantly reduced by shielding with HA. The cytotoxicity of PRA-H was recovered by treatment with hyaluronidase (HAase), which degrades HA and is present in tumors at high concentrations. These results were confirmed by optical microscopy, fluorescence-activated cell sorting (FACs) analysis, and confocal microscopy. The cytotoxic mechanism of PRA was revealed as a type of necrotic lysis by FACs analysis with propidium iodide (PI) staining. Furthermore, PRA increased HCT-8 cell (colon cancer) permeability to doxorubicin (DOX). Therefore, we concluded that PRA-H is a promising new candidate for the treatment of cells with multidrug resistance (MDR) induced by overexpression of P-gp and cancer stem cells.
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PMID:Polycationic nanodrug covered with hyaluronic acid for treatment of P-glycoprotein overexpressing cancer cells. 2068 38

The anticancer drug doxorubicin induces the synthesis of nitric oxide, a small molecule that enhances the drug cytotoxicity and reduces the drug efflux through the membrane pump P-glycoprotein (Pgp). Doxorubicin also induces the translocation on the plasma membrane of the protein calreticulin (CRT), which allows tumour cells to be phagocytized by dendritic cells. We have shown that doxorubicin elicits nitric oxide synthesis and CRT exposure only in drug-sensitive cells, not in drug-resistant ones, which are indeed chemo-immunoresistant. In this work, we investigate the mechanisms by which nitric oxide induces the translocation of CRT and the molecular basis of this chemo-immunoresistance. In the drug-sensitive colon cancer HT29 cells doxorubicin increased nitric oxide synthesis, CRT exposure and cells phagocytosis. Nitric oxide promoted the translocation of CRT in a guanosine monophosphate (cGMP) and actin cytoskeleton-dependent way. CRT translocation did not occur in drug-resistant HT29-dx cells, where the doxorubicin-induced nitric oxide synthesis was absent. By increasing nitric oxide with stimuli other than doxorubicin, the CRT exposure was obtained also in HT29-dx cells. Although in sensitive cells the CRT translocation was followed by the phagocytosis, in drug-resistant cells the phagocytosis did not occur despite the CRT exposure. In HT29-dx cells CRT was bound to Pgp and only by silencing the latter the CRT-operated phagocytosis was restored, suggesting that Pgp impairs the functional activity of CRT and the tumour cells phagocytosis. Our work suggests that the levels of nitric oxide and Pgp critically modulate the recognition of the tumour cells by dendritic cells, and proposes a new potential therapeutic approach against chemo-immunoresistant tumours.
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PMID:Nitric oxide and P-glycoprotein modulate the phagocytosis of colon cancer cells. 2071 30


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