Reduced cyclosporin accumulation in multidrug-resistant cells

Goldberg, Harry; Ling, Victor; Wong, P. Y.; Skorecki, Karl

doi:10.1016/s0006-291x(88)80073-1

Cited by 108 publications

(40 citation statements)

References 14 publications

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“…Cell lines differing only in surface PGP expression (see Methods) were assayed for phosphatase activity in the absence of CsA, immediately after exposure to CsA 100 ug/liter for 1 h (Before recovery) and after being removed from CsA, washed, and resuspended in CsA-free medium for 1 h (After recovery). [21]) in vinblastine-containing medium. This resulted in >90% cell death (by dye exclusion) by either agent, indicating effective inhibition of PGP transport of vinblastine.…”

Section: Resultsmentioning

confidence: 99%

Cyclosporine inhibition of calcineurin activity in human leukocytes in vivo is rapidly reversible.

Batiuk

Pazderka²,

Enns³

et al. 1995

J. Clin. Invest.

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Section: Resultsmentioning

confidence: 99%

Cyclosporine inhibition of calcineurin activity in human leukocytes in vivo is rapidly reversible.

Batiuk

Pazderka²,

Enns³

et al. 1995

J. Clin. Invest.

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“…Several compounds have been studied for their inhibitory effect on ABC transporters. For example, verapamil and cyclosporine A were effective for inhibiting the function of ABCB1 in vitro (Goldberg et al, 1988;Hamada and Tsuruo, 1988). However, because of the toxic dose of these compounds required for inhibition of ABCB1, they led to severe side effects in vivo and made clinical application impossible.…”

Section: Introductionmentioning

confidence: 99%

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance–Linked ATP-Binding Cassette Transporter ABCG2

Murakami

Ohnuma

Fukuda

et al. 2017

Drug Metabolism and Disposition

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Multidrug resistance (MDR) caused by the overexpression of ATPbinding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells.

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“…Chemosensitizing agents (cyclosporin A and verapamil) are believed to reverse the multidrug resistance phenotype by inhibiting the energy-dependent efflux of the cytotoxic agents (2,5). Furthermore, cyclosporin A (CsA) was previously reported to be a substrate for P-gp in renal cell lines (11). Understanding of the molecular mechanism involved in the interactions between P-gp and such a diversity of compounds appears essential for elucidating its mode of action and may contribute to the development of more effective anticancer chemotherapy.…”

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confidence: 99%

Molecular Interactions of Cyclosporin A with P-glycoprotein

Demeule¹,

Wenger²,

Béliveau³

1997

Journal of Biological Chemistry

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The interaction between P-glycoprotein (140 -180 kDa) from the multidrug-resistant Chinese hamster ovary cell line CH R C5 and cyclosporin A was characterized using three different photoactivable cyclosporin A analogs. Two monoclonal antibodies, which are able to discriminate between two major domains of cyclosporin A (the cyclophilin and calcineurin binding domains), were used to detect the photolabeled proteins. A protein of 155 kDa corresponding to P-glycoprotein was much more strongly photolabeled in membranes of CH R C5 cells than in membranes of their drug-sensitive parent cell line AuxB1. The antitumor drug vinblastine and the reversal agents verapamil and cyclosporin A inhibited the photolabeling, and the nonimmunosuppressive derivative PSC-833 caused a stronger inhibition than cyclosporin A. P-glycoprotein photolabeled with cyclosporin A analogs was only detected with the monoclonal antibody that recognizes cyclosporin A and its metabolites, indicating that the calcineurin binding domain recognized specifically by the other antibody is not exposed. These results suggest that the portion of cyclosporin A that binds to calcineurin plays a role in the interaction of cyclosporin A with P-glycoprotein.

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Reduced cyclosporin accumulation in multidrug-resistant cells

Cited by 108 publications

References 14 publications

Cyclosporine inhibition of calcineurin activity in human leukocytes in vivo is rapidly reversible.

Cyclosporine inhibition of calcineurin activity in human leukocytes in vivo is rapidly reversible.

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance–Linked ATP-Binding Cassette Transporter ABCG2

Molecular Interactions of Cyclosporin A with P-glycoprotein

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