1. The Global Cancer Observatory: International Agency for Research on Cancer, World Health Organization; 2018. [Available from: https://gco.iarc.fr/].
2. Stenzl, A., Cowan, N. C., De Santis, M., Kuczyk, M. A., Merseburger, A. S., Ribal, M. J. et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur. Urol. 59, 1009–1018 (2011).
3. Bellmunt, J., de Wit, R., Vaughn, D. J., Fradet, Y., Lee, J. L., Fong, L. et al. Pem- brolizumab as second-line therapy for advanced urothelial carcinoma. New Engl. J. Med. 376, 1015–1026 (2017).
4. von der Maase, H., Sengelov, L., Roberts, J. T., Ricci, S., Dogliotti, L., Oliver, T. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 23, 4602–4608 (2005).
5. Corbett, A., Pickett, J., Burns, A., Corcoran, J., Dunnett, S. B., Edison, P. et al. Drug repositioning for Alzheimer's disease. Nat. Rev. Drug Discov. 11, 833–846 (2012).
6. Ma, Y., Yu, W. D., Trump, D. L. & Johnson, C. S. 1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models. Cancer 116, 3294–3303 (2010).
7. Kobayashi, T., Inoue, T., Shimizu, Y., Terada, N., Maeno, A., Kajita, Y. et al. Activation of Rac1 is closely related to androgen-independent cell proliferation of prostate cancer cells both in vitro and in vivo. Mol. Endocrinol. 24, 722–734 (2010).
8. Matsui, Y., Ueda, S., Watanabe, J., Kuwabara, I., Ogawa, O. & Nishiyama, H. Sen- sitizing effect of galectin-7 in urothelial cancer to cisplatin through the accu- mulation of intracellular reactive oxygen species. Cancer Res. 67, 1212–1220 (2007).
9. Terada, N., Shimizu, Y., Kamba, T., Inoue, T., Maeno, A., Kobayashi, T. et al. Identification of EP4 as a potential target for the treatment of castration- resistant prostate cancer using a novel xenograft model. Cancer Res. 70, 1606–1615 (2010).
10. Inoue, T., Terada, N., Kobayashi, T. & Ogawa, O. Patient-derived xenografts as in vivo models for research in urological malignancies. Nat. Rev. Urol. 14, 267–283 (2017).
11. Song, W., Tang, Z., Shen, N., Yu, H., Jia, Y., Zhang, D. et al. Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance. J. Controlled Release 231, 94–102 (2016).
12. Yoshida, T., Okuyama, H., Endo, H. & Inoue, M. Spheroid cultures of primary urothelial cancer cells: cancer tissue-originated spheroid (CTOS) method. Methods Mol. Biol. 1655, 145–153 (2018).
13. Chou, T. C. & Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzym. Regul. 22, 27–55 (1984).
14. Chaney, S. G., Campbell, S. L., Temple, B., Bassett, E., Wu, Y. & Faldu, M. Protein interactions with platinum-DNA adducts: from structure to function. J. Inorg. Biochem. 98, 1551–1559 (2004).
15. Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 7, 573–584 (2007).
16. Benhar, M., Dalyot, I., Engelberg, D. & Levitzki, A. Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol. Cell. Biol. 21, 6913–6926 (2001).
17. Ishida, S., Lee, J., Thiele, D. J. & Herskowitz, I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc. Natl Acad. Sci. USA 99, 14298–14302 (2002).
18. Katano, K., Kondo, A., Safaei, R., Holzer, A., Samimi, G., Mishima, M. et al. Acqui- sition of resistance to cisplatin is accompanied by changes in the cellular phar- macology of copper. Cancer Res. 62, 6559–6565 (2002).
19. Safaei, R., Holzer, A. K., Katano, K., Samimi, G. & Howell, S. B. The role of copper transporters in the development of resistance to Pt drugs. J. Inorg. Biochem. 98, 1607–1613 (2004).
20. Samimi, G., Katano, K., Holzer, A. K., Safaei, R. & Howell, S. B. Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Mol. Pharmacol. 66, 25–32 (2004).
21. Holzer, A. K., Manorek, G. H. & Howell, S. B. Contribution of the major copper influx transporter CTR1 to the cellular accumulation of cisplatin, carboplatin, and oxaliplatin. Mol. Pharmacol. 70, 1390–1394 (2006).
22. Kalayda, G. V., Wagner, C. H., Buss, I., Reedijk, J. & Jaehde, U. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resis- tance in human ovarian carcinoma cells. BMC Cancer 8, 175 (2008).
23. Samimi, G., Safaei, R., Katano, K., Holzer, A. K., Rochdi, M., Tomioka, M. et al. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Cancer Res. 10, 4661–4669 (2004).
24. Meeks, J. J., Bellmunt, J., Bochner, B. H., Clarke, N. W., Daneshmand, S., Galsky, M. D. et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur. Urol. 62, 523–533 (2012).
25. Johansson, B. A review of the pharmacokinetics and pharmacodynamics of dis- ulfiram and its metabolites. Acta Psychiatr. Scandinavica Supplementum. 369, 15–26 (1992).
26. Lee, S. H., Hu, W., Matulay, J. T., Silva, M. V., Owczarek, T. B., Kim, K. et al. Tumor evolution and drug response in patient-derived organoid models of bladder cancer. Cell 173, 515–28.e17 (2018).
27. Okuyama, H., Yoshida, T., Endo, H., Nakayama, M., Nonomura, N., Nishimura, K. et al. Involvement of heregulin/HER3 in the primary culture of human urothelial cancer. J. Urol. 190, 302–310 (2013).
28. Abe, T., Tada, M., Shinohara, N., Okada, F., Itoh, T., Hamada, J. et al. Establishment and characterization of human urothelial cancer xenografts in severe combined immunodeficient mice. Int. J. Urol. 13, 47–57 (2006).
29. Zargar, H., Shah, J. B., van Rhijn, B. W., Daneshmand, S., Bivalacqua, T. J., Spiess, P. E. et al. Neoadjuvant dose dense MVAC versus gemcitabine and cisplatin in patients with cT3-4aN0M0 bladder cancer treated with radical cystectomy. J. Urol. 199, 1452–1458 (2018).
30. Van Allen, E. M., Mouw, K. W., Kim, P., Iyer, G., Wagle, N., Al-Ahmadie, H. et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 4, 1140–1153 (2014).
31. Plimack, E. R., Dunbrack, R. L., Brennan, T. A., Andrake, M. D., Zhou, Y., Serebriiskii, I. G. et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin- based chemotherapy in muscle-invasive bladder cancer. Eur. Urol. 68, 959–967 (2015).
32. Iyer, G., Balar, A. V., Milowsky, M. I., Bochner, B. H., Dalbagni, G., Donat, S. M. et al. Multicenter prospective phase II trial of neoadjuvant dose-dense gemcitabine plus cisplatin in patients with muscle-invasive bladder cancer. J. Clin. Oncol. 36, 1949–1956 (2018).
33. Iljin, K., Ketola, K., Vainio, P., Halonen, P., Kohonen, P., Fey, V. et al. High- throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin. Cancer Res. 15, 6070–6078 (2009).
34. Irving, C. C., Tice, A. J. & Murphy, W. M. Inhibition of N-n-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder cancer in rats by administration of dis- ulfiram in the diet. Cancer Res. 39, 3040–3043 (1979).
35. Chen, D., Cui, Q. C., Yang, H. & Dou, Q. P. Disulfiram, a clinically used anti- alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 66, 10425–10433 (2006).
36. Zha, J., Chen, F., Dong, H., Shi, P., Yao, Y., Zhang, Y. et al. Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition. J. Transl. Med. 12, 163 (2014).
37. Safi, R., Nelson, E. R., Chitneni, S. K., Franz, K. J., George, D. J., Zalutsky, M. R. et al. Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 74, 5819–5831 (2014).
38. Liu, P., Wang, Z., Brown, S., Kannappan, V., Tawari, P. E., Jiang, W. et al. Liposome encapsulated Disulfiram inhibits NFkappaB pathway and targets breast cancer stem cells in vitro and in vivo. Oncotarget 5, 7471–7485 (2014).
39. Skrott, Z., Mistrik, M., Andersen, K. K., Friis, S., Majera, D., Gursky, J. et al. Alcohol- abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature 552, 194–199 (2017).
40. Dufour, P., Lang, J. M., Giron, C., Duclos, B., Haehnel, P., Jaeck, D. et al. Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study. Biotherapy (Dordr., Neth.). 6, 9–12 (1993).
41. Lun, X., Wells, J. C., Grinshtein, N., King, J. C., Hao, X., Dang, N. H. et al. Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma. Clin. Cancer Res. 22, 3860–3875 (2016).
42. Lovborg, H., Oberg, F., Rickardson, L., Gullbo, J., Nygren, P. & Larsson, R. Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram. Int. J. Cancer J. Int. du Cancer 118, 1577–1580 (2006).
43. Allensworth, J. L., Evans, M. K., Bertucci, F., Aldrich, A. J., Festa, R. A., Finetti, P. et al. Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxi- dative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol. Oncol. 9, 1155–1168 (2015).
44. Peer, D., Karp, J. M., Hong, S., Farokhzad, O. C., Margalit, R. & Langer, R. Nano- carriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).
45. Yang, X. Z., Dou, S., Sun, T. M., Mao, C. Q., Wang, H. X. & Wang, J. Systemic delivery of siRNA with cationic lipid assisted PEG-PLA nanoparticles for cancer therapy. J. Controlled Release 156, 203–211 (2011).
46. Song, W., Tang, Z., Lei, T., Wen, X., Wang, G., Zhang, D. et al. Stable loading and delivery of disulfiram with mPEG-PLGA/PCL mixed nanoparticles for tumor therapy. Nanomedicine: NBM 12, 377–386 (2015).
47. Wang, Z., Tan, J., McConville, C., Kannappan, V., Tawari, P. E., Brown, J. et al. Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem- like cells. Nanomedicine: NBM 13, 641–657 (2016).
48. Zhang, B., Hu, Y. & Pang, Z. Modulating the Tumor Microenvironment to Enhance Tumor Nanomedicine Delivery. Front. Pharmacol. 8, 952 (2017).
49. Fiandra, L., Mazzucchelli, S., De Palma, C., Colombo, M., Allevi, R., Sommaruga, S. et al. Assessing the in vivo targeting efficiency of multifunctional nanoconstructs bearing antibody-derived ligands. ACS Nano. 7, 6092–6102 (2013).
50. Veldhuis, N. A., Gaeth, A. P., Pearson, R. B., Gabriel, K. & Camakaris, J. The multi- layered regulation of copper translocating P-type ATPases. Biometals: an inter- national journal on the role of metal ions in biology. Biochem., Med. 22, 177–190 (2009).
51. Kurtova, A. V., Xiao, J., Mo, Q., Pazhanisamy, S., Krasnow, R., Lerner, S. P. et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer che- moresistance. Nature 517, 209–213 (2015).
52. Chan, K. S. Molecular pathways: targeting cancer stem cells awakened by che- motherapy to abrogate tumor repopulation. Clin. Cancer Res. 22, 802–806 (2016).