Original Article

Investigation of the antifungal activity of panobinostat, tamoxifen, and miltefosine alone and in combination with some conventional antifungal drugs against fluconazole-resistant Candida species

Abstract

Background and Objectives: The increasing incidence of antifungal-resistant Candida infections, particularly among cancer patients, emphasizes the urgency of exploring alternative therapeutic strategies. This study aimed to assess the in vitro antifungal efficacy of three anticancer agents—tamoxifen, panobinostat, and miltefosine—both individually and in combination with the antifungals fluconazole and itraconazole, against fluconazole-resistant Candida strains.
Materials and Methods: A total of 21 clinical Candida isolates (C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, and C. auris) were evaluated. Antifungal susceptibility testing was conducted following the microdilution protocol outlined by CLSI.
Results: The combination of panobinostat with fluconazole exhibited full synergistic activity against C. albicans and C. tropicalis. Conversely, antagonistic effects were observed with C. parapsilosis and C. glabrata, while C. auris displayed an indifferent response. Panobinostat paired with itraconazole showed synergy exclusively against C. albicans. Similarly, miltefosine combined with itraconazole demonstrated synergism with C. albicans, but no interaction was found with fluconazole. Tamoxifen in conjunction with itraconazole revealed a synergistic response against C. albicans, antagonism with C. tropicalis, and indifference with other species.
Conclusion: Certain combinations of antifungals and anticancer agents could potentiate antifungal activity against resistant Candida isolates. Therefore, precise species-level identification is vital for tailoring effective combination therapies, particularly in immunocompromised individuals.

1. Gómez-Gaviria M, Ramírez-Sotelo U, Mora-Montes HM. Non-albicans Candida species: immune response, evasion mechanisms, and new plant-derived alternative therapies. J Fungi (Basel) 2022; 9: 11.
2. Kamali Sarvestani H, Mahmoudi S, Afarinesh Khaki P, Ansari S, Ghaderkhani S, Roostaei D, et al. Epidemiology, risk factors, species distribution, and antifungal susceptibility of candidemia among hospitalized patients with COVID-19. Curr Med Mycol 2021; 7: 12-18.
3. Akinosoglou K, Rigopoulos EA, Papageorgiou D, Schinas G, Polyzou E, Dimopoulou E, et al. Amphotericin B in the era of new Antifungals: where will it stand? J Fungi (Basel) 2024; 10: 278.
4. Tortorano AM, Prigitano A, Morroni G, Brescini L, Barchiesi F. Candidemia: evolution of drug resistance and novel therapeutic approaches. Infect Drug Resist 2021; 14: 5543-5553.
5. Jacobs SE, Jacobs JL, Dennis EK, Taimur S, Rana M, Patel D, et al. Candida auris pan-drug-resistant to four classes of antifungal agents. Antimicrob Agents Chemother 2022; 66(7): e0005322.
6. Meletiadis J, Petraitis V, Petraitiene R, Lin P, Stergiopoulou T, Kelaher AM, et al. Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivo correlation. J Infect Dis 2006; 194: 1008-1018.
7. Su S, Shi X, Xu W, Li Y, Chen X, Jia S, et al. Antifungal activity and potential mechanism of panobinostat in combination with fluconazole against Candida albicans. Front Microbiol 2020; 11: 1584.
8. Carta F, Angeli A, Nielsen CD, Supuran CT, Cilibrizzi A (2019). New biological targets for the treatment of leishmaniasis. In: Medicinal Chemistry of Neglected and tropical diseases. 1st Edition. CRC Press.
9. Sani A, Pourmadadi M, Shaghaghi M, Eshaghi MM, Shahmollaghamsary S, Arshad R, et al. Revolutionizing anticancer drug delivery: Exploring the potential of tamoxifen-loaded nanoformulations. J Drug Deliv Sci Technol 2023; 86: 104642.
10. Ganai SA. Panobinostat: the small molecule metalloenzyme inhibitor with marvelous anticancer activity. Curr Top Med Chem 2016; 16: 427-434.
11. Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 2012; 67: 2576-2597.
12. Kord M, Elmimoghaddam A, Hashemi SJ, Reziae S, Daie Ghazvini R, Salehi M, et al. Comparison of PCR-RFLP with 21-plex PCR and rDNA Sequencing for Identification of clinical yeast isolates. Mycopathologia 2021; 186: 213-220.
13. Clinical and Laboratory Standards Institute (CLSI) (2008). Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard. CLSI document M27-A3. Wayne, PA.
14. Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 2003; 52: 1.
15. Barreto TL, Rossato L, de Freitas AL, Meis JF, Lopes LB, Colombo AL, et al. Miltefosine as an alternative strategy in the treatment of the emerging fungus Candida auris. Int J Antimicrob Agents 2020; 56: 106049.
16. Johnson MD, MacDougall C, Ostrosky-Zeichner L, Perfect JR, Rex JH. Combination antifungal therapy. Antimicrob Agents Chemother 2004; 48: 693-715.
17. Vaezi A, Moghadaszadeh M, Nasri E, Gharibi S, Diba K, Matkowski A, et al. In vitro activity of juglone (5-hydroxy-1,4-naphthoquinone) against both fluconazole-resistant and susceptible Candida isolates. Rev Iberoam Micol 2022; 39: 50-53.
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IssueVol 17 No 5 (2025) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijm.v17i5.19894
Keywords
Panobinostat Tamoxifen Miltefosine Fluconazole Itraconazole Candida
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1.
Amirzadeh-Ghasemi F, Daie Ghazvini R, Khodavaisy S, Hashemi SJ, Ahmadi A, Ardi P, Abastabar M, Roostaei D, Rafat Z. Investigation of the antifungal activity of panobinostat, tamoxifen, and miltefosine alone and in combination with some conventional antifungal drugs against fluconazole-resistant Candida species. Iran J Microbiol. 2025;17(5):848-853.