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Updated: Aug 9, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Preclinical evaluation of itraconazole in docetaxel-resistant prostate cancer xenograft models
Luciano O Souza1, Annette Bartels2, José M A Moreira2
1Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Sino-Danish Center for Education and Research, Aarhus University, Denmark.
Abstract:
Docetaxel (DTX) resistance remains a major barrier in metastatic prostate cancer, often driven by ABCB1 efflux and activation of survival pathways. We investigated the therapeutic impact of itraconazole (ITZ), a multifunctional antifungal agent with activity against Hedgehog/GLI signalling and ABCB1 efflux, in DTX-resistant prostate cancer xenograft models (PC3R and DU145R). Tumour growth was analysed longitudinally, metastatic burden assessed by hCD44-positive micrometastasis enumeration, and pharmacodynamic responses evaluated through Ki-67 indexes, necrotic fractions, and Gli1 expression. Neither DTX alone, ITZ alone, nor their combination reduced primary tumour growth or cumulative tumour burden. However, the combination suppressed development of lung micrometastases in both models. ITZ and DTX + ITZ reduced Ki-67 and Gli1 levels, demonstrating inhibition of proliferation and Hedgehog signalling despite the absence of tumour shrinkage. ITZ monotherapy was well tolerated, whereas DTX-containing regimens produced expected systemic toxicity. These results indicate antimetastatic and pathway-modulating activity of ITZ in resistant prostate cancer and support its further evaluation as a rational adjunct to taxanes in treatment contexts where metastatic control is a key therapeutic objective.
Insights
Itraconazole (ITZ) shows antimetastatic effects in docetaxel-resistant prostate cancer by suppressing lung micrometastases and Hedgehog signalling. This suggests ITZ as a potential adjunct therapy for metastatic prostate cancer.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Docetaxel (DTX) resistance is a significant challenge in metastatic prostate cancer.
- ABCB1 efflux and survival pathway activation contribute to DTX resistance.
- Itraconazole (ITZ) exhibits activity against Hedgehog/GLI signalling and ABCB1 efflux.
Purpose of the Study:
- To investigate the therapeutic impact of ITZ in DTX-resistant prostate cancer xenograft models.
- To evaluate ITZ's effects on tumour growth, metastasis, and relevant signalling pathways.
Main Methods:
- Utilized DTX-resistant prostate cancer xenograft models (PC3R and DU145R).
- Assessed tumour growth, lung micrometastasis, Ki-67 index, necrotic fraction, and Gli1 expression.
- Evaluated pharmacodynamic responses to DTX, ITZ, and their combination.
Main Results:
- Neither DTX, ITZ, nor their combination reduced primary tumour growth.
- The combination therapy suppressed lung micrometastasis development in both models.
- ITZ and combination therapy reduced Ki-67 and Gli1 levels, indicating inhibited proliferation and Hedgehog signalling.
Conclusions:
- Itraconazole demonstrates antimetastatic activity and pathway modulation in resistant prostate cancer.
- ITZ may serve as a rational adjunct to taxanes for controlling metastasis.
- Further evaluation of ITZ in metastatic prostate cancer treatment is warranted.
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