Imidazole Antifungals: A Review of Their Action Mechanisms on Cancerous Cells

Abstract

Imidazoles, together with triazoles, constitute azole sub-group of antifungal drugs which acts by inhibiting cytochrome P450-dependent enzyme, the lanosterol 14-α-demethylase. In addition to their primary use, when it comes to additional anti-cancer function, clotrimazole, econazole and ketoconazole have come to the fore among the imidazoles. Based on the findings up to now, although having different effects, disruption of the glycolytic pathway, blockage of Ca2+ influx and nonspecific inhibition of CYP450 enzymes can be regarded as the main ones responsible for the anti-neoplastic activities of the mentioned drugs, respectively. Considering the advantages of repurposing of drugs with known pharmacology compared to new drug development studies requiring labor, time and cost, it will be extremely important and valuable to continue the clarification of the different mechanisms of these antifungals on cancerous cells and benefit from them especially to increase drug efficacy and overcome drug resistance. In this review, the action mechanisms of imidazole antifungals on cancerous cells and consequently, their potential for use in cancer treatment alone or in combination with conventional therapeutics were discussed in detail.

Keywords

• Imidazole Antifungals
• Clotrimazole
• Econazole
• Ketoconazole
• Cancer

References

1. Almutairi, M.S., Manimaran, D., Joe, I.H., Saleh, O.A., Attia, M.I. (2015). Structural properties and biological prediction of ({[(1E)-3-(1H-Imidazol-1-yl)-1-phenylpropylidene]amino}oxy)(4-methylphenyl) methanone: An in silico approach. Symmetry, 8(1), 1.
2. Campoy, S., Adrio, J.L. (2017). Antifungals. Biochem. Pharmacol., 133, 86-96.
3. Sheehan, D.J., Hitchcock, C.A., Sibley, C.M. (1999). Current and emerging azole antifungal agents. Clin. Microbiol. Rev., 12(1), 40-79.
4. Allen, D., Wilson, D., Drew, R., Perfect, J. (2015). Azole antifungals: 35 years of invasive fungal infection management. Expert Rev. Anti-infect. Ther., 13(6), 787-798.
5. Kadavakollu, S., Stailey, C., Kunapareddy, C.S., White, S. (2014). Clotrimazole as a cancer drug: a short review. Med. Chem., 4(11), 722.
6. Sequeira, S.O., Laia, C.A.T., Phillips, A.J.L., Cabrita, E.J., Macedo, M.F. (2017). Clotrimazole and calcium hydroxide nanoparticles: A low toxicity antifungal alternative for paper conservation. J. Cult. Herit., 24, 45-52.
7. Spiekermann, P.H., Young, M.D. (1976). Clinical evaluation of clotrimazole: a broad-spectrum antifungal agent. Arch. Dermatol., 112(3), 350-352.
8. Hegemann, L., Toso, S.M., Lahijani, K.L., Webster, G.F., Uitto, J. (1993). Direct interaction of antifungal azole-derivatives with calmodulin: a possible mechanism for their therapeutic activity. J. Investig. Dermatol., 100(3), 343-346.

9. Stevens, F.C. (1983) Calmodulin: an introduction. Biochem. Cell Biol., 61(8), 906-910.
10. Hidaka, H., Hartshorne, D.J. (1985). Calmodulin Antagonists and Cellular Physiology, Academic: New York.
11. Arnold, H., Pette, D. (1968). Binding of glycolytic enzymes to structure proteins of the muscle. Eur. J. Biochem., 6(2), 163-171.
12. Gots, R.E., Bessman, S.P. (1974). The functional compartmentation of mitochondrial hexokinase. Arch. Biochem. Biophys., 163(1), 7-14.
13. Gots, R.E., Gorin, F.A., Bessman, S.P. (1972). Kinetic enhancement of bound hexokinase activity by mitochondrial respiration. Biochem. Biophys. Res. Commun., 49(5), 1249-1255.
14. Viitanen, P.V., Geiger, P.J., Erickson-Viitanen, S., Bessman, S.P. (1984). Evidence for functional hexokinase compartmentation in rat skeletal muscle mitochondria. J. Biol. Chem., 259(15), 9679-9686.
15. Eigenbrodt, E., Fister, P., Reinacher, M. New Perspectives on Carbohydrate Metabolism in Tumor Cells In: Regulation of Carbohydrate Metabolism, Rivka Beitner, Ed. CRC Press: Boca Raton, 1985, Vol. 2, pp. 141-79.
16. Kottke, M., Adam, V., Riesinger, I., Bremm, G., Bosch, W., Brdiczka, D., Sandri, G., Panfili, E. (1988). Mitochondrial boundary membrane contact sites in brain: points of hexokinase and creatine kinase location, and control of Ca2+ transport. Biochim. Biophys. Acta-Bioenerg., 935(1), 87-102.
17. Feichter, A., Gmunder, FK. Metabolic control of glucose degradation in yeast and tumor cells. (1989). Adv. Biochem. Eng. Biotechnol., 39, 1–28.
18. Beckner, M.E., Stracke, M.L., Liotta, L.A., Schiffmann, E. (1990). Glycolysis as primary energy source in tumor cell chemotaxis. J. Natl. Cancer. I., 82(23), 1836-1840.
19. Greiner, E.F., Guppy, M., Brand, K. (1994). Glucose is essential for proliferation and the glycolytic enzyme induction that provokes a transition to glycolytic energy production. J. Biol. Chem., 269(50), 31484-31490.
20. Benzaquen, L.R., Brugnara, C., Byers, H.R., Gattoni-Celli, S., Halperin, J.A. (1995). Clotrimazole inhibits cell proliferation in vitro and in vivo. Nat. Med., 1(6), 534.
21. Glass-Marmor, L., Morgenstern, H., Beitner, R. (1996). Calmodulin antagonists decrease glucose 1, 6-bisphosphate, fructose 1, 6-bisphosphate, ATP and viability of melanoma cells. Eur. J. Pharmacol., 313(3), 265-271.
22. Glass-Marmor, L., Beitner, R. (1997). Detachment of glycolytic enzymes from cytoskeleton of melanoma cells induced by calmodulin antagonists. Eur. J. Pharmacol., 328(2-3), 241-248.
23. Penso, J., Beitner, R. (1998). Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells. Eur. J. Pharmacol., 342(1), 113-117.
24. Penso, J., Beitner, R. (2002). Clotrimazole decreases glycolysis and the viability of lung carcinoma and colon adenocarcinoma cells. Eur. J. Pharmacol., 451(3), 227-235.
25. Meira, D.D., Marinho-Carvalho, M.M., Teixeira, C.A., Veiga, V.F., Da Poian, A.T., Holandino, C., S. de Freitas, M., Sola-Penna, M. (2005). Clotrimazole decreases human breast cancer cells viability through alterations in cytoskeleton-associated glycolytic enzymes. Mol. Genet. Metab., 84(4), 354-362.
26. Liu, H., Li, Y., Raisch, K.P. (2010). Clotrimazole induces a late G1 cell cycle arrest and sensitizes glioblastoma cells to radiation in vitro. Anti-Cancer Drugs, 21(9), 841.
27. Furtado, C.M., Marcondes, M.C., Sola-Penna, M., De Souza, M.L., Zancan, P. (2012). Clotrimazole preferentially inhibits human breast cancer cell proliferation, viability and glycolysis. PloS one, 7(2), e30462.
28. McDonald, A.J., Curt, K.M., Patel, R.P., Kozlowski, H., Sackett, D.L., Robey, R.W., Gottesman, M.M, Bates, S.E. (2019). Targeting mitochondrial hexokinases increases efficacy of histone deacetylase inhibitors in solid tumor models. Exp. Cell Res., 375(2), 106-112.
29. Ito, C., Tecchio, C., Coustan-Smith, E., Suzuki, T., Behm, F.G., Raimondi, S.C., Pui, C.H, Campana, D. (2002). The antifungal antibiotic clotrimazole alters calcium homeostasis of leukemic lymphoblasts and induces apoptosis. Leukemia, 16(7), 1344.
30. Wang, J., Jia, L., Kuang, Z., Wu, T., Hong, Y., Chen, X., Leung, W.K., Xia, J., Cheng, B. (2014). The in vitro and in vivo antitumor effects of clotrimazole on oral squamous cell carcinoma. PloS one, 9(6), e98885.
31. Sharma, A., Mehta, V., Parashar, A., Malairaman, U. (2017). Combinational effect of Paclitaxel and Clotrimazole on human breast cancer: Proof for synergistic interaction. Synergy, 5, 13-20.
32. Kavakçıoğlu, B., Tarhan, L. (2018). Yeast caspase-dependent apoptosis in Saccharomyces cerevisiae BY4742 induced by antifungal and potential antitumor agent clotrimazole. Arch. Microbiol., 200(1), 97-106.
33. Robles-Escajeda, E., Martínez, A., Varela-Ramirez, A., Sánchez-Delgado, R.A., Aguilera, R.J. (2013). Analysis of the cytotoxic effects of ruthenium–ketoconazole and ruthenium–clotrimazole complexes on cancer cells. Cell Biol. Toxicol., 29(6), 431-443.
34. Motawi, T.M., Sadik, N.A., Fahim, S.A., Shouman, S.A. (2015). Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells. Chem. Biol. Interact., 233, 147-156.
35. Dellenbach, P., Thomas, J.L., Guerin, V., Ochsenbein, E., Contet‐Audonneau, N. (2000). Topical treatment of vaginal candidosis with sertaconazole and econazole sustained‐release suppositories. Int. J. Gynaecol. Obstet., 71, 47-52.
36. Bossche, H.V., Engelen, M., Rochette, F. (2003). Antifungal agents of use in animal health–chemical, biochemical and pharmacological aspects. J. Vet. Pharmacol. Ther., 26(1), 5-29.
37. Prajna, N.V., John, R.K., Nirmalan, P.K., Lalitha, P., Srinivasan, M. (2003). A randomised clinical trial comparing 2% econazole and 5% natamycin for the treatment of fungal keratitis. Br. J. Ophthalmol., 87(10), 1235-1237.
38. Kuo, D.H., Liu, L.M., Chen, H.W., Chen, F.A., Jan, C.R. (2010). Econazole‐induced Ca2+ fluxes and apoptosis in human oral cancer cells. Drug Dev. Res., 71(4), 240-248.
39. Jiang, Y.Y., Zhang, B., Chen, X.S., Long, K. (1991). Effects of econazole and clotrimazole on TXB2 and PGE2 production in calcimycin-stimulated neutrophils and arachidonic acid-stimulated platelets. Acta Pharmacol. Sin., 12(3), 276-280.
40. Bogle, R.G., Vallance, P. (1996). Functional effects of econazole on inducible nitric oxide synthase: production of a calmodulin‐dependent enzyme. Br. J. Pharmacol., 117(6), 1053-1058.
41. Zhang, Y., Crump, M., Berger, S.A. (2002). Purging of contaminating breast cancer cells from hematopoietic progenitor cell preparations using activation enhanced cell death. Breast Cancer Res. Treat., 72(3), 265-278.
42. Gommerman, J.L., Berger, S.A. (1998). Protection from apoptosis by steel factor but not interleukin-3 is reversed through blockade of calcium influx. Blood, 91(6), 1891-1900.
43. Soboloff, J., Zhang, Y., Minden, M., Berger, S.A. (2002). Sensitivity of myeloid leukemia cells to calcium influx blockade: application to bone marrow purging. Exp. Hematol., 30(10), 1219-1226.
44. Ho, Y.S., Wu, C.H., Chou, H.M., Wang, Y.J., Tseng, H., Chen, C.H., Chen, L.C., Lee, C.H., Lin, S. Y. (2005). Molecular mechanisms of econazole-induced toxicity on human colon cancer cells: G0/G1 cell cycle arrest and caspase 8-independent apoptotic signaling pathways. Food Chem. Toxicol., 43(10), 1483-1495.
45. Huang, J.K., Liu, C.S., Chou, C.T., Liu, S.I., Hsu, S.S., Chang, H.T., Hsieh, C.H., Chang, C.H., Chen, W.C., Jan, C.R. (2005). Effects of econazole on Ca2+ levels in and the growth of human prostate cancer PC3 cells. Clin. Exp. Pharmacol. Physiol., 32(9), 735-741.
46. Mason, M.J., Mayer, B., Hymel, L.J. (1993). Inhibition of Ca2+ transport pathways in thymic lymphocytes by econazole, miconazole, and SKF 96365. Am. J. Physiol. Cell Physiol., 264(3), C654-C662.
47. Hughes, A.D., Schachter, M. (1994). Multiple pathways for entry of calcium and other divalent cations in a vasculr smooth muscle cell line (A7r5). Cell Calcium, 15(4), 317-330.
48. Hornstein, E.H., Vassilopoulos, D., Thomas, D.E., Friedman, F.K., Tsokos, G.C. (1996). Modulation of human T-lymphocyte plasma membrane Ca+2 permeability by imidazole antimycotics. Immunopharmacol. Immunotoxicol., 18(2), 237-245.
49. Gamberucci, A., Fulceri, R., Bygrave, F.L., Benedetti, A. (1997). Unsaturated fatty acids mobilize intracellular calcium independent of IP3 generation and via insertion at the plasma membrane. ‎Biochem. Biophys. Res. Commun., 241(2), 312-316.
50. Jan, C.R., Ho, C.M., Wu, S.N., Huang, J.K., Tseng, C.J. (1998). Mechanism of lanthanum inhibition of extracellular ATP-evoked calcium mobilization in MDCK cells. Life Sci., 62(6), 533-540.
51. Jan, C.R., Ho, C.M., Wu, S.N., Tseng, C. J. (1999). Multiple effects of econazole on calcium signaling: depletion of thapsigargin-sensitive calcium store, activation of extracellular calcium influx, and inhibition of capacitative calcium entry. Biochim. Biophys. Acta-Mol. Cell Res., 1448(3), 533-542.
52. Chang, H.T., Liu, C.S., Chou, C.T., Hsieh, C.H., Chang, C.H., Chen, W.C., Liu, S.I., Hsu, S.S., Chen, J.S., Jiann, B.P., Huang, J.K., Jan, C.R. (2005). Econazole induces increases in free intracellular Ca2+ concentrations in human osteosarcoma cells. Hum. Exp. Toxicol., 24(9), 453-458.
53. Yu, Y., Niapour, M., Zhang, Y., Berger, S.A. (2008). Mitochondrial regulation by c-Myc and hypoxia-inducible factor-1α controls sensitivity to econazole. Mol. Cancer Ther., 7(3), 483-491.
54. Fang, L.I.U., Ping, Z.O.U., Zhang, M., Yaohui, W.U., Juan, X. (2005). Experimental study on apoptosis in leukemia cells induced by econazole. Chin. Ger. J. Clin. Oncol., 4(2), 102-104.
55. Sun, J., Yu, C.H., Zhao, X.L., Wang, Y., Jiang, S.G., Gong, X.F. (2014). Econazole nitrate induces apoptosis in MCF-7 cells via mitochondrial and caspase pathways. Iran J. Pharm. Res., 13(4), 1327.
56. Coelho, R.G., de Castro Calaça, I., de Moura Celestrini, D., Correia, A.H., Costa, M.A.S.M., Sola-Penna, M. (2011). Clotrimazole disrupts glycolysis in human breast cancer without affecting non-tumoral tissues. Mol. Genet. Metab., 103(4), 394-398.
57. Trachtenberg, J., Pont, A. (1984). Ketoconazole therapy for advanced prostate cancer. Lancet, 324(8400), 433-435.
58. Trachtenberg, J., Halpern, N., Pont, A. (1983). Ketoconazole: a novel and rapid treatment for advanced prostatic cancer. J. Urol., 130(1), 152-153.
59. Eichenberger, T., Trachtenberg, J. (1989). Effects of high-dose ketoconazole on patients who have androgen-independent prostatic cancer. Can. J. Surg., 32(5), 349-352.
60. Eichenberger, T., Trachtenberg, J., Toor, P., Keating, A. (1989). Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells. J. Urol., 141(1), 190-191.
61. Pont, A. (1987). Long-term experience with high dose ketoconazole therapy in patients with stage D2 prostatic carcinoma. J. Urol., 137(5), 902-904.
62. Witjes, F. J., Debruyne, F.M., Del Moral, P.F., Geboers, A.D.H., Group, D.S.E.U.C. (1989). Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Urology, 33(5), 411-415.
63. Millikan, R., Baez, L., Banerjee, T., Wade, J., Edwards, K., Winn, R., Smith, T.L., Logothetis, C. (2001). Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Urol. Oncol., 6, 111-115.
64. Small, E.J., Halabi, S., Dawson, N.A., Stadler, W.M., Rini, B.I., Picus, J., Gable, P., Torti, F.M., Kaplan, E., Vogelzang, N.J. (2004). Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J. Clin. Oncol, 22(6), 1025-1033.
65. Figg, W.D., Liu, Y., Arlen, P., Gulley, J., Steinberg, S.M., Liewehr, D.J., Cox, M.C, Zhai, S., Cremers, S., Parr, A., Yang, X., Chen, C.C., Jones, E., Dahut, W.L. (2005). A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases. J. Urol., 173(3), 790-796.
66. Eklund, J., Kozloff, M., Vlamakis, J., Starr, A., Mariott, M., Gallot, L., Jovanovic, B., Schilder, L., Robin, E., Pins, M., Bergan, R.C. (2006). Phase II study of mitoxantrone and ketoconazole for hormone‐refractory prostate cancer. Cancer, 106(11), 2459-2465.
67. Ryan, C.J., Halabi, S., Ou, S.S., Vogelzang, N.J., Kantoff, P., Small, E.J. (2007). Adrenal androgen levels as predictors of outcome in prostate cancer patients treated with ketoconazole plus antiandrogen withdrawal: results from a cancer and leukemia group B study. Clin. Cancer Res., 13(7), 2030-2037.
68. Peer, A., Neumann, A., Sella, A., Rosenbaum, E., Neiman, V., Gottfried, M., Kovel, S., Sarid, D., Gez, E., Mermershtain, W., Rouvinov, K., Carducci, M.A., Eisenberg, M.A., Sinibaldi, V.J., Berger, R., Keizman, D. (2017). Comparison of abiraterone acetate (Abi) versus ketoconazole (Keto) in chemotherapy-naive patients (CN-pts) with metastatic castration resistant prostate cancer (mCRPC). J. Clin. Oncol., 34, 3742-3748.
69. Barata, P.C., Cooney, M., Mendiratta, P., Tyler, A., Dreicer, R., Garcia, J.A. (2018). Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study. Invest. New Drug., 36(6), 1085-1092.
70. Patel, V., Liaw, B., Oh, W. (2018). The role of ketoconazole in current prostate cancer care. Nature Rev. Urol., 15, 643-651.
71. Fernández-Cancio, M., Camats, N., Flück, C., Zalewski, A., Dick, B., Frey, B., Monne, R., Toran, N., Audi, L., Pandey, A. (2018). Mechanism of the dual activities of human CYP17A1 and binding to anti-prostate cancer drug abiraterone revealed by a novel V366M mutation causing 17, 20 lyase deficiency. Pharmaceuticals, 11(2), 37.
72. Monticone, S., Rainey, W.E., Bollag, W.B., Isales, C.M. Regulation of Aldosterone Production In: Textbook of Nephro-Endocrinology, Ajay K. Singh, Gordon H. Williams, Ed. Academic Press, 2018, 2, pp. 429-449.
73. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm (Accessed March 3, 2015).
74. Harris, K.A., Weinberg, V., Bok, R.A., Kakefuda, M., Small, E.J. (2002). Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J. Urol., 168(2), 542-545.
75. Nakabayashi, M., Xie, W., Regan, M.M., Jackman, D.M., Kantoff, P.W., Oh, W.K. (2006). Response to low‐dose ketoconazole and subsequent dose escalation to high‐dose ketoconazole in patients with androgen‐independent prostate cancer. Cancer, 107(5), 975-981.
76. Lo, E.N., Beckett, L.A., Pan, C.X., Robles, D., Suga, J.M., Sands, J.M., Lara Jr, P.N. (2015). Prospective evaluation of low-dose ketoconazole plus hydrocortisone in docetaxel pre-treated castration-resistant prostate cancer patients. Prostate Cancer P. D., 18(2), 144.
77. Martinez, C., Garcia-Martin, E., Pizarro, R.M., Garcia-Gamito, F.J., Agúndez, J.A.G. (2002). Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy. Br. J. Cancer, 87(6), 681.
78. Lim, Y.W., Goh, B.C., Wang, L.Z., Tan, S.H., Chuah, B.Y.S., Lim, S.E., Lau, P., Buhari, S.A, Chan, C.W., Sukri, N.B., Cordero, M.T., Soo, R., Lee, S.C. (2010). Pharmacokinetics and pharmacodynamics of docetaxel with or without ketoconazole modulation in chemonaive breast cancer patients. Ann. Oncol., 21(11), 2175-2182.
79. Blagosklonny, M.V., Dixon, S.C., Figg, W.D. (2000). Efficacy of microtubule-active drugs followed by ketoconazole in human metastatic prostate cancer cell lines. J. Urol., 163(3), 1022-1026.
80. Nakabayashi, M., Oh, W.K., Jacobus, S., Regan, M.M., Taplin, M.E., Kantoff, P.W., Rosenberg, J.E. (2010). Activity of ketoconazole after taxane‐based chemotherapy in castration‐resistant prostate cancer. BJU Int., 105(10), 1392-1396.
81. Beer, T.M, Armstrong, A.J., Rathkopf, D.E., Loriot, Y., Sternberg, C.N., Higano, C.S., Iversen, P., Bhattacharya, S., Carles, J., Chowdhury, S., Davis, I.D., de Bono, J.S., Evans, C.P., Fizazi, K., Joshua, A.M., Kim, C.S., Kimura, G., Mainwaring, P., Mansbach, H., Miller, K., Noonberg, S.B., Perabo, F., Phung, D., Saad, F., Scher, H.I., Taplin, M.E., Venner, P.M., Tombal, B. (2014). Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med., 371(5), 424-433.
82. Fizazi, K., Tran, N., Fein, L., Matsubara, N., Rodriguez-Antolin, A., Alekseev, B.Y., Özgüroğlu, M., Ye, D., Feyerabend, S., Protheroe, A., De Porre, P., Kheoh, T., Park, Y.C., Todd, M.B., Chi, K.N. (2017). Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N. Engl. J. Med., 377(4), 352-360.
83. Smith, M.R., Saad, F., Chowdhury, S., Oudard, S., Hadaschik, B.A., Graff, J.N., Olmos, D., Mainwaring, P.N., Lee, J.Y., Uemura, H., Lopez-Gitlitz, A., Trudel, G.C., Espina, B.M., Shu, Y., Park, Y.C., Rackoff, W.R., Yu, M.K., Small, E.J. (2018). Apalutamide treatment and metastasis-free survival in prostate cancer. N. Engl. J. Med., 378(15), 1408-1418.
84. Naftalovich, S., Yefenof, E., Eilam, Y. (1991). Antitumor effects of ketoconazole and trifluoperazine in murine T-cell lymphomas. Cancer Chemother. Pharmacol., 28(5), 384-390.
85. Ho, Y.S., Tsai, P.W., Yu, C.F., Liu, H.L., Chen, R.J., Lin, J.K. (1998). Ketoconazole-induced apoptosis through P53-dependent pathway in human colorectal and hepatocellular carcinoma cell lines. Toxicol. Appl. Pharmacol., 153(1), 39-47.
86. Chen, R.J., Lee, W.S., Liang, Y.C., Lin, J.K., Wang, Y.J., Lin, C.H., Hsieh, J.Y., Chaing, C.C., Ho, Y.S. (2000). Ketoconazole induces G0/G1 arrest in human colorectal and hepatocellular carcinoma cell lines. Toxicol. Appl. Pharmacol., 169(2), 132-141.
87. Lin, K.L., Huang, C.C., Cheng, J.S., Tsai, J.Y., Lu, Y.C., Chang, H.T., Jan, C.R. (2009). Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. Toxicol. In Vitro, 23(7), 1268-1276.
88. Agnihotri, S., Mansouri, S., Burrell, K., Li, M., Mamatjan, Y., Liu, J., Nejad, R., Kumar, S., Jalali, S., Singh, S.K., Vartanian, A., Chen, E.X., Karimi, S., Singh, O., Bunda, S., Mansouri, A., Aldape, K.D., Zadeh, G. (2019). Ketoconazole and posaconazole selectively target HK2-expressing glioblastoma cells. Clin. Cancer. Res., 25(2), 844-855.
89. Rodriguez, R.J., Acosta Jr, D. (1996). Inhibition of mitochondrial function in isolated rat liver mitochondria by azole antifungals. J. Biochem. Toxicol., 11(3), 127-131.
90. Hynes, J., Nadanaciva, S., Swiss, R., Carey, C., Kirwan, S., Will, Y. (2013). A high-throughput dual parameter assay for assessing drug-induced mitochondrial dysfunction provides additional predictivity over two established mitochondrial toxicity assays. Toxicol. In Vitro, 27(2), 560-569.
91. Chen, Y., Chen, H.N., Wang, K., Zhang, L., Huang, Z., Liu, J., Zhang, Z., Luo, M., Lei, Y., Peng, Y., Zhou, Z.G., Wei, Y., Huang, C. (2019). Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma. J. Hepatol., 70(1), 66-77.
92. Power, E.C., Ganellin, C.R., Benton, D.C. (2006). Partial structures of ketoconazole as modulators of the large conductance calcium-activated potassium channel (BKCa). Bioorg. Med. Chem., 16(4), 887-890.
93. Huang, H., Wang, H., Sinz, M., Zoeckler, M., Staudinger, J., Redinbo, M.R., Teotico, D.G., Locker, J., Kalpana, G.V., Mani, S. (2007). Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene, 26(2), 258.
94. Korashy, H.M., Brocks, D.R., El-Kadi, A.O. (2007). Induction of the NAD (P) H: quinone oxidoreductase 1 by ketoconazole and itraconazole: a mechanism of cancer chemoprotection. Cancer Lett., 258(1), 135-143.
95. Pedarzani, P., Stocker, M. (2008). Molecular and cellular basis of small-and intermediate-conductance, calcium-activated potassium channel function in the brain. Cell. Mol. Life Sci, 65(20), 3196-3217.
96. Huang, X., Jan, L.Y. (2014). Targeting potassium channels in cancer. J. Cell Biol., 206(2), 151-162.
97. Zanger, U.M., Schwab, M. (2013). Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Therapeut., 138(1), 103-141.
98. Venkatakrishnan, K., Rader, M., Ramanathan, R.K., Ramalingam, S., Chen, E., Riordan, W., Trepicchio, W., Cooper, M., Karol, M., Moltke, L., Neuwirth, R., Egorin, M., Chatta, G. (2009). Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: A prospective, multicenter, open-label, randomized, two-way crossover drug-drug interaction study. Clin. Ther., 31, 2444-2458.
99. Kast, R.E., Boockvar, J.A., Brüning, A., Cappello, F., Chang, W.W., Cvek, B., Ping Dou, Q., Duenas-Gonzalez, A., Efferth, T., Focosi, D., Ghaffari, S.H., Karpel-Massler, G., Ketola, K., Khoshnevisan, A., Keizman, D., Magné, N., Marosi, C., McDonald, K., Muñoz, M., Paranjpe, A., Pourgholami, M.H., Sardi, L., Sella, A., Srivenugopal, K.S., Tuccori, M., Wang, W., Wirtz, C.R., Halatsch, M.E. (2013). 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, 4(4), 502.
100. Agarwal, S.K., Salem, A.H., Danilov, A.V., Hu, B., Puvvada, S., Gutierrez, M., Chien, D., Lewis, L.D., Wong, S.L. (2017). Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL‐2 inhibitor, in patients with non‐Hodgkin lymphoma. Br. J. Clin. Pharmacol., 83(4), 846-854.
101. Cheng, J.S., Chou, C.T., Liang, W.Z., Kuo, C.C., Shieh, P., Kuo, D.H., Jan, C.R. (2014). The mechanism of bifonazole-induced [Ca2+]i rises and non-Ca2+-triggered cell death in PC3 human prostate cancer cells. J. Recept. Sig. Transd., 34(6), 493-499.
102. Robey, R.W., McDonald, A.J., Kozlowski, H., Gottesman, M.M., Bates, S.E. Short-Term Romidepsin Treatment Combined with Clotrimazole or Bifonazole Leads to Decreased Mitochondrial Hexokinase 2 and Apoptosis in Cancer Cells In: Proceedings of the American Association for Cancer Research Annual Meeting, Washington, DC., Philadelphia, April 1-5, 2017, doi:10.1158/1538-7445.AM2017-4040.
103. Bruserud, O. (2001). Effects of azoles on human acute myelogenous leukemia blasts and T lymphocytes derived from acute leukemia patients with chemotherapy-induced cytopenia. Int. Immunopharmacol., 1(12), 2183-2195.
104. Yuan, S.Y., Shiau, M.Y., Ou, Y.C., Huang, Y.C., Chen, C.C., Cheng, C.L., Chiu, K.Y., Wang, S.S., Tsai, K.J. (2017). Miconazole induces apoptosis via the death receptor 5-dependent and mitochondrial-mediated pathways in human bladder cancer cells. Oncol. Rep., 37(6), 3606-3616.
105. Shahbazfar, A.A., Zare, P., Ranjbaran, M., Tayefi-Nasrabadi, H., Fakhri, O., Farshi, Y., Shadi, S., Khoshkerdar, A. (2014). A survey on anticancer effects of artemisinin, iron, miconazole, and butyric acid on 5637 (bladder cancer) and 4T1 (Breast cancer) cell lines. J. Cancer Res. Ther., 10(4), 1057.
106. Wu, C.H., Jeng, J.H., Wang, Y.J., Tseng, C.J., Liang, Y.C., Chen, C.H., Lee, H.M., Lin, J.K., Lin, C.H., Lin, S.Y., Li, C.P., Ho, Y.S. (2002). Antitumor effects of miconazole on human colon carcinoma xenografts in nude mice through induction of apoptosis and G0/G1 cell cycle arrest. Toxicol. Appl. Pharm., 180(1), 22-35.
107. Mun, Y.J., Lee, S.W., Jeong, H.W., Lee, K.G., Kim, J.H., Woo, W.H. (2004). Inhibitory effect of miconazole on melanogenesis. Biol. Pharm. Bull., 27(6), 806-809.
108. Lee, K.P., Kim, J.E., Park, W.H. (2015). Cytoprotective effect of rhamnetin on miconazole-induced H9c2 cell damage. Nutr. Res. Pract., 9(6), 586-591.
109. Won, K.J., Lin, H.Y., Jung, S., Cho, S.M., Shin, H.C., Bae, Y.M., Lee, S.H., Kim, H.J., Jeon, B.H., Kim, B. (2012). Antifungal miconazole induces cardiotoxicity via inhibition of APE/Ref-1-related pathway in rat neonatal cardiomyocytes. Toxicol. Sci., 126(2), 298-305.
110. Ashbee, H.R., Gilleece, M.H. (2014). Pharmacogenomics of Antifungal Agents In: Handbook of Pharmacogenomics and Stratified Medicine, Sandosh Padmanabhan, Ed. Academic Press, pp. 879-896.
111. Dash, A.K., & Elmquist, W.F. (2001). Fluconazole In: Profiles of Drug Substances, Excipients and Related Methodology, HG Brittain, Academic Press: San Diego, 27, 67-113.
112. Le, A., Farmakiotis, D., Tarrand, J.J., Kontoyiannis, D.P. (2017). Initial treatment of cancer patients with fluconazole-susceptible dose-dependent Candida glabrata fungemia: better outcome with an echinocandin or polyene compared to an azole? Antimicrob. Agents Chemother., 61(8), e00631-17.
113. da Silva, C.R., de Andrade Neto, J.B., de Sousa Campos, R., Figueiredo, N.S., Sampaio, L.S., Magalhães, H.I.F., Cavalcanti, B.C., Gaspar, D.M., de Andrade, G.M., Lima, I.S.P., de Barros Viana, G.S., de Moraes, M.O., Lobo, M.D.P., Grangeiro, T.B., Júnior, H.V.N. (2014). Synergistic effect of the flavonoid catechin, quercetin, or epigallocatechin gallate with fluconazole induces apoptosis in Candida tropicalis resistant to fluconazole. Antimicrob. Agents Chemother., 58(3), 1468-1478.
114. Singh, B.N., Upreti, D.K., Singh, B.R., Pandey, G., Verma, S., Roy, S., Naqvi, A.H., Rawat, A.K.S. (2015). Quercetin sensitizes fluconazole-resistant Candida albicans to induce apoptotic cell death by modulating quorum sensing. Antimicrob. Agents Chemother., 59(4), 2153-2168.
115. Wang, X., Wei, S., Zhao, Y., Shi, C., Liu, P., Zhang, C., Lei, Y., Zhang, B., Bai, B., Huang, Y., Zhang, H. (2017). Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death. Cancer Lett., 385, 128-136.
116. Hu, Q., Hou, Y.C., Huang, J., Fang, J.Y., Xiong, H. (2017). Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells. J. Exp. Clin. Canc. Res., 36(1), 50.
117. Liu, R., Li, J., Zhang, T., Zou, L., Chen, Y., Wang, K., Lei, Y., Yuan, K., Li, Y., Lan, J., Cheng, L., Xie, N., Xiang, R., Nice, E.C., Huang, C., Wei, Y. (2014). Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking. Autophagy, 10(7), 1241-1255.
118. Chen, M.B., Liu, Y.Y., Xing, Z.Y., Zhang, Z.Q., Jiang, Q., Lu, P.H., Cao, C. (2018). Itraconazole-induced inhibition on human esophageal cancer cell growth requires AMPK activation. Mol. Cancer Ther., 17(6), 1229-1239.
119. Liang, G., Liu, M., Wang, Q., Shen, Y., Mei, H., Li, D., Liu, W. (2017). Itraconazole exerts its anti-melanoma effect by suppressing Hedgehog, Wnt, and PI3K/mTOR signaling pathways. Oncotarget, 8(17), 28510.
120. Hara, M., Nagasaki, T., Shiga, K., Takeyama, H. (2016). Suppression of cancer-associated fibroblasts and endothelial cells by itraconazole in bevacizumab-resistant gastrointestinal cancer. Anticancer Res., 36(1), 169-177.
121. Aftab, B.T., Dobromilskaya, I., Liu, J.O., Rudin, C.M. (2011). Itraconazole inhibits angiogenesis and tumor growth in non–small cell lung cancer. Cancer Res., 71(21), 6764-6772.
122. Wang, J., Xu, X., Zhou, R., Guo, K. (2015). Effects of itraconazole plus doxorubicin on proliferation and apoptosis in acute myeloid leukemia cells. Chin. J. Cancer, 95(4), 299-305.
123. Sari, I.N., Phi, L.T.H., Jun, N., Wijaya, Y.T., Lee, S., Kwon, H.Y. (2018). Hedgehog signaling in cancer: a prospective therapeutic target for eradicating cancer stem cells. Cells, 7(11), 208.
124. Tsubamoto, H., Ueda, T., Inoue, K., Sakata, K., Shibahara, H., Sonoda, T. (2017). Repurposing itraconazole as an anticancer agent. Oncology letters, 14(2), 1240-1246.
125. Peyton, L.R., Gallagher, S., Hashemzadeh, M. (2015). Triazole antifungals: a review. Drug. Today (Barc), 51(12), 705-718.
126. Choi, S.H., Lee, S.Y., Hwang, J.Y., Lee, S.H., Yoo, K.H., Sung, K.W., Koo, H.H., Kim, Y.J. (2013). Importance of voriconazole therapeutic drug monitoring in pediatric cancer patients with invasive aspergillosis. Pediatr. Blood Cancer, 60(1), 82-87.
127. Pham, A.N., Bubalo, J.S., Lewis, J.S. (2016). Comparison of posaconazole serum concentrations from haematological cancer patients on posaconazole tablet and oral suspension for treatment and prevention of invasive fungal infections. Mycoses, 59(4), 226-233.
128. Takahashi, H., Abe, M., Sugawara, T., Tanaka, K., Saito, Y., Fujimura, S., Shibuya, M., Sato, Y. (1998). Clotrimazole, an imidazole antimycotic, is a potent inhibitor of angiogenesis. Jpn. J. Clin. Oncol., 89(4), 445-451.
129. Khalid, M.H., Shibata, S., Hiura, T. (1999). Effects of clotrimazole on the growth, morphological characteristics, and cisplatin sensitivity of human glioblastoma cells in vitro. J. Neurosurg., 90(5), 918-927.
130. Khalid, M.H., Shibata, S., Hiura, T. (1999). Effects of clotrimazole on the growth, morphological characteristics, and cisplatin sensitivity of human glioblastoma cells in vitro. J. Neurosurg., 90(5), 918-927.
131. Adinolfi, B., Carpi, S., Romanini, A., Da Pozzo, E., Castagna, M., Costa, B., Martini, C., Olesen, S.P., Schmitt, N., Breschi, M.C., Nieri, P., Fogli, S. (2015). Analysis of the antitumor activity of clotrimazole on A375 human melanoma cells. Anticancer Res., 35(7), 3781-3786.
132. McDonald, A.J., Curt, K.M., Patel, R.P., Kozlowski, H., Sackett, D.L., Robey, R.W., Gottesman, M.M., Bates, S.E. (2019). Targeting mitochondrial hexokinases increases efficacy of histone deacetylase inhibitors in solid tumor models. Exp. Cell Res., 375(2), 106-112.
133. Dong, C., Yang, R., Li, H., Ke, K., Luo, C., Yang, F., Shi, X.N., Zhu, Y., Liu, X., Wong, M.H., Lin, G., Wang, X., Leung, K.S., Kung, H.F., Chen, C., Lin, M.C. (2017). Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells. Sci. Rep., 7(1), 17987.
134. Rochlitz, C.F., Damon, L.E., Russi, M.B., Geddes, A., Cadman, E.C. (1988). Cytotoxicity of ketoconazole in malignant cell lines. Cancer Chemother. Pharmacol., 21(4), 319-322.
135. Lu, C.T., Leong, P.Y., Hou, T.Y., Kang, Y.T., Chiang, Y.C., Hsu, C.T., Lin, Y.D., Ko, J.L., Hsiao, Y.P. (2019). Inhibition of proliferation and migration of melanoma cells by ketoconazole and Ganoderma immunomodulatory proteins. Oncol. Lett., 18(1), 891-897.