Repurposing itraconazole for the treatment of cancer (Review)

Pounds,Rachel; Leonard,Sarah; Dawson,Christopher; Kehoe,Sean

doi:10.3892/ol.2017.6569

Repurposing itraconazole for the treatment of cancer (Review)

Authors:
- Rachel Pounds
- Sarah Leonard
- Christopher Dawson
- Sean Kehoe
View Affiliations

Affiliations: Obstetrics and Gynaecology Department, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Published online on: July 10, 2017 https://doi.org/10.3892/ol.2017.6569
Pages: 2587-2597

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Abstract

The repurposing of drugs is becoming increasingly attractive as it avoids the lengthy process and cost implications associated with bringing a novel drug to market. Itraconazole is a broad‑spectrum anti‑fungal agent. An emerging body of in vivo, in vitro and clinical evidence have confirmed that it also possesses antineoplastic activities and has a synergistic action when combined with other chemotherapeutic agents. It acts via several mechanisms to prevent tumour growth, including inhibition of the Hedgehog pathway, prevention of angiogenesis, decreased endothelial cell proliferation, cell cycle arrest and induction of auto‑phagocytosis. These allow itraconazole, either alone or in combination with other cytotoxic agents, to increase drug efficacy and overcome drug resistance. This study reviews the reported literature on the use of itraconazole in a variety of malignancies and highlights the recent insights into the critical pathways acted upon to prevent tumour growth.

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1	Chong CR and Sullivan DJ Jr: New uses for old drugs. Nature. 448:645–646. 2007. View Article : Google Scholar : PubMed/NCBI
2	Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP and Vikas P: The repurposing drugs in oncology (ReDO) project. Ecancermedicalscience. 8:4422014. View Article : Google Scholar : PubMed/NCBI
3	DiMasi JA, Hansen RW and Grabowski HG: The price of innovation: New estimates of drug development costs. J Health Econ. 22:151–185. 2003. View Article : Google Scholar : PubMed/NCBI
4	Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, et al: Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 17:388–399. 2010. View Article : Google Scholar : PubMed/NCBI
5	Navec BA, Grassi P, Dell A, Haslam SM and Liu JO: The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signalling in endothelial cells. J Biol Chem. 286:44045–44056. 2011. View Article : Google Scholar : PubMed/NCBI
6	Kim DJ, Kim J, Spaunhurst K, Montoya J, Khodosh R, Chandra K, Fu T, Gilliam A, Molgo M, Beachy PA and Tang JY: Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol. 32:745–751. 2014. View Article : Google Scholar : PubMed/NCBI
7	Wang Y, Yao Y, Liu H, Ma X, Lv T, Yuan D, Xiao X, Yin J and Song Y: Itraconazole can inhibit malignant pleural effusion by suppressing lymphangiogenesis in mice. Transl Lung Cancer Res. 4:27–35. 2015.PubMed/NCBI
8	Aftab BT, Dobromilskaya I, Liu JO and Rudin CM: Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer. Cancer Res. 71:6764–6772. 2011. View Article : Google Scholar : PubMed/NCBI
9	Pantziarka P, Sukhatme V, Bouche G, Meheus L and Sukhatme VP: Repurposing drugs in oncology (ReDO)-itraconazole as an anti-cancer agent. Ecancermedicalscience. 9:5212015. View Article : Google Scholar : PubMed/NCBI
10	Lockhart NR, Waddell JA and Schrock NE: Itraconazole therapy in a pancreatic adenocarcinoma patient: A case report. J Oncol Pharm Pract. 22:528–532. 2016. View Article : Google Scholar : PubMed/NCBI
11	Dirix L: Discovery and exploitation of novel targets by approved drugs. J Clin Oncol. 32:720–721. 2014. View Article : Google Scholar : PubMed/NCBI
12	Pace JR, DeBerardinis AM, Sail V, Tacheva-Grigorova SK, Chan KA, Tran R, Raccuia DS, Wechsler-Reya RJ and Hadden MK: Repurposing the clinically efficacious antifungal agent itraconazole as an anticancer chemotherapeutic. J Med Chem. 59:3635–3649. 2016. View Article : Google Scholar : PubMed/NCBI
13	You M, Varona-Santos J, Singh S, Robbins DJ, Savaraj N and Nguyen DM: Targeting the hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro. J Thorac Cardiovasc Surg. 147:508–516. 2014. View Article : Google Scholar : PubMed/NCBI
14	Kast RE, Karpel-Massler G and Halatsch ME: CUSP9* treatment protocol for recurrent glioblastoma: Aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget. 5:8052–8082. 2014. View Article : Google Scholar : PubMed/NCBI
15	Inoue K, Tsubamoto H, Sakata K, Sakane R, Hao H, Hirota S, Sonoda T and Shibahara H: Expression of hedgehog signals and growth inhibition by itraconazole in endometrial cancer. Anticancer Res. 36:149–153. 2016.PubMed/NCBI
16	Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, Kim J, Chen B, King EM, Borodovsky A, et al: Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 23:23–34. 2013. View Article : Google Scholar : PubMed/NCBI
17	Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ Jr and Liu JO: Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol. 2:263–270. 2007. View Article : Google Scholar : PubMed/NCBI
18	Rudin CM, Brahmer JR, Juergens RA, Hann CL, Ettinger DS, Sebree R, Smith R, Aftab BT, Huang P and Liu JO: Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small cell lung cancer. J Thorac Oncol. 8:619–623. 2013. View Article : Google Scholar : PubMed/NCBI
19	Tsubamoto H, Sonoda T, Yamasaki M and Inoue K: Impact of combination chemotherapy with itraconazole on survival for patients with recurrent or persistent ovarian clear cell carcinoma. Anticancer Res. 34:2007–2014. 2014.PubMed/NCBI
20	Takara K, Tanigawara Y, Komada F, Nishiguchi K, Sakaeda T and Okumura K: Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs. Biol Pharm Bull. 22:1355–1359. 1999. View Article : Google Scholar : PubMed/NCBI
21	Gupta A, Unadkat JD and Mao Q: Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP). J Pharm Sci. 96:3226–3235. 2007. View Article : Google Scholar : PubMed/NCBI
22	Kurosawa M, Okabe M, Hara N, Kawamura K, Suzuki S, Sakurada K and Asaka M: Reversal effect of itraconazole on adriamycin and etoposide resistance in human leukemia cells. Ann Hematol. 72:17–21. 1996. View Article : Google Scholar : PubMed/NCBI
23	Tsubamoto H, Sonoda T, Yamasaki M and Inoue K: Impact of combination chemotherapy with itraconazole on survival of patients with refractory ovarian cancer. Anticancer Res. 34:2481–2487. 2014.PubMed/NCBI
24	Antonarakis ES, Heath EI, Smith DC, Rathkopf D, Blackford AL, Danila DC, King S, Frost A, Ajiboye AS, Zhao M, et al: Repurposing itraconazole as a treatment for advanced prostate cancer: A noncomparative randomised phase II trial in men with metastatic castration-resistant prostate cancer. Oncologist. 18:163–173. 2013. View Article : Google Scholar : PubMed/NCBI
25	Suzman DL and Antonarakis ES: High-dose itraconazole as a noncastrating therapy for a patient with biochemically recurrent prostate cancer. Clin Genitourin Cancer. 12:e51–e53. 2014. View Article : Google Scholar : PubMed/NCBI
26	Ademuyiwa FO, Zhao Q, Perkins SM, Gebregziabher N, Jones DR, Vaughn LG, Sledge GW and Miller K: A pilot trial of itraconazole pharmacokinetics in patients with metastatic breast cancer. J Clin Oncol. 29:(15 Suppl). e135652011. View Article : Google Scholar
27	Tsubamoto H, Sonoda T and Inoue K: Impact of itraconazole on the survival of heavily pre-treated patients with triple-negative breast cancer. Anticancer Res. 34:3839–3844. 2014.PubMed/NCBI
28	Wahid M, Jawed A, Mandal RK, Dar SA, Khan S, Akhter N and Haque S: Vismodegib, itraconazole and sonidegib as hedgehog pathway inhibitors and their relative competencies in the treatment of basal cell carcinomas. Crit Rev Oncol Hematol. 98:235–241. 2016. View Article : Google Scholar : PubMed/NCBI
29	Ally MS, Ransohoff K, Sarin K, Atwood SX, Rezaee M, Bailey-Healy I, Kim J, Beachy PA, Chang AL, Oro A, et al: Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma. JAMA Dermatol. 152:452–456. 2016. View Article : Google Scholar : PubMed/NCBI
30	Tsubamoto H, Sonoda T, Ikuta S, Tani S, Inoue K and Yamanaka N: Combination chemotherapy with itraconazole for treating metastatic pancreatic cancer in the second-line or additional setting. Anticancer Res. 35:4191–4196. 2015.PubMed/NCBI
31	Tsubamoto H, Sonoda T, Ikuta S, Tani S, Inoue K and Yamanaka N: Impact of itraconazole after first-line chemotherapy on survival of patients with metastatic biliary tract cancer. Anticancer Res. 35:4923–4927. 2015.PubMed/NCBI
32	Cooper SM, Sheridan A and Burge S: Mycosis fungoides responding to systemic itraconazole. J Eur Acad Dermatol Venereol. 17:588–590. 2003. View Article : Google Scholar : PubMed/NCBI
33	Vreugdenhil G, Raemaekers JM, van Dijke BJ and de Pauw BE: Itraconazole and multidrug resistance: Possible effects on remission rate and disease-free survival in acute leukaemia. Ann Haematol. 67:107–109. 1993. View Article : Google Scholar
34	Kalderon D: Transducing the hedgehog signal. Cell. 103:371–374. 2000. View Article : Google Scholar : PubMed/NCBI
35	di Pasca Magliano M and Hebrok M: Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 3:903–911. 2003. View Article : Google Scholar : PubMed/NCBI
36	Ruiz i Altaba A, Sánchez P and Dahmane N: Gli and hedgehog in cancer: Tumours, embryos and stem cells. Nat Rev Cancer. 2:361–372. 2002. View Article : Google Scholar : PubMed/NCBI
37	Stecca B, Ruiz I and Altaba A: Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J Mol Cell Biol. 2:84–95. 2010. View Article : Google Scholar : PubMed/NCBI
38	Rimkus TK, Carpenter RL, Qasem S, Chan M and Lo HW: Targeting the sonic hedgehog signaling pathway: Review of smoothened and GLI inhibitors. Cancers (Basel). 8:pii: E22. 2016. View Article : Google Scholar : PubMed/NCBI
39	Sekulic A and Von Hoff D: Hedgehog pathway inhibition. Cell. 164:8312016. View Article : Google Scholar : PubMed/NCBI
40	Sarkar S, Goldgar S, Byler S, Rosenthal S and Heerboth S: Demethylation and re-expression of epigenetically silenced tumor suppressor genes: Sensitization of cancer cells by combination therapy. Epigenomics. 5:87–94. 2013. View Article : Google Scholar : PubMed/NCBI
41	Callaghan R, Luk F and Bebawy M: Inhibition of the multidrug resistance P-glycoprotein: Time for a change of strategy? Drug Metab Dispos. 42:623–631. 2014. View Article : Google Scholar : PubMed/NCBI
42	Undevia SD, Gomez-Abuin G and Ratain MJ: Pharmacokinetic variability of anticancer agents. Nat Rev Cancer. 5:447–458. 2005. View Article : Google Scholar : PubMed/NCBI
43	Itamochi H, Kigawa J, Sultana H, Iba T, Akeshima R, Kamazawa S, Kanamori Y and Terakawa N: Sensitivity to anticancer agents and resistance mechanisms in clear cell carcinoma of the ovary. Jpn J Cancer Res. 93:723–728. 2002. View Article : Google Scholar : PubMed/NCBI
44	Maringe C, Walters S, Butler J, Coleman MP, Hacker N, Hanna L, Mosgaard BJ, Nordin A, Rosen B, Engholm G, et al: Stage at diagnosis and ovarian cancer survival: Evidence from the international cancer benchmarking partnership. Gynecol Oncol. 127:75–82. 2012. View Article : Google Scholar : PubMed/NCBI
45	Cancer research UK cancer statistics, ovarian cancer survival statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ovarian-cancer#heading-TwoAccessed. April;2017.
46	Perez RP, Hamilton TC, Ozols RF and Young RC: Mechanisms and modulation of resistance to chemotherapy in ovarian cancer. Cancer. 71:(4 Suppl). S1571–S1580. 1993. View Article : Google Scholar
47	Yoshino K, Enomoto T, Fujita M, Ueda Y and Kimura T, Kobayashi E, Tsutsui T and Kimura T: Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: A single-institution experience for a series of 20 patients. Int J Clin Oncol. 18:148–153. 2013. View Article : Google Scholar : PubMed/NCBI
48	Kajiyama H, Shibata K, Mizuno M, Yamamoto E, Fujiwara S, Umezu T, Suzuki S, Nakanishi T, Nagasaka T and Kikkawa F: Postrecurrent oncologic outcome of patients with ovarian clear cell carcinoma. Int J Gynecol Cancer. 22:801–806. 2012. View Article : Google Scholar : PubMed/NCBI
49	Tsubaoto H, Ito Y, Kanazawa R, Wada R, Hosoda Y, Honda O, Takeyama R, Sakane R, Wakimoto Y and Shibahara H: Benefit of palliative chemotherapy and hospice enrolment in late-stage ovarian cancer patients. J Obstet Gynaecol Res. 40:1399–1406. 2014. View Article : Google Scholar : PubMed/NCBI
50	Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 351:1502–1512. 2004. View Article : Google Scholar : PubMed/NCBI
51	Brufsky A, Valero V, Tiangco B, Dakhil S, Brize A, Rugo HS, Rivera R, Duenne A, Bousfoul N and Yardley DA: Second-line bevacizumab-containing therapy in patients with triple-negative breast cancer: Subgroup analysis of the RIBBON-2 trial. Breast Cancer Res Treat. 133:1067–1075. 2012. View Article : Google Scholar : PubMed/NCBI
52	Staudacher L, Cottu PH, Diéras V, Vincent-Salomon A, Guilhaume MN, Escalup L, Dorval T, Beuzeboc P, Mignot L and Pierga JY: Platinum-based chemotherapy in metastatic triple-negative breast cancer: The institut curie experience. Ann Oncol. 22:848–856. 2011. View Article : Google Scholar : PubMed/NCBI
53	Liu M, Mo QG, Wei CY, Qin QH, Huang Z and He J: Platinum-based chemotherapy in triple-negative breast cancer: A meta-analysis. Oncol Lett. 5:983–991. 2013.PubMed/NCBI
54	American cancer society, . cancer facts and figures 201s. 2016 https://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdfAccessed. April;2017.
55	Miller DL and Weinstock MA: Nonmelanoma skin cancer in the United States: Incidence. J Am Acad Dermatol. 30:774–778. 1994. View Article : Google Scholar : PubMed/NCBI
56	Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, et al: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 366:2171–2179. 2012. View Article : Google Scholar : PubMed/NCBI
57	Pivotal data for Novartis' investigational compound LDE225 show marked tumor responses in advanced basal cell carcinoma. 2014 http://www.oncotrends.de/pivotal-data-for-novartis-investigational-compound-lde225-sonidegib-show-marked-tumor-responses-in-advanced-basal-cell-carcinoma-422202Accessed. April;2017.
58	Migden MR, Guminski AD, Gutzmer R, Dirix LY, Lewis KD, Combemale P, Herd R, Gogov S, Yi T, Mone M, et al: Randomized, double-blind study of sonidegib (LDE225) in patients (pts) with locally advanced (La) or metastatic basal-cell carcinoma (BCC). J Clin Oncol. 32:5s2014.
59	Rahma OE, Duffy A, Liewehr DJ, Steinberg SM and Greten TF: Second-line treatment in advanced pancreatic cancer: A comprehensive analysis of published clinical trials. Ann Oncol. 24:1972–1979. 2013. View Article : Google Scholar : PubMed/NCBI
60	Patel T: Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 33:1353–1357. 2001. View Article : Google Scholar : PubMed/NCBI
61	Lamarca A, Hubner RA, David Ryder W and Valle JW: Second-line chemotherapy in advanced biliary cancer: A systematic review. Ann Oncol. 25:2328–2338. 2014. View Article : Google Scholar : PubMed/NCBI
62	Vreugdenhil G, Van Dijke BJ, Donnelly JP, Novakova IR, Raemaekers JM, Hoogkamp-Korstanje MA, Koster M and de Pauw BE: Efficacy of itraconazole in the prevention of fungal infections among neutropenic patients with hematologic malignancies and intensive chemotherapy. A double blind, placebo controlled study. Leuk Lymphoma. 11:353–358. 1993. View Article : Google Scholar : PubMed/NCBI
63	Gupta S, Kim J and Gollapudi S: Reversal of daunorubicin resistance in P388/ADR cells by itraconazole. J Clin Invest. 87:1467–1469. 1991. View Article : Google Scholar : PubMed/NCBI