Doxorubicin induced expression of P-glycoprotein in a canine osteosarcoma cell line

Mealey, Katrina L.; Barhoumi, Rola; Rogers, Kenita S.; Kochevar, Deborah T.

doi:10.1016/s0304-3835(98)00004-4

Cited by 40 publications

(33 citation statements)

References 13 publications

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“…However, chemotherapy resistance is observed (Calvert et al 1982, Brandão et al 2002 and resistance mechanisms are not completely understood. In humans, the multiple drug resistance is the main obstacle to the success in chemotherapy (Munoz et al 2007) and supposedly also in canine neoplasms (Bergman et al 1996, Lee et al 1996, Mealey et al 1998, Uozurmi et al 2005.…”

Section: Discussionmentioning

confidence: 99%

Expression of P-glycoprotein, multidrug resistance-associated protein, glutathione-S-transferase pi and p53 in canine transmissible venereal tumor

et al. 2014

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Pesq. Vet. Bras. 34(1):71-78, janeiro 2014 71 RESUMO.-[Expressão da glicoproteína-P, proteína associada à múltiplas drogas, glutationa-S-transferase pi e p53 no tumor venéreo transmissível canino.] A superexpressão das proteínas glicoproteína-P (Gp-P), proteína associada à resistência à múltiplas drogas 1 (MRP1) e p53 mutante e a enzima glutationa-S-transferase pi (GSTpi) está relacionada com resistência à quimioterapia em neoplasias humanas e caninas. Este estudo avaliou a expressão, por meio da imuno-histoquímica desses marcadores em espéci-mes de TVT caninos sem histórico de quimioterapia prévia (TVT1, n=9) e em TVT caninos que apresentaram resposta clínica insatisfatória ao sulfato de vincristina (TVT2, n=5). A porcentagem de espécimes positivos para Gp-P, MRP1, GSTpi e p53 foram, respectivamente 88,8%, 0%, 44,5% e 22,2% no grupo TVT1 e 80%, 0%, 80% e 0% no grupo TVT2. No TVT1, um espécime apresentou expressão positiva para três marcadores e quatro para dois marcadores. No TVT2, três espécimes expressaram a Gp-P e GSTpi. Em conclusão, os TVTs caninos estudados expressaram os quatro marcadores avaliados, no entanto apenas a Gp-P e GSTpi foram significativamente expressas, principalmente no citoplasmas e no citoplasma e no núcleo, respectivamente, The overexpression of proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP1), mutant p53, and the enzyme glutathione-S-transferase (GSTpi) are related to resistance to chemotherapy in neoplasms. This study evaluated the expression of these markers by immunohistochemistry in two groups of canine TVT, without history of prior chemotherapy (TVT1, n=9) and in TVTs presented unsatisfactory clinical response to vincristine sulfate (TVT2, n=5). The percentage of specimens positively stained for P-gp, MRP1, GSTpi and p53 were, respectively 88.8%, 0%, 44.5% and 22.2% in TVT1 and 80%, 0%, 80% and 0% in TVT2. In TVT1, one specimen presented positive expression for three markers and four specimens for two markers. In TVT2, three specimens expressed P-gp and GSTpi. In conclusion, the canine TVTs studied expressed the four markers evaluated, but just P-gp and GSTpi were significantly expressed, mainly at cytoplasm and cytoplasm and nuclei, respectively, either before chemotherapy as after vincristine sulfate exposure. Future studies are needed to demonstrate the function of these two markers in conferring multidrug resistance (MDR) or predict the response to chemotherapy in canine TVT.

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Section: Discussionmentioning

confidence: 99%

Expression of P-glycoprotein, multidrug resistance-associated protein, glutathione-S-transferase pi and p53 in canine transmissible venereal tumor

et al. 2014

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“…Although the most common treatment is surgical removal of the entire tumor, doxorubicin (DXR)-based chemotherapy has been the current treatment for patients with locally advanced inoperable or metastatic disease [1]. However, the clinical effectiveness of DXR is limited by severe toxicity and the development of multidrug resistance (MDR), the latter mainly involving high cellular expression of ATP-binding cassette (ABC) transporters in the plasma membrane, including P-glycoprotein (P-gp) and multidrug resistance-related protein 1 (MRP-1) [2], [3]. These proteins are ATP-dependent pumps that carry xenobiotic agents, such as the antineoplastic compound DXR, out of the cells, thereby reducing its antitumoral effect.…”

Section: Introductionmentioning

confidence: 99%

Nilotinib Counteracts P-Glycoprotein-Mediated Multidrug Resistance and Synergizes the Antitumoral Effect of Doxorubicin in Soft Tissue Sarcomas

Villar¹,

Vögler²,

Martínez-Serra³

et al. 2012

PLoS ONE

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The therapeutic effect of doxorubicin (DXR) in the treatment of soft tissue sarcomas (STS) is limited by its toxicity and the development of multidrug resistance (MDR), the latter mainly induced by high expression of efflux pumps (e.g., P-glycoprotein [P-gp]). Therefore, the search for alternative therapies, which sensitize these tumors to chemotherapy while maintaining a low toxicity profile, is a rational approach. We assessed efficacy and molecular mechanisms involved in the antiproliferative effects of the tyrosine kinase inhibitors, nilotinib and imatinib, as single agents or in combination with DXR, in human synovial sarcoma SW982 and leiomyosarcoma SK-UT-1 cells. As single compound nilotinib (1–10 µM) was more potent than imatinib inhibiting the growth of SK-UT-1 and SW982 cells by 33.5–59.6%, respectively. Importantly, only nilotinib synergized the antitumoral effect of DXR (0.05–0.5 µM) by at least 2-fold, which clearly surpassed the mere sum of effects according to isobolographic analysis. Moreover, nilotinib in combination with DXR had a sustained effect on cell number (−70.3±5.8%) even 12 days after withdrawal of drugs compared to DXR alone. On the molecular level, only nilotinib fully blocked FBS-induced ERK1 and p38 MAPK activation, hence, reducing basal and DXR-induced up-regulation of P-gp levels. Moreover, efflux activity of the MDR-related proteins P-gp and MRP-1 was inhibited, altogether resulting in intracellular DXR retention. In high-risk STS tumors 53.8% and 15.4% were positive for P-gp and MRP-1 expression, respectively, with high incidence of P-gp in synovial sarcoma (72.7%). In summary, nilotinib exhibits antiproliferative effects on cellular models of STS and sensitizes them to DXR by reverting DXR-induced P-gp-mediated MDR and inhibiting MRP-1 activity, leading to a synergistic effect with potential for clinical treatment.

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“…Overexpression of PGP results in reduced accumulation of certain drugs within the cell, and is linked to the MDR phenotype. PGP expression is high in canine and feline tumor cell lines that show the MDR phenotype [7,10,11]. PGP has been detected immunohistochemically in several normal and neoplastic canine tissues [4].…”

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confidence: 99%

Immunohistochemical Detection of P-Glycoprotein (PGP) and Multidrug Resistance-Associated Protein (MRP) in Canine Cutaneous Mast Cell Tumors.

Miyoshi

Tojo

Oishi

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. Fifty-four canine cutaneous mast cell tumors were evaluated immunohistochemically for the expression of P-glycoprotein (PGP) and multidrug-resistance-associated protein (MRP). All tumors examined were graded according to the histological malignancy, ranging from grade I to III. The expression of PGP was confirmed in 15% (8/54) of whole, 33% (5/15) of grade I, 10% (3/31) of grade II, and 0% (0/8) of grade III tumors. The expression of MRP was found in 18% (10/54) of whole, 26% (4/15) of grade I, 19% (6/31) of grade II, and 0% (0/8) of grade III tumors. The cases positive to at least one of these 2 multidrug markers were 26%, 47%, 23% and 0% of whole and grade I to III tumors, respectively. These results indicate that at least 26% of canine cutaneous mast cell tumors express PGP and/or MRP and that these tumors may be resistant to several anti-cancer drugs. KEY WORDS: canine, mast cell tumor, multidrug resistance.

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Doxorubicin induced expression of P-glycoprotein in a canine osteosarcoma cell line

Cited by 40 publications

References 13 publications

Expression of P-glycoprotein, multidrug resistance-associated protein, glutathione-S-transferase pi and p53 in canine transmissible venereal tumor

Expression of P-glycoprotein, multidrug resistance-associated protein, glutathione-S-transferase pi and p53 in canine transmissible venereal tumor

Nilotinib Counteracts P-Glycoprotein-Mediated Multidrug Resistance and Synergizes the Antitumoral Effect of Doxorubicin in Soft Tissue Sarcomas

Immunohistochemical Detection of P-Glycoprotein (PGP) and Multidrug Resistance-Associated Protein (MRP) in Canine Cutaneous Mast Cell Tumors.

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