Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Wang, Zhipeng; Tan, Jiao; McConville, Christopher; Kannappan, Vinodh; Tawari, Patricia Erebi; Brown, James; Ding, Jin; Armesilla, Angel L.; Irache, Juan M.; Mei, Qi-Bing; Tan, Yuhuan; Liu, Ying; Jiang, Wenguo; Bian, Xiu-Wu; Wang, Weiguang (2017)
Publisher: Elsevier
Journal: Nanomedicine
Languages: English
Types: Article
Subjects: RC0254, Medicine (miscellaneous), PLGA, Pharmaceutical Science, Biomedical Engineering, Disulfiram, Drug delivery, Drug repositioning, Bioengineering, Materials Science(all), Original Article, Molecular Medicine, Liver cancer, Nano-technology, RM, Cancer stem cells

Classified by OpenAIRE into

mesheuropmc: technology, industry, and agriculture, macromolecular substances
Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2 minutes to 7 hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver cancer stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU or Sorafenib. It also demonstrated very promising anticancer efficacy and antimetastatic effect in liver cancer mouse model. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into liver cancer treatment.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. Clin 2014;64:9-29.
    • 2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. Clin 2011;61:69-90.
    • 3. Asghar U, Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol 2012;56:686-95.
    • 4. Kane RC, Farrell AT, Madabushi R, Booth B, Chattopadhyay S, Sridhara R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist 2009;14:95-100.
    • 5. Kitisin K, Shetty K, Mishra L, Johnson LB. Hepatocellular stem cells. Cancer Biomark 2007;3:251-62.
    • 6. Liu P, Wang Z, Brown S, Kannappan V, Tawari PE, Jiang J, et al. Liposome encapsulated disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo. Oncotarget 2014;5:7471-85.
    • 7. Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest 2013;123:1911-8.
    • 8. Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 2004;3:673-83.
    • 9. Schreck R, Meier B, Mannel DN, Droge W, Baeuerle PA. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 1992;175:1181-94.
    • 10. Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL, et al. Disulfiram modulated ROS-MAPK and NFkB pathways and targeted breast cancer cells with cancer stem cell like properties. Cancer 2011;104:1564-74.
    • 11. Chen D, Cui QC, Yang H, Dou QP. Disulfiram, a clinically used antialcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res 2006;66:10425-33.
    • 12. Kast RE, Boockvar JA, Bruning A, Cappello F, Chang WW, Cvek B, et al. A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the international initiative for accelerated improvement of glioblastoma care. Oncotarget 2013;4:502-30.
    • 13. Hothi P, Martins TJ, Chen LP, Deleyrolle L, Yoon JG, Reynolds B, et al. High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells. Oncotarget 2012;3:1124-36.
    • 14. Wang W, McLeod HL, Cassidy J. Disulfiram-mediated inhibition of NFkappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Cancer 2003;104:504-11.
    • 15. Guo X, Xu B, Pandey S, Goessl E, Brown J, Armesilla AL, et al. Disulfiram/copper complex inhibiting NFkappaB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines. Cancer Lett 2010;291:104-13.
    • 16. Liu P, Brown S, Goktug T, Channathodiyil P, Kannappan V, Hugnot JP, et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Cancer 2012;107:1488-97.
    • 17. Estey T, Piatigorsky J, Lassen N, Vasiliou V. ALDH3A1: a corneal crystallin with diverse functions. Exp Eye Res 2007;84:3-12.
    • 18. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1:555-67.
    • 19. Agarwal RP, McPherson RA, Phillips M. Rapid degradation of disulfiram by serum albumin. Res Commun Chem Pathol Pharmacol 1983;42:293-310.
    • 20. Cen D, Brayton D, Shahandeh B, Meyskens Jr FL, Farmer PJ. Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. J Med Chem 2004;47:6914-20.
    • 21. Brar SS, Grigg C, Wilson KS, Holder Jr WD, Dreau D, Austin C, et al. Disulfiram inhibits activating transcription factor/cyclic AMPresponsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. Mol Cancer Ther 2004;3:1049-60.
    • 22. Tawari PE, Wang Z, Najlah M, Tsang CW, Kannappan V, Liu P, McConville C, He B, Armesilla AL, Wang W. The cytotoxic mechanisms of disulfiram and copper(II) in cancer cells. Toxicol Res 2015;4:1439-42.
    • 23. D'Autreaux B, Toledano MB. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 2007;8:813-24.
    • 24. Lewis DJ, Deshmukh P, Tedstone AA, Tuna F, O'Brien P. On the interaction of copper(II) with disulfiram. Chem Commun 2014;50:13334-7.
    • 25. Johansson B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr Scand Suppl 1992;369:15-26.
    • 26. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27-55.
    • 27. Singec I, Knoth R, Meyer RP, Maciaczyk J, Volk B, Nikkhah G, et al. Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology. Nat Methods 2006;3:801-6.
    • 28. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc 2006;1:2315-9.
    • 29. Walker I, Newell H. Do molecularly targeted agents in oncology have reduced attrition rates? Nat Rev Drug Discov 2009;8:15-6.
    • 30. Liu P, Kumar IS, Brown S, Kannappan V, Tawari PE, Tang JZ, et al. Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells. Cancer 2013.
    • 31. Safi R, Nelson ER, Chitneni SK, Franz KJ, George DJ, Zalutsky MR, et al. Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res 2014;74:5819-31.
    • 32. Duan L, Shen H, Zhao G, Yang R, Cai X, Zhang L, et al. Inhibitory effect of disulfiram/copper complex on non-small cell lung cancer cells. Biochem Biophys Res Commun 2014;446:1010-6.
    • 33. Wang W. Disulfiram formulation and uses thereof. International Application Published under the Patent Cooperation Treaty (PCT) WO2012/076897 A1; 2012.
    • 34. Agarwal RP, Phillips M, McPherson RA, Hensley P. Serum albumin and the metabolism of disulfiram. Biochem Pharmacol 1986;35:3341-7.
    • 35. Gessner T, Jakubowski M. Diethyldithiocarbamic acid methyl ester. A metabolite of disulfiram. Biochem Pharmacol 1972;21:219-30.
    • 36. Kaslander J. Formation of an S-glucuronide from tetraethylthiuram disulfide (Antabuse) in man. Biochim Biophys Acta 1963;71:730-1.
    • 37. Prickett CS, Johnston CD. The in vivo production of carbon disulfide from tetraethylthiuramdisulfide (antabuse). Biochim Biophys Acta 1953;12:542-6.
    • 38. Zhang XQ, Xu X, Bertrand N, Pridgen E, Swami A, Farokhzad OC. Interactions of nanomaterials and biological systems: implications to personalized nanomedicine. Adv Drug Deliv Rev 2012;64:1363-84.
    • 39. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med 2011;17:313-9.
    • 40. Vaupel P, Hockel M, Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 2007;9:1221-35.
    • 41. Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 2010;7:380-90.
    • 42. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev 2005;5:275-84.
    • 43. Kast RE, Belda-Iniesta C. Suppressing glioblastoma stem cell function by aldehyde dehydrogenase inhibition with chloramphenicol or disulfiram as a new treatment adjunct: an hypothesis. Curr Stem Cell Res Ther 2009;4:314-7.
    • 44. Triscott J, Pambid MR, Dunn SE. Bullseye: targeting cancer stem cells to improve the treatment of gliomas by repurposing disulfiram. Stem Cells 2015;33:1042-6.
    • 45. Wong CC, Kai AK, Ng IO. The impact of hypoxia in hepatocellular carcinoma metastasis. Front Med 2014;8:33-41.
    • 46. Sampieri K, Fodde R. Cancer stem cells and metastasis. Semin Cancer Biol 2012;22:187-93.
    • 47. Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002;235:373-82.
    • 48. Zhang C, Rao J, Tu Z, Ni Y. Surgical resection of resectable thoracic metastatic hepatocellular carcinoma after liver transplantation. J Thorac Cardiovasc Surg 2009;138:240-1.
    • 49. Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol 2003;38(Suppl 1):S136-49.
    • 50. Bruix J, Sherman M, Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005;42:1208-36.
  • No similar publications.

Share - Bookmark

Cite this article