Itraconazole synergistically increases therapeutic effect of paclitaxel and 99mTc-MIBI accumulation, as a probe of P-gp activity, in HT-29 tumor-bearing nude mice
Abstract
P-glycoprotein (P-gp), is an important efflux pump involved in chemotherapy resistance in human colon cancer. We investigated the efficacy of itraconazole as a P-gp inhibitor and its therapeutic synergistic relationship to paclitaxel through 99m Tc-MIBI accumulation in HT-29 tumor-bearing nude mice. Histopathological screening along with in vitro experiments was done for further assessment. Itraconazole successfully inhibited P-gp mediated 99m Tc-MIBI efflux, increasing its in vitro accumulation in itraconazole-receiving dishes. Notably, the co-administration of itraconazole with paclitaxel significantly enhanced the in vitro cytotoxicity effect of paclitaxel in itraconazole + paclitaxel wells containing HT-29 cells. Compared to the control, tumor volume in mice treated with itraconazole, paclitaxel and itraconazole +paclitaxel showed growth suppression approximately by 36.21, 60.02, and 73.3% respectively. And compared to paclitaxel group, the nude mice co-treated with paclitaxel and itraconazole showed suppression of tumor growth by about 33.31 % at the end of the treatment period. Also the biodistribution result showed that the co-administration of itraconazole with paclitaxel raised the mean tumor radioactivity accumulation compared to control and paclitaxel group. When given paclitaxel alone, the ID% of hepatic and cardiac tissue was reduced while co-administration of itraconazole with paclitaxel increased 99m Tc-MIBI accumulation in these organs. Furthermore, the histopathological findings confirmed the biodistribution results. These results demonstrate that although monotherapy with itraconazole or paclitaxel has anti-tumor activity against HT-29 human colorectal cancer, a synergistic anti-tumor activity can be achieved when itraconazole is co-administered with paclitaxel. Also, 99m Tc-MIBI is an effective radiotracer for monitoring response to treatment in MDR tumors.
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Nude mice co-treated with paclitaxel and ITZ demonstrated a decrease of tumor growth of roughly 33.31 percent compared to the paclitaxel group.
“At the conclusion of the treatment period, the nude mice co-treated with paclitaxel and ITZ demonstrated a decrease of tumor growth of roughly 33.31 percent in comparison to the paclitaxel group.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
Co-administration of paclitaxel and ITZ considerably increased paclitaxel's in vitro cytotoxicity impact in HT-29 cell-containing ITZ + paclitaxel wells.
“The co-administration of paclitaxel and ITZ considerably increased the paclitaxel's in vitro cytotoxicity impact in HT-29 cell-containing ITZ + paclitaxel wells.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
The ID% of cardiac and hepatic tissue decreased when paclitaxel was administered alone, while 99mTc-MIBI accumulation in these organs increased when ITZ and paclitaxel were administered together.
“The ID% of cardiac and hepatic tissue decreased when paclitaxel was administered alone, while 99mTc-MIBI accumulation in these organs increased when ITZ and paclitaxel were administered together.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
ITZ, paclitaxel, and ITZ + paclitaxel-treated mice had tumor volumes roughly 36.21, 60.02, and 73.3% smaller than the control group.
“ITZ, paclitaxel, and ITZ + paclitaxel-treated mice had tumor volumes that were roughly 36.21, 60.02, and 73.3% smaller than the control group.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
Although paclitaxel or ITZ by themselves are effective against HT-29 human colorectal cancer, co-administration of the two drugs can have a synergistic anti-tumor impact.
“These results demonstrated that although paclitaxel or ITZ by themselves are effective against HT-29 human colorectal cancer, co-administration of the two drugs can have a synergistic anti-tumor impact.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
99mTc-MIBI is a useful radiotracer for tracking how well multidrug-resistant tumors are responding to treatment.
“Additionally, 99mTc-MIBI is a useful radiotracer for tracking how well multidrug-resistant (MDR) tumors are responding to treatment.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
Mean tumor radioactivity accumulation increased when ITZ and paclitaxel were administered together compared to the control and paclitaxel groups.
“Additionally, the biodistribution result demonstrated that, in comparison to the control and paclitaxel groups, the mean tumor radioactivity accumulation increased when ITZ and paclitaxel were administered together.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
In vitro accumulation of 99mTc-MIBI in ITZ-receiving dishes increased as a result of ITZ's effective inhibition of P-gp-mediated efflux.
“In vitro accumulation of 99mTc-MIBI in ITZ-receiving dishes increased as a result of ITZ's effective inhibition of P-gp-mediated efflux.”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
ITZ's effects on the P-gp mediated 99mTc-MIBI efflux pump are associated with a synergistic effect with paclitaxel against HT-29 colon cancer cells in nude mice, with 73.3% growth suppression compared to 60.02% for paclitaxel alone.
“Additionally, its effects on P-gp mediated 99mTc-MIBI efflux pump has been associated with synergistic effect with paclitaxel against HT-29 colon cancer cells in nude mice with 73.3% of growth suppression compared to 60.02% for paclitaxel singly.70”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [70]
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References 103 · Cited by 17
- Authors
- Ghadi, M., Hosseinimehr, S. J., Amiri, F. T., Mardanshahi, A., & Noaparast, Z.
- Affiliations
- Mazandaran University of Medical Sciences (IR)
- Corresponding author
- Noaparast, Zohreh
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 895
- Pages
- 173892
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W3124125339
- Cited by
- 17
- References
- 103
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 1
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mazandaran University of Medical Sciences
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- itraconazole, paclitaxel, P-glycoprotein, multidrug resistance, 99mTc-MIBI, radioactive tracers, drug efflux inhibition, colon cancer, HT-29 cells, tumor growth inhibition, tissue distribution, chemoresistance, synergistic drug combination
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Antineoplastic Agents, Phytogenic, Colonic Neoplasms, Drug Synergism, Female, Humans, Mice, Nude, Tissue Distribution, Paclitaxel, Technetium Tc 99m Sestamibi, Itraconazole, ATP Binding Cassette Transporter, Subfamily B, HT29 Cells, Radiopharmaceuticals, Xenograft Model Antitumor Assays, Mice, Whole Body Imaging
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