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. 1992 Mar;65(3):335–340. doi: 10.1038/bjc.1992.68

Effects of cyclosporin A and a non-immunosuppressive analogue, O-acetyl cyclosporin A, upon the growth of parent and multidrug resistant human lung cancer cells in vitro.

P R Twentyman 1, K A Wright 1, H M Wallace 1
PMCID: PMC1977618  PMID: 1313690

Abstract

We have studied the ability of cyclosporin A (CsA) and a non-immunosuppressive analogue, O-acetyl cyclosporin A (OACsA, B3-243) to inhibit the growth of human lung cancer cells in vitro. Using continuous drug exposure and the MTT colorimetric assay to determine cell growth we found that CsA produced partial growth inhibition at doses ranging from 0.5 to 3.0 micrograms ml-1 (0.4-2.4 microM). At progressively higher doses, complete growth inhibition and in situ cell lysis were seen. The P-glycoprotein expressing multidrug resistant (MDR) variant H69/LX4 of the small cell line H69/P was less sensitive to cyclosporins than the parent line, but this was not true of the non-P-glycoprotein expressing MDR variants of large cell line COR-L23 or adenocarcinoma line MOR. Sensitivity to OACsA was approximately 2-fold higher than that to CsA in most of the lines although not in the most sensitive line, COR-L88. Even in COR-L88, exposed to CsA or OACsA for 24 h, clonogenic cell survival was reduced only to 50%. There was no reduction in polyamine content of COR-L23 or COR-L88 cells following 48 h of exposure to CsA or OACsA. The effects on cell growth could not be inhibited by the addition of exogenous putrescine, nor could they be enhanced by the addition of alpha-difluoromethylorthinine. It does not appear therefore that inhibition of polyamine synthesis is the basis of the observed growth inhibition.

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Selected References

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  1. Baillie-Johnson H., Twentyman P. R., Fox N. E., Walls G. A., Workman P., Watson J. V., Johnson N., Reeve J. G., Bleehen N. M. Establishment and characterisation of cell lines from patients with lung cancer (predominantly small cell carcinoma). Br J Cancer. 1985 Oct;52(4):495–504. doi: 10.1038/bjc.1985.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Borel J. F., Feurer C., Gubler H. U., Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976 Jul;6(4):468–475. doi: 10.1007/BF01973261. [DOI] [PubMed] [Google Scholar]
  3. Chambers S. K., Hait W. N., Kacinski B. M., Keyes S. R., Handschumacher R. E. Enhancement of anthracycline growth inhibition in parent and multidrug-resistant Chinese hamster ovary cells by cyclosporin A and its analogues. Cancer Res. 1989 Nov 15;49(22):6275–6279. [PubMed] [Google Scholar]
  4. Courtenay V. D., Mills J. An in vitro colony assay for human tumours grown in immune-suppressed mice and treated in vivo with cytotoxic agents. Br J Cancer. 1978 Feb;37(2):261–268. doi: 10.1038/bjc.1978.35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Elliott J. F., Lin Y., Mizel S. B., Bleackley R. C., Harnish D. G., Paetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science. 1984 Dec 21;226(4681):1439–1441. doi: 10.1126/science.6334364. [DOI] [PubMed] [Google Scholar]
  6. Fidelus R. K., Laughter A. H., Twomey J. J., Taffet S. M., Haddox M. K. The effect of cyclosporine on ornithine decarboxylase induction with mitogens, antigens, and lymphokines. Transplantation. 1984 Apr;37(4):383–387. doi: 10.1097/00007890-198404000-00014. [DOI] [PubMed] [Google Scholar]
  7. Foa P., Maiolo A. T., Baldini L., Maisto A., Spano M., Starace G., Quarto di Palo F., Polli E. E. Antiproliferative activity of cyclosporin A on human T-lymphoblastic leukaemia cell line. Lancet. 1981 Apr 11;1(8224):838–838. doi: 10.1016/s0140-6736(81)92712-4. [DOI] [PubMed] [Google Scholar]
  8. Foxwell B. M., Mackie A., Ling V., Ryffel B. Identification of the multidrug resistance-related P-glycoprotein as a cyclosporine binding protein. Mol Pharmacol. 1989 Oct;36(4):543–546. [PubMed] [Google Scholar]
  9. Goldberg H., Ling V., Wong P. Y., Skorecki K. Reduced cyclosporin accumulation in multidrug-resistant cells. Biochem Biophys Res Commun. 1988 Apr 29;152(2):552–558. doi: 10.1016/s0006-291x(88)80073-1. [DOI] [PubMed] [Google Scholar]
  10. Handschumacher R. E., Harding M. W., Rice J., Drugge R. J., Speicher D. W. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984 Nov 2;226(4674):544–547. doi: 10.1126/science.6238408. [DOI] [PubMed] [Google Scholar]
  11. Haynes M., Fuller L., Haynes D. H., Miller J. Cyclosporin partitions into phospholipid vesicles and disrupts membrane architecture. Immunol Lett. 1985;11(5-6):343–349. doi: 10.1016/0165-2478(85)90118-x. [DOI] [PubMed] [Google Scholar]
  12. Hess A. D., Tutschka P. J., Santos G. W. Effect of cyclosporin A on human lymphocyte responses in vitro. II. Induction of specific alloantigen unresponsiveness mediated by a nylon wool adherent suppressor cell. J Immunol. 1981 Mar;126(3):961–968. [PubMed] [Google Scholar]
  13. Jabbar S. A., Twentyman P. R., Watson J. V. The MTT assay underestimates the growth inhibitory effects of interferons. Br J Cancer. 1989 Oct;60(4):523–528. doi: 10.1038/bjc.1989.306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kreis W., Soricelli A. Cyclosporins: immunosuppressive agents with antitumor activity. Experientia. 1979 Nov 15;35(11):1506–1508. doi: 10.1007/BF01962813. [DOI] [PubMed] [Google Scholar]
  15. McLachlan G., Thomson A. W., Wallace H. M. Effects of cyclosporin A on growth and polyamine metabolism of MOLT-4 T-lymphoblastic leukaemia cells. Br J Cancer. 1991 Aug;64(2):255–258. doi: 10.1038/bjc.1991.287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Meador J., Sweet P., Stupecky M., Wetzel M., Murray S., Gupta S., Slater L. Enhancement by cyclosporin A of daunorubicin efficacy in Ehrlich ascites carcinoma and murine hepatoma 129. Cancer Res. 1987 Dec 1;47(23):6216–6219. [PubMed] [Google Scholar]
  17. Moreland A. A., Robertson D. B., Heffner L. T. Treatment of cutaneous T cell lymphoma with cyclosporin A. J Am Acad Dermatol. 1985 May;12(5 Pt 1):886–887. doi: 10.1016/s0190-9622(85)80124-9. [DOI] [PubMed] [Google Scholar]
  18. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  19. Mátyus L., Balázs M., Aszalós A., Mulhern S., Damjanovich S. Cyclosporin A depolarizes cytoplasmic membrane potential and interacts with Ca2+ ionophores. Biochim Biophys Acta. 1986 May 29;886(3):353–360. doi: 10.1016/0167-4889(86)90170-9. [DOI] [PubMed] [Google Scholar]
  20. Prince H. E., John J. K. Cyclosporine inhibits the expression of receptors for interleukin 2 and transferrin on mitogen-activated human T lymphocytes. Immunol Invest. 1986 Aug;15(5):463–472. doi: 10.3109/08820138609054917. [DOI] [PubMed] [Google Scholar]
  21. Puttick L., Pollock A., Fairburn E. Treatment of Sézary syndrome with cyclosporin A. J R Soc Med. 1983 Dec;76(12):1063–1065. doi: 10.1177/014107688307601216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Reeve J. G., Rabbitts P. H., Twentyman P. R. Amplification and expression of mdr1 gene in a multidrug resistant variant of small cell lung cancer cell line NCI-H69. Br J Cancer. 1989 Sep;60(3):339–342. doi: 10.1038/bjc.1989.282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Reeve J. G., Rabbitts P. H., Twentyman P. R. Non-P-glycoprotein-mediated multidrug resistance with reduced EGF receptor expression in a human large cell lung cancer cell line. Br J Cancer. 1990 Jun;61(6):851–855. doi: 10.1038/bjc.1990.190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Saydjari R., Townsend C. M., Jr, Barranco S. C., James E., Thompson J. C. Effects of cyclosporin A and alpha-difluoromethylornithine on the growth of hamster pancreatic cancer in vitro. J Natl Cancer Inst. 1986 Nov;77(5):1087–1092. [PubMed] [Google Scholar]
  25. Saydjari R., Townsend C. M., Jr, Barranco S. C., Thompson J. C. Effects of cyclosporine and alpha-difluoromethylornithine on the growth of mouse colon cancer in vitro. Life Sci. 1987 Jan 26;40(4):359–366. doi: 10.1016/0024-3205(87)90137-8. [DOI] [PubMed] [Google Scholar]
  26. Slater L. M., Sweet P., Stupecky M., Gupta S. Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J Clin Invest. 1986 Apr;77(4):1405–1408. doi: 10.1172/JCI112450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sonneveld P., Nooter K. Reversal of drug-resistance by cyclosporin-A in a patient with acute myelocytic leukaemia. Br J Haematol. 1990 Jun;75(2):208–211. doi: 10.1111/j.1365-2141.1990.tb02650.x. [DOI] [PubMed] [Google Scholar]
  28. Szamel M., Berger P., Resch K. Inhibition of T lymphocyte activation by cyclosporin A: interference with the early activation of plasma membrane phospholipid metabolism. J Immunol. 1986 Jan;136(1):264–269. [PubMed] [Google Scholar]
  29. Tropschug M., Hofmann R. FK506 and protein kinase C. Nature. 1991 May 16;351(6323):195–195. doi: 10.1038/351195a0. [DOI] [PubMed] [Google Scholar]
  30. Twentyman P. R., Fox N. E., White D. J. 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. 1987 Jul;56(1):55–57. doi: 10.1038/bjc.1987.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Twentyman P. R., Fox N. E., Wright K. A., Bleehen N. M. Derivation and preliminary characterisation of adriamycin resistant lines of human lung cancer cells. Br J Cancer. 1986 Apr;53(4):529–537. doi: 10.1038/bjc.1986.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wallace H. M., Gordon A. M., Keir H. M., Pearson C. K. Activation of ADP-ribosyltransferase in polyamine-depleted mammalian cells. Biochem J. 1984 Apr 1;219(1):211–221. doi: 10.1042/bj2190211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wallace H. M., Nuttall M. E., Robinson F. C. Acetylation of spermidine and methylglyoxal bis(guanylhydrazone) in baby-hamster kidney cells (BHK-21/C13). Biochem J. 1988 Jul 1;253(1):223–227. doi: 10.1042/bj2530223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Walls G. A., Twentyman P. R. Cloning of human lung cancer cells. Br J Cancer. 1985 Oct;52(4):505–513. doi: 10.1038/bjc.1985.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yanagihara R. H., Adler W. H. Direct antiproliferative effects of cyclosporin A on murine lymphoreticular tumor cells in culture. J Biol Response Mod. 1983;2(2):121–132. [PubMed] [Google Scholar]

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