ABSTRACT
Abiraterone acetate has been clinically approved for the treatment of patients with advanced-stage prostate cancer. It reduces testosterone production by blocking the enzyme cytochrome P450 17 alpha-hydroxylase. Despite improved survival outcomes with abiraterone, almost all patients develop therapeutic resistance and disease recurrence, progressing to a more aggressive and lethal phenotype. Bioinformatics analyses predicted activation of canonical Wnt/ß-catenin and involvement of stem cell plasticity in abiraterone-resistant prostate cancer. Increased expression of androgen receptor (AR) and ß-catenin and their crosstalk causes activation of AR target genes and regulatory networks for which overcoming acquired resistance remains a major challenge. Here we show that co-treatment with abiraterone and ICG001, a ß-catenin inhibitor, overcomes therapeutic resistance and significantly inhibited markers of stem cell and cellular proliferation in abiraterone-resistant prostate cancer cells. Importantly, this combined treatment abrogated the association between AR and ß-catenin; diminished SOX9 expression from the complex more prominently in abiraterone-resistant cells. In addition, combined treatment inhibited tumor growth in an in vivo abiraterone-resistant xenograft model, blocked stemness, migration, invasion, and colony formation ability of cancer cells. This study opens new therapeutic opportunity for advanced-stage castration-resistant prostate cancer patients.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Drug Resistance, Neoplasm , beta Catenin/metabolism , Neoplasm Recurrence, Local , Receptors, Androgen/genetics , Receptors, Androgen/metabolismABSTRACT
OBJECTIVE: To determine the selectivity of 5-aminolevulinic acid (5-ALA) as a photosensitizer to malignant prostatic cells in men undergoing radical retropubic prostatectomy. PATIENTS AND METHODS: Nineteen patients with localized prostate cancer were included in the study. Eighteen patients received 5-ALA and one patient did not receive it and was used as a control. The dose was 20mg /kg body weight, 15 patients received 5-ALA 4 hours before radical prostatectomy, two patients received it 2 hours before prostatectomy through a Ryle tube, and one patient received 5-ALA 12 hours before the operation. The removed prostates were examined for protoporphyrin IX (PpIX) fluorescence macroscopically, by fluorescence microscopy and by light microscopy. RESULTS: All carcinomas showed a clear evidence of PpIX-enrichment except in the control case. The enrichments were strong (++) in 15 cases and weak (+) in 3 cases. Two of those three cases were given 5-ALA two hours through a Ryle tube before excision of the prostate as well as the patient who was given 5-ALA 12 hours preoperatively. No PpIX enrichment was observed in the stroma of the prostate gland or in the benign tissue sections in any case (0/19). CONCLUSION: Oral 5-ALA is selectively concentrated in malignant cells of the prostate. This may lead to the clinical application of photodynamic therapy for localized prostate cancer.