Level of protein kinase C activity correlates directly with resistance to adriamycin in murine fibrosarcoma cells

O’Brian, Catherine A.; Fan, Dominic; Ward, Nancy E.; Seid, Christopher A.; Fidler, Isaiah J.

doi:10.1016/0014-5793(89)80257-1

Cited by 80 publications

(28 citation statements)

References 12 publications

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“…This finding is to some extent reinforced by some observations showing that the level of PKC activity correlates with the degree of multidrug resistance to a specific drug (doxorubicin) as has been reported in a series of UV-2237M cell lines (O'Brian et al, 1989). We found the same in a series of KB cells selected in colchicine (Drew et al 1994).…”

Section: Pkc Activity In Mdr Cell Linessupporting

confidence: 86%

Protein kinases and multidrug resistance

Rumsby¹,

Drew²,

Warr³

1998

Multiple Drug Resistance in Cancer 2

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The role of protein kinases in the multidrug resistance phenotype of cancer cell lines is discussed with an emphasis on protein kinase C and protein kinase A. Evidence that P-glycoprotein is phosphorylated by these kinases is summarised and the relationship between P-glycoprotein phosphorylation and the multidrug-resistant phenotype discussed. Results showing that protein kinase C, particularly the alpha subspecies, is overexpressed in many MDR cell lines are described: this common but by no means universal finding seems to be drug-and cell line-dependent and in only in a few cases is there a direct correlation between protein kinase C activity and multidrug resistance. From co-immunoprecipitation results it is suggested that P-glycoprotein is a specific protein kinase C receptor, as well as being a substrate. Revertant experiments provide conflicting results as to a direct relationship between expression of P-glycoprotein and protein kinase C. Evidence that protein kinase A influences P-glycoprotein expression at the gene level is well documented and the mechanisms by which this occurs are becoming clarified. Results on the relationship between protein kinase C and multidrug resistance using many inhibitors and phorbol esters are difficult to interpret because such compounds bind to P-glycoprotein. In spite of huge effort, a direct involvement of protein kinase C in regulating multidrug resistance has not yet been firmly established. However, evidence that PKC regulates a Pgp-independent mechanism of drug resistance is accumulating.

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Section: Pkc Activity In Mdr Cell Linessupporting

confidence: 86%

Protein kinases and multidrug resistance

Rumsby¹,

Drew²,

Warr³

1998

Multiple Drug Resistance in Cancer 2

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“…In DOX-resistant HL-60 cells, a non-P-gp-expressing human promyelocytic leukaemia cell line, MRP was identified primarily in the endoplasmic reticulum, with lower levels also present in the plasma membrane (Marquardt and Center, 1992;Krishnamachary and Center, 1993), whereas a predominant function as a plasma membrane efflux pump has been demonstrated in a SCLC and in a non-small-cell lung carcinoma (NSCLC) cell line selected by exposure to DOX (Zaman et al, 1994 76(1), [67][68][69][70][71][72][73][74][75][76] In the present study, an additional possible mechanism for the intrinsically resistant phenotype of LoVo/C7 cells has been examined, namely alterations of PKC isoform pattern. Increases in overall PKC expression and/or activity have been demonstrated to correlate with a MDR phenotype in a number of cell lines O'Brian et al, 1989;Dong et al, 1991;Chaudary and Roninson, 1992;Gollapudi et al, 1992), with the Ca2+-dependent isoform oc-PKC specifically implicated in this phenomenon (Yu et al, 1991;Ahmad and Glazer, 1993). In a preliminary report, we analysed the role of Ca2+-dependent PKC isoforms in LoVo/C7 cells and our findings suggested a contribution of oc-PKC to the intrinsically resistant phenotype (Dolfini et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin

Dolfini

Dasdia²,

Arancia³

et al. 1997

Br J Cancer

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Summary Intrinsic low-level resistance to anti-cancer drugs is a major problem in the treatment of gastrointestinal malignancies. To address the problem presented by intrinsically resistant tumours, we have isolated two monoclonal lines from LoVo human colon adenocarcinoma cells: LoVo/C7, which is intrinsically resistant to doxorubicin (DOX); and LoVo/C5, which shows the same resistance index for DOX as the mixed parental cell population. For comparison, we have included in the study a LoVo-resistant line selected by continuous exposure to DOX and expressing a typical multidrug resistant (MDR) phenotype. In these cell lines we have studied the expression and/or activity of a number of proteins, including P-glycoprotein 170 (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione (GSH)-dependent enzymes and protein kinase C (PKC) isoforms, which have been implicated in anti-cancer drug resistance. Intracellular DOX distribution has been assessed by confocal microscopy. The results of the present study indicate that resistance in LoVo/C7 cells cannot be attributed to alterations in P-gp, LRP or GSH/GSH-dependent enzyme levels. Increased expression of MRP, accompanied by alterations in the subcellular distribution of DOX, has been observed in LoVo/C7 cells; changes in PKC isoform pattern have been detected in both intrinsically and pharmacologically resistant cells.

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“…In addition to overexpression of P-glycoprotein, other mechanisms also have been implicated to modulate MDR, including changes in transmembrane signalling pathways. Protein kinase C (PKC) activity has been shown to be elevated in a number of drugresistant cell types [5][6][7][8]. Other studies have shown that treatment of MDR cells with agents which alter PKC activity also altered the drug-resistant phenotype [5,6,9,10], further suggesting a role for PKC in multidrug resistance.…”

Section: Introductionmentioning

confidence: 99%

Phorbol ester selectively stimulates the phospholipase D-mediated hydrolysis of phosphatidylethanolamine in multidrug-resistant MCF-7 human breast carcinoma cells

Kiss

Tomono

Anderson

1994

Biochemical Journal

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The phospholipase D (PLD)-mediated synthesis of phosphatidylethanol (PtdEtOH) and the hydrolysis of phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho) were examined in drug-sensitive and multidrug-resistant lines of MCF-7 human breast carcinoma cells. In drug-sensitive (MCF-7/WT) cells, the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) failed to enhance either the synthesis of PtdEtOH or the hydrolysis of either phospholipid. In the drug-resistant (MCF-7/MDR) cells, 100 nM PMA greatly enhanced both the synthesis of PtdEtOH (approximately 21-fold) and the hydrolysis of PtdEtn (approximately 29-fold), but had no effect on the hydrolysis of PtdCho. The PLD activators sphingosine and H2O2 were found to elicit only a slight (1.28-1.4-fold) stimulatory effect on PtdCho hydrolysis in both the MCF-7/WT and MCF-7/MDR cell types, and had only a small effect on PtdEtn hydrolysis in the MCF-7/WT cells as well. However, these agents significantly (approximately 2.6-3.5-fold) stimulated PtdEtn hydrolysis in the MCF-7/MDR cells. These data indicate that MCF-7/MDR cells contain a PtdEtn-specific PLD activity which can be selectively stimulated by PMA, sphingosine and H2O2.

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Level of protein kinase C activity correlates directly with resistance to adriamycin in murine fibrosarcoma cells

Cited by 80 publications

References 12 publications

Protein kinases and multidrug resistance

Protein kinases and multidrug resistance

Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin

Phorbol ester selectively stimulates the phospholipase D-mediated hydrolysis of phosphatidylethanolamine in multidrug-resistant MCF-7 human breast carcinoma cells

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