morphinans and Prostatic-Neoplasms

Background Prostate cancer is an extremely common disease in males, and the mortality of prostate cancer has been rising year by year. Sinomenine has been reported to exhibit anti-tumor effect on various cancers, but the function of Sinomenine in prostate cancer remains unclear. The study aimed to explore the effect of Sinomenine on proliferation, apoptosis, migration and invasion in prostate cancer cells. Methods PC3 cells were stimulated by different concentrations of Sinomenine, then cell proliferation, migration, invasion and apoptosis were examined by CCK-8, BrdU, Transwell and flow cytometry, respectively. Subsequently, miR-23a mimic and miR-23a inhibitor were transfected into PC3 and LNCaP cells, cell proliferation, apoptosis, migration and invasion were reassessed in these transfected cells. The related factors of cell cycle, apoptosis, metastasis and PI3K/AKT and JAK/STAT signal pathways were measured by western blot. Results Sinomenine significantly suppressed cell proliferation, promoted apoptosis and inhibited migration and invasion, as well as down-regulated Cyclin D1, CDK4, Bcl-2, MMP-2, MMP-9, Vimentin protein levels and up-regulated p16 and Bax protein levels in PC3 cells. Additionally, Sinomenine decreased the expression level of miR-23a, and overexpression of miR-23a reversed the effects of Sinomenine on cell proliferation, apoptosis, migration and invasion in PC3 and LNCaP cells. Further, Sinomenine inactivated PI3K/AKT and JAK/STAT signal pathways by regulation of miR-23a. Conclusions The data suggested that Sinomenine could suppress cell proliferation, migration, invasion, and promote apoptosis of prostate cancer cells through regulation of miR-23a. These findings might provide a possible strategy for the clinical treatment of prostate cancer.

Topics: Apoptosis; Cell Movement; Cell Proliferation; Humans; Male; MicroRNAs; Morphinans; Neoplasm Invasiveness; Prostatic Neoplasms

The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.. We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.. A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.. Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).

Topics: Androstenes; Androstenols; Benzamides; Drug Resistance, Neoplasm; Humans; Male; Morphinans; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Survival Analysis

Opioid agonists (ethylketocyclazocine, etorphine, [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Ala2, N-Me-Phe4-Gly-ol]enkephalin (DAGO), [D-Ser2,Leu5]enkephalin-Thr6 (DSLET) and morphine were found to inhibit the proliferation of human prostate cancer cell lines (LNCaP, DU145, and PC3), in a dose-dependent manner. The 50% inhibitory concentrations (IC50) were in the picomolar range. In many cases, this effect was antagonized by the general opioid antagonist, diprenorphine, indicating the existence of specific opioid binding sites. Saturation binding experiments with selective ligands and effectors showed no opioid sites on the LNCaP cell line, kappa1 and mu sites on the PC3 cell line, and kappa1, kappa3 and mu sites on the DU145 cell line. In other cases, the opioid effect was not antagonized by diprenorphine, indicating that the action of opioids might be mediated through other membrane receptors. Furthermore, casomorphin peptides, issued from bovine alpha- (alpha-casein-90-95 and alpha-casein-90-96) and beta-caseins (beta-casomorphin and beta-casomorphin-1-5), and human alphaS1-casein (alphas -casomorphin and alphaS1-casomorphin amide) inhibited cell proliferation of human prostate cell lines, also by a mechanism partly involving opioid receptors. As opioid neurons can be found in the prostate gland, and casomorphin peptides might reach the gland through the general circulation, the above findings indicate a putative role of opioids in prostate cancer cell growth.

Topics: Binding Sites; Caseins; Cell Division; Cell Survival; Enkephalins; Ethylketocyclazocine; Humans; Ligands; Male; Morphinans; Narcotic Antagonists; Narcotics; Prostatic Neoplasms; Receptors, Opioid; Tumor Cells, Cultured

Long-term treatment for more than 3 months with a central nervous system (CNS)-active drug, the opioid agonist bremazocine, at a dose of 1 mg/kg per day elicited an 80% inhibition of the volume of the subcutaneously transplanted rat prostate adenocarcinoma Dunning R3327H. Whereas, under this therapy, prostate tumour and prostatic weights were decreased, testes and pituitary weights remained normal. Bremazocine inhibited not only the growth of freshly transplanted tumours but also that of well-grown Dunning prostate carcinomas since, after 41 days of treatment, such tumours showed a volume inhibition of 52%. In these experiments bremazocine decreased LH and testosterone plasma levels significantly. Bremazocine, therefore, probably acts mainly through suprapituitary CNS-opiate receptor sites, which indirectly, rather than locally, mediate LH inhibition. Indeed, no specific receptors for bremazocine could be found in the Dunning tumour, which makes a local action of bremazocine in this tissue unlikely. the efficient tumour growth inhibition through the supra-pituitary action of bremazocine makes such opiate drugs, which lack respiratory and side effects due to improper use, of potential interest for treatment of prostatic tumours.

Topics: Adenocarcinoma; Animals; Benzomorphans; Central Nervous System; Luteinizing Hormone; Male; Morphinans; Organ Size; Prostate; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Testosterone