Summary: A group of closely related cyclic undecapeptides from the fungi Trichoderma polysporum and Cylindocarpon lucidum. They have some antineoplastic and antifungal action and significant immunosuppressive effects. Cyclosporins have been proposed as adjuvants in tissue and organ transplantation to suppress graft rejection.

Top Publications

  1. ten Tije A, Synold T, Spicer D, Verweij J, Doroshow J, Sparreboom A. Effect of valspodar on the pharmacokinetics of unbound paclitaxel. Invest New Drugs. 2003;21:291-8 pubmed
  2. Gallay P. Cyclophilin inhibitors. Clin Liver Dis. 2009;13:403-17 pubmed publisher
    ..Recent clinical studies demonstrate that Cyp inhibitors are potent anti-HCV drugs, with a novel mechanism of action and efficacy profiles that make them attractive candidates for combination with current and future HCV treatments. ..
  3. Carlson R, O Neill A, Goldstein L, Sikic B, Abramson N, Stewart J, et al. A pilot phase II trial of valspodar modulation of multidrug resistance to paclitaxel in the treatment of metastatic carcinoma of the breast (E1195): a trial of the Eastern Cooperative Oncology Group. Cancer Invest. 2006;24:677-81 pubmed
    ..1-17.3 months). The toxicity experienced was acceptable. Combination valspodar plus paclitaxel is an active regimen and has acceptable toxicity. The combination is not clearly more active than single agent paclitaxel. ..
  4. Loor F, Tiberghien F, Wenandy T, Didier A, Traber R. Cyclosporins: structure-activity relationships for the inhibition of the human FPR1 formylpeptide receptor. J Med Chem. 2002;45:4613-28 pubmed
    ..To establish structure-activity relationships (SAR) for FPR function inhibition, 59 cyclosporins were now studied by this standardized assay (with differentiated human leukemic cell line HL-60 as FPR-..
  5. Fracasso P, Westervelt P, Fears C, Rosen D, Zuhowski E, Cazenave L, et al. Phase I study of paclitaxel in combination with a multidrug resistance modulator, PSC 833 (Valspodar), in refractory malignancies. J Clin Oncol. 2000;18:1124-34 pubmed
    ..The addition of PSC 833 alters the pharmacokinetics of paclitaxel, which explains the enhanced neutropenia experienced by patients treated with this drug combination. ..
  6. Chen G, Duran G, Steger K, Lacayo N, Jaffrezou J, Dumontet C, et al. Multidrug-resistant human sarcoma cells with a mutant P-glycoprotein, altered phenotype, and resistance to cyclosporins. J Biol Chem. 1997;272:5974-82 pubmed
    ..These data suggest that Phe335 is an important binding site on P-glycoprotein for substrates such as dactinomycin and vinblastine and for inhibitors such as cyclosporine and PSC 833. ..
  7. Bates S, Bakke S, Kang M, Robey R, Zhai S, Thambi P, et al. A phase I/II study of infusional vinblastine with the P-glycoprotein antagonist valspodar (PSC 833) in renal cell carcinoma. Clin Cancer Res. 2004;10:4724-33 pubmed
  8. Krishna R, Mayer L. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci. 2000;11:265-83 pubmed
  9. Crompton M, Ellinger H, Costi A. Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J. 1988;255:357-60 pubmed
    ..It is concluded that cyclosporin A is a potent inhibitor of the pore. ..

More Information


  1. Bates S, Kang M, Meadows B, Bakke S, Choyke P, Merino M, et al. A Phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (valspodar). Cancer. 2001;92:1577-90 pubmed
    ..Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies. ..
  2. Angelin A, Tiepolo T, Sabatelli P, Grumati P, Bergamin N, Golfieri C, et al. Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins. Proc Natl Acad Sci U S A. 2007;104:991-6 pubmed
    ..This study represents an essential step toward a pharmacological therapy of Ullrich congenital muscular dystrophy with cyclosporin A and methylAla(3)ethylVal(4) cyclosporin. ..
  3. Chico I, Kang M, Bergan R, Abraham J, Bakke S, Meadows B, et al. Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833. J Clin Oncol. 2001;19:832-42 pubmed
    ..Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs. ..
  4. Moons P, De Geest S, Versteven K, Abraham I, Vlaminck H, Moens G, et al. Psychometric properties of the "Modified Transplant Symptom Occurrence and Symptom Distress Scale". J Nurs Meas. 2001;9:115-34 pubmed
    ..These findings document the validity of the "Modified Transplant Symptom Occurrence and Symptom Distress Scale" as an instrument to measure symptom experience with immunosuppressive drugs. ..
  5. Walter R, Raden B, Hong T, Flowers D, Bernstein I, Linenberger M. Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells. Blood. 2003;102:1466-73 pubmed
    ..Because MK-571 and CSA failed to affect cytotoxicity in a portion of Pgp-positive/MRP-positive AML samples, additional resistance mechanisms are likely important. ..
  6. Fukuda H, Arai M, Soh T, Yamauchi N, Hattori M. Progesterone regulation of the expression and function of multidrug resistance type I in porcine granulosa cells. Reprod Toxicol. 2006;22:62-8 pubmed
    ..Aminoglutethimide suppressed the MDR1 expression and P-gp activity, but which were completely restored by P. These results indicate that P participates in MDR1 expression and P-gp function of granulosa cells. ..
  7. Raggers R, Vogels I, van Meer G. Multidrug-resistance P-glycoprotein (MDR1) secretes platelet-activating factor. Biochem J. 2001;357:859-65 pubmed
    ..While efficient transport of PAF across the apical plasma membrane may be physiologically relevant in MDR1-expressing epithelia, PAF secretion in multidrug-resistant tumours may stimulate angiogenesis and thereby tumour growth...
  8. Ubrich N, Schmidt C, Bodmeier R, Hoffman M, Maincent P. Oral evaluation in rabbits of cyclosporin-loaded Eudragit RS or RL nanoparticles. Int J Pharm. 2005;288:169-75 pubmed
    ..Based on comparison of the area under the blood concentration-time curve values, the relative bioavailability of CyA from each nanoparticulate formulation ranged from 20 to 35%. ..
  9. Baer M, George S, Dodge R, O Loughlin K, Minderman H, Caligiuri M, et al. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002;100:1224-32 pubmed
    ..Moreover, for patients with PSC-833-modulated efflux, median disease-free survival was 5 months with ADE and 14 months with ADEP (P =.07). Further modulation trials in older patients must await the design of less-toxic regimens. ..
  10. Visani G, Milligan D, Leoni F, Chang J, Kelsey S, Marcus R, et al. Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia. Leukemia. 2001;15:764-71 pubmed
    ..In conclusion, the MEC plus PSC 833 tested regimen was well tolerated and the 26% CR rate warrants further testing of this regimen in a randomized, phase III trial. ..
  11. Kankesan J, Vanama R, Yusuf A, Thiessen J, Ling V, Rao P, et al. Effect of PSC 833, an inhibitor of P-glycoprotein on N-methyl-N-nitrosourea induced mammary carcinogenesis in rats. Carcinogenesis. 2004;25:425-30 pubmed
  12. Sakaguchi S, Sakaguchi N. Thymus and autoimmunity. Transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice. J Exp Med. 1988;167:1479-85 pubmed
    ..Thus, CsA appears to interfere selectively with the thymic production of certain suppressor T cells controlling self-reactive (autoimmune) T cells, allowing the latter to expand and cause autoimmune disease. ..
  13. Zhao Y, Ke H. Crystal structure implies that cyclophilin predominantly catalyzes the trans to cis isomerization. Biochemistry. 1996;35:7356-61 pubmed
    ..On the basis of the structure, it is proposed that Arg55 hydrogen-bonds to the nitrogen to deconjugate the resonance of the prolyl amide bond and thus facilitates the cis-trans rotation. ..
  14. Feurer C, Chow L, Borel J. Preventive and therapeutic effects of cyclosporin and valine2-dihydro-cyclosporin in chronic relapsing experimental allergic encephalomyelitis in the Lewis rat. Immunology. 1988;63:219-23 pubmed
    ..We conclude that both drugs, in this model, are beneficial during administration; however, in contrast to CS, (Val2)DH-CS possesses an important, curative action when applied therapeutically. ..
  15. Logan R, Camp R. Severe atopic eczema: response to oral cyclosporin A. J R Soc Med. 1988;81:417-8 pubmed
  16. Neild G, Ivory K, Hiramatsu M, Williams D. Cyclosporin A inhibits acute serum sickness nephritis in rabbits. Clin Exp Immunol. 1983;52:586-94 pubmed
    ..These results show that Cy A inhibits the renal injury of acute serum sickness and indicate that T cells may play a role in mediating the nephritis in this condition. ..
  17. Crowe A, Wong P. Potential roles of P-gp and calcium channels in loperamide and diphenoxylate transport. Toxicol Appl Pharmacol. 2003;193:127-37 pubmed
    ..Additionally, efflux inhibitors had little impact on transport or accumulation, suggesting that diphenoxylate was not a substrate for an efflux mechanism. ..
  18. Matheis K, Com E, Gautier J, Guerreiro N, Brandenburg A, Gmuender H, et al. Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers. Toxicol Appl Pharmacol. 2011;252:112-22 pubmed publisher
    ..The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value. ..
  19. Azare J, Pankova Kholmyansky I, Salnikow K, Cohen D, Flescher E. Selective susceptibility of transformed T lymphocytes to induction of apoptosis by PSC 833, an inhibitor of P-glycoprotein. Oncol Res. 2001;12:315-23 pubmed
    ..In addition, normal lymphocytes are not susceptible to induction of apoptosis by PSC 833. This difference between normal lymphocytes and leukemia cells presents a potential target for chemotherapy. ..
  20. Nadeau K, Das A, Walsh C. Hsp90 chaperonins possess ATPase activity and bind heat shock transcription factors and peptidyl prolyl isomerases. J Biol Chem. 1993;268:1479-87 pubmed
    ..We also detect binding of the other family of PPIases, the cyclophilins, to immobilized hsp90, consistent with a functional convergence of protein foldases. ..
  21. Dorr R, Karanes C, Spier C, Grogan T, Greer J, Moore J, et al. Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia. J Clin Oncol. 2001;19:1589-99 pubmed
    ..Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure. ..
  22. Vautier S, Lacomblez L, Chacun H, Picard V, Gimenez F, Farinotti R, et al. Interactions between the dopamine agonist, bromocriptine and the efflux protein, P-glycoprotein at the blood-brain barrier in the mouse. Eur J Pharm Sci. 2006;27:167-74 pubmed
    ..In vivo, at the mouse BBB level and in our experimental conditions, bromocriptin is a Pgp substrate but is not a Pgp modulator. ..
  23. Sato H, Liu H, Adachi I, Ueno M, Lemaire M, Horikoshi I. Enhancement of the intestinal absorption of a cyclosporine derivative by milk fat globule membrane. Biol Pharm Bull. 1994;17:1526-8 pubmed
    ..Thus, it was suggested that MFGM can be used as an intestinal absorption enhancer of cyclosporines. ..
  24. Nicolas de Prado I, Miras López M, Morán Sánchez S, Mercader Martínez J. [Rhabdomyolisis associated with cerivastatin and cyclosporine combination therapy]. Med Clin (Barc). 2002;118:716-7 pubmed
  25. Lopes E, Scolnik M, Alvarez E, Hajos S. Modulator activity of PSC 833 and cyclosporin-A in vincristine and doxorubicin-selected multidrug resistant murine leukemic cells. Leuk Res. 2001;25:85-93 pubmed
    ..Cross-resistance was found between VCR, DOX and other antineoplasic agents on murine leukemic cell line. VCR was more effective to induce MDR since the resistant cell lines were more stable to the MDR phenotype. ..
  26. Segoloni G. [New immunodepressant drugs for the prevention and control of kidney transplant rejection]. G Ital Nefrol. 2005;22:3-15 pubmed
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    ..We conclude therefore that after BMT the number and phenotype of circulating T cells reflects the T cell distribution seen in the regenerating BM. ..
  28. Karyekar C, Eddington N, Garimella T, Gubbins P, Dowling T. Evaluation of P-glycoprotein-mediated renal drug interactions in an MDR1-MDCK model. Pharmacotherapy. 2003;23:436-42 pubmed
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    ..In conclusion, CsA increased the rate of proliferation of PASMCs, while SDZ IMM 125 induced a weaker effect. Anti-ET-1 antibody, VP, and SDT significantly inhibited CsA-induced PASMC proliferation. ..
  30. Born S, Marsch W. [Postoperative pyoderma gangrenosum]. Chirurg. 2001;72:1043-7 pubmed
    ..The purpose of this paper was to describe the clinical characteristics of pyoderma gangrenosum, its prevention and its therapy. ..
  31. Hoppert M, Gentzsch C, Schörgendorfer K. Structure and localization of cyclosporin synthetase, the key enzyme of cyclosporin biosynthesis in Tolypocladium inflatum. Arch Microbiol. 2001;176:285-93 pubmed
    ..A considerable proportion of cyclosporin synthetase and D-alanine racemase was detected at the vacuolar membrane. The product cyclosporin was localized in the fungal vacuole. ..
  32. Ganten M, Encke J, Flosdorff P, Grüber Hoffmann B, Erb G, Hansmann J. [Follow up of Crohn's disease under therapy with hydro-MRI]. Radiologe. 2003;43:26-33 pubmed
    ..Hydro-MRI is a modality for the evaluation of inflammatory changes in patients with Crohn's disease. Independent from clinical symptoms persistence of Crohn's disease is detectable. ..
  33. Fricker G, Gutmann H, Droulle A, Drewe J, Miller D. Epithelial transport of anthelmintic ivermectin in a novel model of isolated proximal kidney tubules. Pharm Res. 1999;16:1570-5 pubmed
    ..The mechanism of excretion of the anthelmintic drug ivermectin was investigated in a novel experimental model of functionally intact proximal tubules isolated from a teleost fish (Fundulus heteroclitus)...
  34. Ladona M, Spalding D, Ekman L, Linström B, Rane A. Human fetal and adult liver metabolism of ethylmorphine. Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids. Biochem Pharmacol. 1989;38:3147-55 pubmed
    ..These results are of interest in the discussion about the physiological role of the human fetal cytochrome P-450 HLp which has an unprecedented relative abundance in the liver. ..
  35. Dai H, Luo S, Yin A, Peng A. [Reversal of multidrug-resistance in human leukemia cell line K562/A02 by a cyclosporin D analogue PSC 833]. Zhonghua Xue Ye Xue Za Zhi. 2002;23:23-6 pubmed
    ..05). PSC 833 is at least 3 approximately 10 fold more potent than CsA or Ver with respect to MDR reversing activity, and it may function by inhibiting the function of P-gp and not reducing the levels of mdr1 mRNA and P-gp directly. ..
  36. Puyang X, Poulin D, Mathy J, Anderson L, Ma S, Fang Z, et al. Mechanism of resistance of hepatitis C virus replicons to structurally distinct cyclophilin inhibitors. Antimicrob Agents Chemother. 2010;54:1981-7 pubmed publisher
    ..The interaction of cyclophilin with NS5A seems to be the most critical, since the NS5A mutations have the largest impact on resistance. ..
  37. Petroianu A, Alberti L, Vasconcellos L. [Endocrinological, morphological and gestational assessment of intact and sliced ovarian orthotopic reimplantation or transplantation without vascular pedicle]. Rev Assoc Med Bras (1992). 2006;52:447-52 pubmed
    ..Intact or sliced orthotopic allogeneic and autologous ovarian transplantation without a vascular pedicle is viable in rabbits, and preserves their fertility and hormonal functions. ..
  38. Lopes de Menezes D, Hu Y, Mayer L. Combined treatment of Bcl-2 antisense oligodeoxynucleotides (G3139), p-glycoprotein inhibitor (PSC833), and sterically stabilized liposomal doxorubicin suppresses growth of drug-resistant growth of drug-resistant breast cancer in severely combined im. J Exp Ther Oncol. 2003;3:72-82 pubmed
    ..The improved efficacy of this treatment was attributed to Bcl-2 antisense-induced apoptosis, combined with cellular retention of DOX in tumor cells via P-gp blockade. ..
  39. Scorrano L, Petronilli V, Di Lisa F, Bernardi P. Commitment to apoptosis by GD3 ganglioside depends on opening of the mitochondrial permeability transition pore. J Biol Chem. 1999;274:22581-5 pubmed
    ..These results provide compelling evidence that opening of the permeability transition pore is causally related to apoptosis. ..
  40. Thevenod F, Friedmann J, Katsen A, Hauser I. Up-regulation of multidrug resistance P-glycoprotein via nuclear factor-kappaB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis. J Biol Chem. 2000;275:1887-96 pubmed
    ..These data suggest that mdr1 up-regulation, at least in part, provides anti-apoptotic protection for PT cells against cadmium-mediated stress. ..
  41. Mahon F, Belloc F, Lagarde V, Chollet C, Moreau Gaudry F, Reiffers J, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368-73 pubmed
    ..The possible role of MDR overexpression in clinical resistance to imatinib remains to be defined. We therefore confirm that imatinib should be added to the extensive list of drugs that can be affected by the MDR phenomenon. ..
  42. Sorof J, Goldstein S, Brewer E, Steiger H, Portman R. Serial estimation of glomerular filtration rate in children after renal transplant. Pediatr Nephrol. 1999;13:737-41 pubmed
    ..These results are similar to those reported in multi-center studies using the outcome variable of graft failure and suggest that serial eGFR may be valid as an outcome variable to study chronic renal allograft dysfunction in children. ..
  43. Binkhathlan Z, Elhasi S, Brocks D, Lavasanifar A. Characterization of the self assembly of methoxy poly(ethylene oxide)-block-poly(?-benzyl carboxylate-?-caprolactone) for the solubilization and in vivo delivery of valspodar. Curr Drug Deliv. 2012;9:164-71 pubmed
    ..In conclusion, the results show a potential for PEO-b-PBCL nanocarriers as efficient solubilizing agents for delivery of valspodar. ..
  44. Treijtel N, Van Eijkeren J, Nijmeijer S, de Greef van der Sandt I, Freidig A. Clearance and clearance inhibition of the HIV-1 protease inhibitors ritonavir and saquinavir in sandwich-cultured rat hepatocytes and rat microsomes. Toxicol In Vitro. 2009;23:185-93 pubmed publisher
    ..In conclusion, for saquinavir the metabolism rate and the amount of metabolites produced was higher than for ritonavir. Ritonavir had a strong inhibitory effect on the metabolism of saquinavir and seemed to be excreted into the bile. ..
  45. Smith S, Pennline K, Terminelli C, DaFonseca M, Pellerito F, Umland S. Inhibition of graft-vs-host induced immunodeficiency with immunosuppressive therapy. Immunopharmacol Immunotoxicol. 1988;10:545-78 pubmed
  46. Kolitz J, George S, Benson D, Maharry K, Marcucci G, Vij R, et al. Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808. Cancer. 2014;120:1010-7 pubmed publisher
    ..Neither DFS nor OS was found to be significantly improved. ..
  47. van der Holt B, Breems D, Berna Beverloo H, van den Berg E, Burnett A, Sonneveld P, et al. Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value: results from a prospective clinical trial. Br J Haematol. 2007;136:96-105 pubmed
    ..Large studies to confirm the prognosis of individual cytogenetic aberrations are warranted. ..
  48. Lippuner V, Chou I, Scott S, Ettinger W, Theg S, Gasser C. Cloning and characterization of chloroplast and cytosolic forms of cyclophilin from Arabidopsis thaliana. J Biol Chem. 1994;269:7863-8 pubmed
    ..Thus, this activity is not essential for protein import into chloroplasts. ..
  49. Fukushima T, Yamashita T, Takemura H, Suto H, Kishi S, Urasaki Y, et al. Effect of PSC 833 on the cytotoxicity and pharmacodynamics of mitoxantrone in multidrug-resistant K562 cells. Leuk Res. 2000;24:249-54 pubmed
    ..8-fold by 0.4 microM PSC 833, which is a clinically achievable plasma concentration. These results suggest that the combination of PSC 833 with MIT could be a promising treatment in reversing PGP-mediated MDR in leukemia patients. ..
  50. Kankesan J, Yusuf A, Laconi E, Vanama R, Bradley G, Thiessen J, et al. Effect of PSC 833, an inhibitor of P-glycoprotein, on 1,2-dimethylhydrazine-induced liver carcinogenesis in rats. Carcinogenesis. 2003;24:1977-84 pubmed
    ..Taken together the results indicate a possible intrinsic role for Pgp in liver cancer development and introduce another promising unexplored therapeutic approach in liver cancer treatment. ..
  51. Sugiura Y, Sugita Konishi Y, Kumagai S, Reiss E. Experimental murine hyalohyphomycosis with soil-derived isolates of Fusarium solani. Med Mycol. 2003;41:241-7 pubmed
    ..Mouse passage increased the pathogenicity of two soil-derived F. solani strains. ..
  52. Tidefelt U, Liliemark J, Gruber A, Liliemark E, Sundman Engberg B, Juliusson G, et al. P-Glycoprotein inhibitor valspodar (PSC 833) increases the intracellular concentrations of daunorubicin in vivo in patients with P-glycoprotein-positive acute myeloid leukemia. J Clin Oncol. 2000;18:1837-44 pubmed
    ..In the three patients with Pgp-negative leukemia, no significant difference was observed. These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo. ..