Preclinical evaluation of itraconazole in docetaxel-resistant prostate cancer xenograft models.

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.