Abstract
Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.
Highlights
Prostate cancer (PCa) represents the most common non-cutaneous malignancy diagnosed in men, with more than 1,200,000 new estimated cases each year and over 350,000 deaths worldwide [1]. it can be successfully treated in its early stage with radiation therapy and radical prostatectomy, once it has escaped the prostate gland treatment is mainly by using androgen deprivation therapy (ADT)
Patients who no longer respond to ADT develop an aggressive and often untreatable form of PCa known as castrate-resistant prostate cancer (CRPC), which is characterized by a high propensity for metastasis and short median survival rates ranging from 12.1 to 27.0 months [4,5,6]
Prostate cancer stem cells (PCSCs) that possess tumor-initiating capacity represent a small percentage of the whole cancer population, yet these are considered to play a major role in patient relapse
Summary
Prostate cancer (PCa) represents the most common non-cutaneous malignancy diagnosed in men, with more than 1,200,000 new estimated cases each year and over 350,000 deaths worldwide [1] It can be successfully treated in its early stage with radiation therapy and radical prostatectomy, once it has escaped the prostate gland treatment is mainly by using androgen deprivation therapy (ADT). Members of the ALDH1A family seem to be important in many cancer types, including PCa, where both ALDH1A1 and 1A3 isoforms have been reported to be expressed at higher levels in tumor tissue compared to benign prostatic hyperplasia and normal prostate [26] while 1A2 may have value as a tumor suppressor gene [27] They are acknowledged to promote clonogenic and migration cell capabilities in vitro and enhance the metastatic potential in vivo [28] while expression correlates with higher Gleason score (G8–9) in vivo [29]. Functional efficacy of the compounds was assessed in both established prostate cell lines, as well as patient-derived primary prostate tumor epithelial cells
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