We investigated the chemosensitisation of the parental EMT6 mouse mammary tumour cell line by low doses of cyclosporin A (CsA). This cell line has not previously been exposed to cytotoxic drugs but expresses low levels of P-glycoprotein. We produced >2-fold sensitisation to doxorubicin, colchicine and vincristine using 0.084 μM (0.1 μg/ml) CsA. Cellular accumulation of doxorubicin and daunorubicin was also increased by this dose. In the MDR subline EMT6/AR1.0, much higher doses of CsA were required to effect optimal restoration of doxorubicin or daunorubicin accumulation. The effects of CsA on the parent line could not be increased by extended preincubation of cells with the sensitiser. These, effects of CsA in the EMT6 parent cell line occur at a dose that is 1 order of magnitude lower than those previously reported to produce significant chemosensitisation.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Chambers SH, Bleehen NM, Watson JV (1984) Effect of cell density on intracellular Adriamycin concentration and cytotoxicity in experimental amd plateau phase EMT6 cells. Br J Cancer 49:301
Coley HM, Twentyman PR, Workman P (1989) Improved, cellular accumulation is characteristic of anthracyclines which retain high activity in multidrug resistant cell lines, alone or in combination with verapamil or cyclosporin A. Biochem Pharmacol 38:4467
Cornwell MM, Pastan I, Gottesman MM (1987), Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J Biol Chem 262:2166
Dalton WS, Grogan TM, Meltzer PS, Scheper RJ, Durie BGM, Taylor CW, Miller TP, Salmon SE (1989). Drug resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy. J Clin Oncol 7:415
Endicott JA, Ling V (1989) The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 58:137
Gavériaux C, Boesch D, Boelsterli JJ, Bollinger P, Eberle MK, Hiestand P, Payne T, Traber R, Wenger R, Loor F (1989) Overcoming multidrug resistance in Chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and nonimmunosuppressive derivatives. Br J Cancer 60:867
Goldstein LJ, Gaski H, Fojo A, Willingham M, Lai S-L, Gazdar A, Pirker R, Green A, Crist W, Brodeur GM, Lieber M, Cossman J, Gottesman MM, Pastan I (1989) Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 81:116
Hu XF, Luise M de, Martin TJ, Zalcberg JR (1990) Effect of cyclosporin and verapamil on the cellular kinetics of daunorubicin. Eur J Cancer 26 (7):814
Jones RD, Kerr DJ, Harnett AN, Rankin EM, Ray S, Kaye SB (1990) A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer. Br J Cancer 62:133
Juranka PF, Zastawny R, Ling V (1989) P-glycoprotein: multidrugresistance and superfamily of membrane-associated transport proteins. FASEB J 3:2583
Kartner N, Evernden-Porelle D, Bradley G, Ling V (1985) Detection of P-glycoprotein in multidrug resistant cell lines by monoclonal antibodies. Nature 316:820
Meador J, Sweet P, Stupecky M, Wetzel M, Murray S, Gupta S, Slater LM (1987) Enhancement by cyclosporin A of daunorubicin efficacy in Ehrlich ascites carcinoma and murine hepatoma 129. Cancer Res 47:6216
Naito M, Tsuruo T (1989) Competitive inhibition by verapamil of ATP-dependent high-affinity vincristine binding to the plasma membrane of multidrug-resistant K562 cells without calcium ion involvement. Cancer Res 49:1452
Reeve JG, Rabbitts PH, Twentyman PR (1989) Amplification and expression of mdr-l gene in a multidrug resistant variant of small-cell lung cancer line NCI-H69. Br J Cancer 60:339
Rockwell SC, Kallman RF, Fajardo LF (1972) Characteristics of a serially transplanted mouse mammary tumor and its tissue-cultureadapted derivative. J Natl Cancer Inst 49:735
Safa AR, Glover CJ, Sewell JL, Meyers MB, Biedler JL, Felsted RL (1987) Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers. J Biol Chem 262:7884
Silbermann MH, Boersma AWM, Janssen ALW, Scheper RJ, Herweijer H, Nooter K (1989) Effects of cyclosporin A and verapamil on the intracellular daunorubicin accumulation in Chinese hamster ovary cells with increasing levels of drug resistance. Int J Cancer 44:722
Slater LM, Sweet P, Stupecky M, Gupta S (1986) Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J Clin Invest 77:1405
Sonneveld P, Nooter K (1990) Reversal of drug resistance by cyclosporin A in a patient with acute myelocytic leukaemia. Br J Haematol 75:208
Tsuruo T, Iida H, Kitatani V, Yokota K, Tsukagoshi S, Sakurai Y (1984) Effect of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and Adriamycin in drug-resistant tumour cell lines. Cancer Res 44:4303
Twentyman PR (1980) Response to chemotherapy of EMT6 spheroids as measured by growth delay and cell survival. Br J Cancer 42:297
Twentyman PR, Fox NE, White DJG (1987) Cyclosporin A and its analogues as modifiers of Adriamycin and vincristine resistance in a multi-drug resistant human lung cancer cell line. Br J Cancer 56:55
Twentyman PR, Reeve JG, Koch G, Wright KA (1990) Chemosensitisation by verapamil and cyclosporin A in mouse tumour cells expressing different levels of P-glycoprotein and CP22 (sorcin). Br J Cancer 62:89
About this article
Cite this article
Twentyman, P.R., Wright, K.A. Chemosensitisation of a drug-sensitive parental cell line by low-dose cyclosporin A. Cancer Chemother. Pharmacol. 29, 24–28 (1991). https://doi.org/10.1007/BF00686331
- Parent Cell Line