Application of New Syncretic Antifungal Formulations against Candida Species Associated with Oral Cancer

Shatha Ghani Abbas (1) , Dr. Rajaa Abdulrazzaq Al Anbagi (2)
(1) Department of Medical Biotechnology, Faculty of Biotechnology, Al-Qasim Green University, Babylon 51013, Iraq. , Iraq
(2) Department of Medical Biotechnology, Faculty of Biotechnology, Al-Qasim Green University, Babylon 51013, Iraq. , Iraq

Abstract

Background: Human oral microbiomes constitute from diverse and multifaceted structure of microorganisms including fungi and bacteria. That complex structure is dynamic and plays important roles in human health and disease. They might influence the progress of infectious diseases like oral cancer. Some of oral mycobiota may transform to bloodstream causing severe systematic diseases and a greater risk of sickness and death up to 79% of oral cancer patients. Oral cancer isolates were detected to be more virulent compared with other studied isolates including non-cancer isolates.


Aims: The aims of this study were to investigate the in vitro effects of ZnO NPs and apple cider vinegar (ACV) independently against Iraqi isolates of Candida albicans and Candida tropicalis isolated from oral cancer patients and healthy individuals. Dual and triple combinations of ZnO NPs or/and ACV combined with fluconazole (Flu) and Amphotericin B (AmphB) were tested against Candida isolates and first applied as alternative therapies in Iraq and in some application points around the world.


Methods: The two most common types C. tropicalis (P128), (H25) and C. albicans (P111), (H10) were selected against a range of concentrations of ZnO NPs, Flu and amphB (0.01-0.06 and 0.1 µg/ml) and six concentrations of ACV (50,000-780µg/ml) using micro dilution method. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) for each antifungal agent and their interactions among these drugs were also detected.


Result: The oral cancer isolates were more resistance to tested antifungals and their combinations compared with non-cancer isolates. Dual and triple combinations were synergistic and showed significant reductions in fungal growth in a dose dependent matter. The triple combination of ZnO NPs and ACV with Flu or AmphB revealed notable reduction in MICs and MFCs values.


Conclusion: These concentration-dependent interactions may have critical effects that need further study in animal models of investigated species.


The dual combination of ZnO NPs and ACV had a significant similarity with triple antifungal combinations of antifungal activity against Candida tropicalis.

Full text article

Generated from XML file

References

Abd Ulrahman Majeed, M., Jasim Mohammed, A., & Sadik Shalal, O. (2024). Genetic prevalence of antifungal resistance gene in cancer patients with Oropharyngeal Candidiasis from Iraq. Baghdad Science Journal, 21(12), 3762–3771. https://doi.org/10.21123/bsj.2024.9415

Abomuti, M. A., Danish, E. Y., Firoz, A., Hasan, N., & Malik, M. A. (2021). Green Synthesis of Zinc Oxide Nanoparticles Using Salvia officinalis Leaf Extract and Their Photocatalytic and Antifungal Activities. Biology, 10(11), 1075. https://doi.org/10.3390/biology10111075

Al Anbagi, R. A. A., Alshuwaili, F. R. H., Chijo, A. S., & Awad, G. W. (2025). Comparison of mucosal oral fungal colonization between diabetic patients and non-diabetic individuals in Babylon using molecular identification. Indian Journal of Microbiology Research, 12(1), 106–112. https://doi.org/10.18231/j.ijmr.2025.016

Berkow, E. L., Lockhart, S. R., & Ostrosky-Zeichner, L. (2020). Antifungal Susceptibility Testing: Current Approaches. Clinical Microbiology Reviews, 33(3), e00069-19. https://doi.org/10.1128/CMR.00069-19

Botton B., Breton A., Febre M., et al. Useful and Harmful Moulds. Industrial Importance. 2nd. Masson, Paris, France: 1990.

Branda, F., Petrosillo, N., Ceccarelli, G., Giovanetti, M., De Vito, A., Madeddu, G., Scarpa, F., & Ciccozzi, M. (2025). Antifungal Agents in the 21st Century: Advances, Challenges, and Future Perspectives. Infectious Disease Reports, 17(4), 91. https://doi.org/10.3390/idr17040091

Castillo, G. D. V., Blanc, S. L. D., Sotomayor, C. E., & Azcurra, A. I. (2018). Study of virulence factor of Candida species in oral lesions and its association with potentially malignant and malignant lesions. Archives of Oral Biology, 91, 35–41. https://doi.org/10.1016/j.archoralbio.2018.02.012

Chand, P., Kumari, S., Mondal, N., Singh, S. P., & Prasad, T. (2021). Synergism of Zinc Oxide Quantum Dots with Antifungal Drugs: Potential Approach for Combination Therapy against Drug Resistant Candida albicans. Frontiers in Nanotechnology, 3, 624564. https://doi.org/10.3389/fnano.2021.624564

Chauhan, A. K., Kataria, N., & Garg, V. K. (2020). Green fabrication of ZnO nanoparticles using Eucalyptus spp. Leaves extract and their application in wastewater remediation. Chemosphere, 247, 125803. https://doi.org/10.1016/j.chemosphere.2019.125803

Chiu, Y.-S., Chang, S.-C., Hsueh, P.-R., Wang, J.-L., Sun, H.-Y., & Chen, Y.-C. (2006). Survey of amphotericin B susceptibility of Candida clinical isolates determined by Etest. Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi, 39(4), 335–341.

Cornely, O. A., Sprute, R., Bassetti, M., Chen, S. C.-A., Groll, A. H., Kurzai, O., Lass-Flörl, C., Ostrosky-Zeichner, L., Rautemaa-Richardson, R., Revathi, G., Santolaya, M. E., White, P. L., Alastruey-Izquierdo, A., Arendrup, M. C., Baddley, J., Barac, A., Ben-Ami, R., Brink, A. J., Grothe, J. H., … Zhu, L.-P. (2025). Global guideline for the diagnosis and management of candidiasis: An initiative of the ECMM in cooperation with ISHAM and ASM. The Lancet Infectious Diseases, 25(5), e280–e293. https://doi.org/10.1016/S1473-3099(24)00749-7

de Aquino Lemos, J., Costa, C. R., de Araújo, C. R., Souza, L. K. H. E., & Silva, M. do R. R. (2009). Susceptibility testing of Candida albicans isolated from oropharyngeal mucosa of HIV(+) patients to fluconazole, amphotericin B and Caspofungin. Killing kinetics of caspofungin and amphotericin B against fluconazole resistant and susceptible isolates. Brazilian Journal of Microbiology: [Publication of the Brazilian Society for Microbiology], 40(1), 163–169. https://doi.org/10.1590/S1517-838220090001000028

Defta, C. L., Albu, C.-C., Albu, Ş.-D., & Bogdan-Andreescu, C. F. (2024). Oral Mycobiota: A Narrative Review. Dentistry Journal, 12(4), 115. https://doi.org/10.3390/dj12040115

Fayed, B., El-Sayed, H. S., Luo, S., & Reda, A. E. (2025). Comparative evaluation of biologically and chemically synthesized zinc oxide nanoparticles for preventing Candida auris biofilm. BioMetals, 38(3), 817–830. https://doi.org/10.1007/s10534-025-00678-6

Hadi, A. J., Nayef, U. M., Mutlak, F. A.-H., Jabir, M. S., & Muayad, M. W. (2025). Antibacterial and Anticancer Properties of Zinc Oxide Nanoparticles: A Review of Current Advances and Future Directions. Journal of Applied Sciences and Nanotechnology, 5(3), 60–87. https://doi.org/10.53293/jasn.2025.7541.1330

Hora, S. S., & Patil, S. K. (2022). Oral Microflora in the Background of Oral Cancer: A Review. Cureus. https://doi.org/10.7759/cureus.33129

Iyer, K. R., Robbins, N., & Cowen, L. E. (2022). The role of Candida albicans stress response pathways in antifungal tolerance and resistance. iScience, 25(3), 103953. https://doi.org/10.1016/j.isci.2022.103953

Jabalameli, Z., Sabzghabaee, A.-M., Mohaghegh, M.-A., Maherolnaghsh, M., Safavizadeh, H., & Dehghan, P. (2017). Antifungal Susceptibility of Candida Species Isolated from Cancer Patients with Oral Lesions Undergoing Chemotherapy. International Journal of Infection, 4(4). https://doi.org/10.5812/iji.14178

Khalifa, H. O., Watanabe, A., & Kamei, K. (2023). Antifungal Resistance and Genotyping of Clinical Candida parapsilosis Complex in Japan. Journal of Fungi, 10(1), 4. https://doi.org/10.3390/jof10010004

Lakshmy, J., Katragadda, R., & Balaji, J. (2016). Speciation and antifungal susceptibility of esophageal candidiasis in cancer patients in a tertiary care hospital in South India. Journal of Medical and Allied Sciences, 6(1), 29. https://doi.org/10.5455/jmas.214436

Lalla, R. V., Latortue, M. C., Hong, C. H., Ariyawardana, A., D’Amato-Palumbo, S., Fischer, D. J., Martof, A., Nicolatou-Galitis, O., Patton, L. L., Elting, L. S., Spijkervet, F. K. L., Brennan, M. T., & Fungal Infections Section, Oral Care Study Group, Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). (2010). A systematic review of oral fungal infections in patients receiving cancer therapy. Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer, 18(8), 985–992. https://doi.org/10.1007/s00520-010-0892-z

Li, Y., Liu, Y., Jiang, Y., Yang, Y., Ni, W., Zhang, W., & Tan, L. (2025). New antifungal strategies and drug development against WHO critical priority fungal pathogens. Frontiers in Cellular and Infection Microbiology, 15, 1662442. https://doi.org/10.3389/fcimb.2025.1662442

Lima, R., Ribeiro, F. C., Colombo, A. L., & De Almeida, J. N. (2022). The emerging threat antifungal-resistant Candida tropicalis in humans, animals, and environment. Frontiers in Fungal Biology, 3, 957021. https://doi.org/10.3389/ffunb.2022.957021

Lopez Venditti, E. D., Crespo Andrada, K. F., Bustos, P. S., Maldonado Torales, M., Manrrique Hughes, I., Paraje, M. G., & Guiñazú, N. (2025). Antibacterial, antifungal, and antibiofilm activities of biogenic zinc nanoparticles against pathogenic microorganisms. Frontiers in Cellular and Infection Microbiology, 15, 1545119. https://doi.org/10.3389/fcimb.2025.1545119

Makled, A. F., Ali, S. A. M., Labeeb, A. Z., Salman, S. S., Shebl, D. Z. M., Hegazy, S. G., & Sabal, M. S. (2024). Characterization of Candida species isolated from clinical specimens: Insights into virulence traits, antifungal resistance and molecular profiles. BMC Microbiology, 24(1), 388. https://doi.org/10.1186/s12866-024-03515-x

Meng, L., Li, J., Wang, D., Han, M., Gao, S., Zhang, Y., Zhu, W., & Liu, C. (2025). Epidemiology, risk factors, and antifungal susceptibility analysis of Candida tropicalis and non-C.tropicalis candidemia. BMC Infectious Diseases, 25(1), 1089. https://doi.org/10.1186/s12879-025-11445-w

Mohammed, S. W., Jabbar, F., Nayyef, H. J., Al-Malkey, M. K., Misha’al, K. I., & Taqi, E. Ab. (2021). The Efficiency of Apple Vinegar as A Solvent in Comparison to Water and Ethanol for The Extraction of Some Plants used Against Candida Spp. Biofilm Formation. Iraqi Journal of Science, 1829–1835. https://doi.org/10.24996/ijs.2021.62.6.8

Monsen, R. E., Kristoffersen, A. K., Gay, C. L., Herlofson, B. B., Fjeld, K. G., Hove, L. H., Nordgarden, H., Tollisen, A., Lerdal, A., & Enersen, M. (2023). Identification and susceptibility testing of oral candidiasis in advanced cancer patients. BMC Oral Health, 23(1), 223. https://doi.org/10.1186/s12903-023-02950-y

Monteiro, J. S., Kaushik, K., De Arruda, J. A. A., Georgakopoulou, E., Vieira, A. T., Silva, T. A., Devadiga, D., Anyanechi, C. E., & Shetty, S. (2024). Fungal footprints in oral cancer: Unveiling the oral mycobiome. Frontiers in Oral Health, 5, 1360340. https://doi.org/10.3389/froh.2024.1360340

Mota, A. C. L. G., De Castro, R. D., De Araújo Oliveira, J., & De Oliveira Lima, E. (2015a). Antifungal Activity of Apple Cider Vinegar on Candida Species Involved in Denture Stomatitis. Journal of Prosthodontics, 24(4), 296–302. https://doi.org/10.1111/jopr.12207

Mota, A. C. L. G., De Castro, R. D., De Araújo Oliveira, J., & De Oliveira Lima, E. (2015b). Antifungal Activity of Apple Cider Vinegar on Candida Species Involved in Denture Stomatitis. Journal of Prosthodontics, 24(4), 296–302. https://doi.org/10.1111/jopr.12207

Ousaaid, D., Laaroussi, H., Bakour, M., Ennaji, H., Lyoussi, B., & El Arabi, I. (2021). Antifungal and Antibacterial Activities of Apple Vinegar of Different Cultivars. International Journal of Microbiology, 2021, 1–6. https://doi.org/10.1155/2021/6087671

Pfaller, M. A., & Diekema, D. J. (2012). Progress in Antifungal Susceptibility Testing of Candida spp. By Use of Clinical and Laboratory Standards Institute Broth Microdilution Methods, 2010 to 2012. Journal of Clinical Microbiology, 50(9), 2846–2856. https://doi.org/10.1128/JCM.00937-12

Radaic, A., & Kapila, Y. L. (2021). The oralome and its dysbiosis: New insights into oral microbiome-host interactions. Computational and Structural Biotechnology Journal, 19, 1335–1360. https://doi.org/10.1016/j.csbj.2021.02.010

Schelenz, S., Abdallah, S., Gray, G., Stubbings, H., Gow, I., Baker, P., & Hunter, P. R. (2011). Epidemiology of oral yeast colonization and infection in patients with hematological malignancies, head neck and solid tumors: Oral candidiasis in cancer patients. Journal of Oral Pathology & Medicine, 40(1), 83–89. https://doi.org/10.1111/j.1600-0714.2010.00937.x

Scorzoni, L., De Paula E Silva, A. C. A., Marcos, C. M., Assato, P. A., De Melo, W. C. M. A., De Oliveira, H. C., Costa-Orlandi, C. B., Mendes-Giannini, M. J. S., & Fusco-Almeida, A. M. (2017). Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis. Frontiers in Microbiology, 08. https://doi.org/10.3389/fmicb.2017.00036

Smith, C., & Lee, S. C. (2022). Current treatments against mucormycosis and future directions. PLOS Pathogens, 18(10),e1010858. https://doi.org/10.1371/journal.ppat.1010858

Spitzer, M. H., Carmi, Y., Reticker-Flynn, N. E., Kwek, S. S., Madhireddy, D., Martins, M. M., Gherardini, P. F., Prestwood, T. R., Chabon, J., Bendall, S. C., Fong, L., Nolan, G. P., & Engleman, E. G. (2017). Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell, 168(3),487-502.e15. https://doi.org/10.1016/j.cell.2016.12.022

Vila, T., Sultan, A. S., Montelongo-Jauregui, D., & Jabra-Rizk, M. A. (2020). Oral Candidiasis: A Disease of Opportunity. Journal of Fungi, 6(1), 15. https://doi.org/10.3390/jof6010015

Vitale, R. G., Afeltra, J., & Dannaoui, E. (2005). Antifungal Combinations. In E. J. Ernst & P. D. Rogers, Antifungal Agents (Vol. 118, pp. 143–152). Humana Press. https://doi.org/10.1385/1-59259-943-5:143

Woods, R. A., Bard, M., Jackson, I. E., & Drutz, D. J. (1974). Resistance to Polyene Antibiotics and Correlated Sterol Changes in Two Isolates of Candida tropicalis from a Patient with an Amphotericin B-resistant Funguria. Journal of Infectious Diseases, 129(1), 53–58. https://doi.org/10.1093/infdis/129.1.53

Yassin, M. T., Al-Otibi, F. O., Al-Askar, A. A., & Elmaghrabi, M. M. (2023). Synergistic Anticandidal Effectiveness of Greenly Synthesized Zinc Oxide Nanoparticles with Antifungal Agents against Nosocomial Candidal Pathogens. Microorganisms, 11(8), 1957. https://doi.org/10.3390/microorganisms11081957

Yassin, M. T., Al-Otibi, F. O., Maniah, K., Mohamed, S., Hasan, K. A., Negi, A., & AbdelGawwad, M. R. (2025). Synergistic Antifungal Efficiency of Eco-FriendlySynthesized Zinc Oxide Nanoparticlesin Combination with Fluconazole againstDrug-Resistant Candidal Strains. Polish Journal of Environmental Studies, 34(2), 1851–1865. https://doi.org/10.15244/pjoes/188144

Zhang, D., Wang, Y., Shen, S., Hou, Y., Chen, Y., & Wang, T. (2020). The mycobiota of the human body: A spark can start a prairie fire. Gut Microbes, 11(4), 655–679. https://doi.org/10.1080/19490976.2020.1731287

Authors

Shatha Ghani Abbas
Dr. Rajaa Abdulrazzaq Al Anbagi
Shatha Ghani Abbas, & Al Anbagi, D. R. A. (2026). Application of New Syncretic Antifungal Formulations against Candida Species Associated with Oral Cancer. Journal of Current Medical Research and Opinion, 9(03), 4704–4724. https://doi.org/10.52845/CMRO/2026/9-3-5

Article Details