- Synthesis of new chalcone-based homoserine lactones and their antiproliferative activity evaluation. [Journal Article]
- EJEur J Med Chem 2018 Dec 07; 163:500-511
- Three series of new homoserine lactone analogs were efficiently synthesized starting from methionine and further evaluated for their antiproliferative activity against different cancer cell lines. Am...
Three series of new homoserine lactone analogs were efficiently synthesized starting from methionine and further evaluated for their antiproliferative activity against different cancer cell lines. Among these compounds, some of the chalcone containing compounds 6a-n showed acceptable antiproliferative activity against prostate cancer cells DU145 and PC-3 with the IC50 values less than 10 μM. Compounds 6c, 6e and 6h inhibited growth of DU145 and PC-3 cells at low micromolar levels with the IC50 values ranging from 3.0 to 5.0 μM, much more potent than natural OdDHL. Compound 6e concentration-dependently inhibited colony formation and cell migration of DU145 cells. A synergistic effect on the growth inhibition and the apoptosis of DU145 cells was observed when compound 6e was used in combination with TRAIL. OdDHL or 6e treatment concentration-dependently activated TRAIL death receptor DR5 which may account for the observed synergistic effect of 6e or OdDHL with TRAIL on the growth inhibition and cell apoptosis. Compound 6e also inhibited migration of DU145 cells in a time- and concentration-dependent manner. The data suggest that quorum sensing molecules OdDHL and 6e may improve the sensitivity of DU145 cells toward TRAIL via activating DR5, compound 6e may be used as a potential lead compound for developing new TRAIL receptor agonists.
- Prostate Cancer Genomic Classifier Relates More Strongly to Gleason Grade Group than PI-RADS Score in Multi-Parametric Prostate MRI-Ultrasound Fusion Targeted Biopsies. [Journal Article]
- UUrology 2018 Dec 12
- CONCLUSIONS: High-risk genomic classification can be seen across all combinations of PI-RADS categories and Gleason GG1 and GG2, confirming a potential utility for Decipher testing in men with low- to favorable intermediate-risk prostate cancer. The Decipher biopsy genomic test related to Gleason GG independent of PI-RADSv2 score. Confirmatory genomic testing for patients undergoing active surveillance appears more valuable than PIRADSv2 score.
- Resveratrol promotes apoptosis through the induction of dual specificity phosphatase 1 and sensitizes prostate cancer cells to cisplatin. [Journal Article]
- FCFood Chem Toxicol 2018 Dec 12
- Resveratrol is a polyphenol with chemopreventive properties against prostate cancer; however, the mechanisms underlying its actions are not completely understood. Previously, we demonstrated that DUS...
Resveratrol is a polyphenol with chemopreventive properties against prostate cancer; however, the mechanisms underlying its actions are not completely understood. Previously, we demonstrated that DUSP1 induces apoptosis in prostate cancer cells; therefore in the present study we investigated the role of this phosphatase on resveratrol effects. Moreover, we analysed the efficiency of combined treatment of resveratrol and the chemotherapeutic drug cisplatin on cellular viability and apoptosis and its relation with DUSP1 in prostate cancer cells. We found that resveratrol up-regulates DUSP1 expression in androgen-independent prostate cancer cells, which in turn, is involved in the inhibition of the NF-κB pathway and Cox-2 expression. This phosphatase is required for the induction of apoptosis achieved by resveratrol, but does not regulate the effects of this compound on cell cycle. Furthermore, we show that resveratrol cooperates with cisplatin both in the up-regulation of DUSP1 levels and in the promotion of apoptosis, suggesting that DUSP1 is a major determinant of cisplatin sensitivity to apoptosis. These results reveal a novel molecular mechanism by which resveratrol induces apoptosis in prostate cancer cells, and highlight the importance of DUSP1 in future therapeutic approaches based in the use of this polyphenol and cisplatin.
- Darpp-32 and t-Darpp protein products of PPP1R1B: old dogs with new tricks. [Review]
- BPBiochem Pharmacol 2018 Dec 12
- The PPP1R1B gene is located on chromosome 17q12 (39,626,208-39,636,626[GRCh38/hg38]), which codes for multiple transcripts and two experimentally-documented proteins Darpp-32 and t-Darpp. Darpp-32 (D...
The PPP1R1B gene is located on chromosome 17q12 (39,626,208-39,636,626[GRCh38/hg38]), which codes for multiple transcripts and two experimentally-documented proteins Darpp-32 and t-Darpp. Darpp-32 (Dopamine and cAMP Regulated Phosphoprotein), discovered in the early 1980s, is a protein whose phosphorylation is upregulated in response to cAMP in dopamine-responsive tissues in the brain. It's phosphorylation profile modulates its ability to bind and inhibit Protein Phosphatase 1 activity, which, in turn, controls the activity of hundreds of phosphorylated proteins. PPP1R1B knockout mice exhibit subtle learning defects. In 2002, the second protein product of PPP1R1B was discovered in gastric cancers: t-Darpp (truncated Darpp-32). The start codon of t-Darpp is amino acid residue 37 of Darpp-32 and it lacks the domain responsible for modulating Protein Phosphatase 1. Aside from gastric cancers, t-Darpp and/or Darpp-32 is overexpressed in tumor cells from breast, colon, esophagus, lung and prostate tissues. More than one research team has demonstrated that these proteins, through mechanisms that to date remain cloudy, activate AKT, a protein whose phosphorylation leads to cell survival and blocks apoptosis. Furthermore, in Her2 positive breast cancers (an aggressive form of breast cancer), t-Darpp/Darpp-32 overexpression causes resistance to the frequently-administered anti-Her2 drug, trastuzumab (Herceptin), likely through AKT activation. Here we briefly describe how Darpp-32 and t-Darpp were discovered and report on the current state of knowledge of their involvement in cancers. We present a case for the development of an anti-t-Darpp therapeutic agent and outline the unique challenges this endeavor will likely encounter.
- Polymorphisms in XPC gene and risk for prostate cancer. [Journal Article]
- MBMol Biol Rep 2018 Dec 14
- Single nucleotide polymorphisms (SNP) in repair gene DNA such as XPC gene can reduce the DNA repair capacity (DRC). Reduced DRC induce genetic instability and may increase the susceptibility to prost...
Single nucleotide polymorphisms (SNP) in repair gene DNA such as XPC gene can reduce the DNA repair capacity (DRC). Reduced DRC induce genetic instability and may increase the susceptibility to prostate cancer (PC). We conducted a case-controls study to examine the relationship between XPC Lys939Gln and XPC-PAT polymorphisms and the risk for prostate cancer in Tunisian population. We have also correlated molecular results with clinical parameters (Gleason score and TNM status) and lifestyle factors (tobacco status, alcohol consumption, and exposition to professional risk factors) of prostate cancer patients. We have found that the XPC Lys939Gln polymorphism was not associated with a risk of prostate cancer. However the XPC PAT I/I genotype was found to be associated with 3.83-fold increased risk of prostate cancer compared to controls (p = 0.00006; OR 3.83; 95% CI (1.83-8.05)). The test of linkage disequilibrium showed that XPC-PAT polymorphism is in linkage disequilibrium with XPC Lys939Gln variants. The combined analysis of XPC Lys939Gln and XPC-PAT variants showed that patients who inherited (Lys/Gln + PAT D/D) genotypes were protected against prostate cancer development compared to controls. In the other hand, no significant association has been found between XPC polymorphisms and clinical parameters or between XPC polymorphisms and lifestyle factors.
- Predicting 7-year mortality for use with evidence-based guidelines for Prostate-Specific Antigen (PSA) testing: findings from a large prospective study of 123 697 Australian men. [Journal Article]
- BOBMJ Open 2018 Dec 14; 8(12):e022613
- CONCLUSIONS: We developed prediction scores for short-term mortality using age and self-reported health measures and validated the scores against national mortality rates. Along with age, simple measures such as self-rated health, which can be easily obtained without physical examination, were strong predictors of all-cause mortality in the 45 and Up Study. Seven-year mortality risk estimates from Model-3 suggest that the impact of the mortality risk prediction tool on men's decision making would be small in the recommended age (50-69 years) for PSA testing, but it may discourage testing at older ages.
- Impact of 68Ga-PSMA-PET/CT on the radiotherapeutic approach for prostate cancer in comparison to CT - a retrospective analysis. [Journal Article]
- JNJ Nucl Med 2018 Dec 14
- 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) offers unprecedented accuracy for staging of primary, persistent or recurrent prostate...
68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) offers unprecedented accuracy for staging of primary, persistent or recurrent prostate cancer. Thus, we hypothesized that PSMA PET/CT prior to radiotherapy significantly impacts the radiotherapeutic approach in comparison to the current standard of CT based approach. Methods: Between February 2014 and December 2017, a total of 172 patients received PSMA PET/CT before radiotherapy and were included in this retrospective analysis. Twenty-two (13%) patients were referred for primary definitive radiotherapy, 51% (88/172) for PSA persistence and 36% (62/172) for PSA recurrence after radical prostatectomy. An experienced radiation oncologist, blinded to the CT and PET/CT imaging results, decided on the radiation treatment management of all patients based on the clinical and pathological variables. The potential increase in diagnostic accuracy, and the subsequent change of radiotherapeutic approach was documented separately for PET/CT versus CT. Results: Overall detection rate was 70% (120/172) in 68Ga-PSMA PET/CT. Patients with pre-PSMA PET/CT PSA-level >0.5 ng/ml (98/111; 88%) had significantly more often PET-positive results. Overall, PSMA PET/CT revealed a total of 171 lesions, PET alone 156 and CT alone 85. For all patients a continuous diagnostic increase in positive findings was observed for primary tumor/local recurrence (CT: 18% vs. PET/CT: 37%), pelvic lymph node (CT: 21% vs. PET/CT: 44%) and distant metastases (CT: 7% vs. PET/CT: 19%) when comparing CT vs. PET/CT. Compared to CT, the combination of PET/CT information resulted in a change of treatment in 107/172 (62%) patients, i.e. 8/22 (36%) patients prior to any treatment, 31/62 (50%) with PSA recurrence and 68/88 (77%) with PSA persistence. Comparing the different radiotherapy indications with each other, there was a higher change of management in postoperative patients vs. patients prior to any treatment. Conclusion: Compared to conventional CT, PSMA PET/CT had a remarkable impact on radiotherapeutic approach especially in postoperative patients. Thus, considering the growing amount of data on PSMA PET/CT's impact in postoperative patients, PSMA PET/CT has recently been endorsed as an imaging modality in patients with PSA persistence/recurrence in a few cancer guidelines, for instance the German S3 guideline and the European association of urology guideline.
- Combination of 68Ga-PSMA PET/CT and multiparameter MRI improves the detection of clinically significant prostate cancer: a lesion by lesion analysis. [Journal Article]
- JNJ Nucl Med 2018 Dec 14
- Purpose: To explore whether 68Ga-PSMA PET/CT (PET/CT) or the combination of mpMRI and 68Ga-PSMA PET/CT (com-MRI/PET) can improve the detection of csPCa. Methods: We retrospectively enrolled 54 pati...
Purpose: To explore whether 68Ga-PSMA PET/CT (PET/CT) or the combination of mpMRI and 68Ga-PSMA PET/CT (com-MRI/PET) can improve the detection of csPCa. Methods: We retrospectively enrolled 54 patients who underwent both mpMRI and PET/CT before radical prostatectomy. Regions of interest (ROI) on imaging from mpMRI, PET/CT and pathology were marked. A lesion was defined when ROI was marked in the same location on continuous imaging at any of the imaging setting. All lesions were recorded by Prostate Imaging Reporting and Data System (PI-RADS), miPSMA expression score (MI-ES) and pathology results and analyzed. The diagnostic performance was analyzed by receiver operating characteristics (ROC) analysis. Specific improvement for lesions with different PI-RADS score and were analyzed by net reclassification improvement (NRI). Results: Totally, 90 lesions from 54 patients were analyzed, among which 66 lesions were csPCa. ROC analysis showed improvement of com-MRI/PET comparing with mpMRI for csPCa detection (Δ area under the curves (ΔAUC) 0.06; 95% CI, 0.01-0.12; p<0.05). With calculated cutoff, com-MRI/PET has a significant overall improvement compared with mpMRI (NRI, 21.9%, p<0.01), with an improvement on sensitivity (89% versus 76%, p<0.01) and no sacrifice on specificity (96% versus 88%, p>0.05). Diagnostic improvement for csPCa detection happened on lesions with PI-RADS 3 (NRI 66.7%, P<0.01). Conclusion: The com-MRI/PET improves the detection of csPCa for lesions with PI-RADS 3.
- Rapid modulation of PSMA expression by Androgen deprivation: Serial 68Ga PSMA-11 PET in men with hormone sensitive and castrate resistant prostate cancer commencing androgen blockade. [Journal Article]
- JNJ Nucl Med 2018 Dec 14
- Prostate specific membrane antigen (PSMA) may be targeted for both diagnostic and therapeutic purposes in the management of prostate cancer (PCa). In pre-clinical models, androgen blockade (AB) incre...
Prostate specific membrane antigen (PSMA) may be targeted for both diagnostic and therapeutic purposes in the management of prostate cancer (PCa). In pre-clinical models, androgen blockade (AB) increases expression of PSMA in both hormone sensitive and castrate resistant xenotypes. The aim of this study was to evaluate the effect of AB treatment on Ga68PSMA-11 PET imaging in hormone naive (Luteinising hormone-releasing hormone (LHRH) ± bicalutamide), and in castrate resistant men (enzalutamide or abiraterone) with metastatic PCa. MATERIALS AND METHODS: Serial 68GaPSMA-11 PET were prospectively performed at baseline, days 9, 18 and 28, in 8 men with measurable metastatic hormone sensitive PCa commencing LHRH ± bicalutamide (cohort 1), and 7 men with castrate resistant PCa commencing either enzalutamide or abiraterone (cohort 2). Gleason score (GS), age, time since diagnosis and prior treatments were documented. Testosterone and PSA were measured at baseline and all imaging time points. PET/CT was quantitatively analysed for SUV max, SUV mean and total tumour volume (TTV). RESULTS: Cohort 1: A median 30% (IQR 5-61) reduction in SUV max was recorded by day 9 post AB. A reduction from baseline SUV max occurred in 86.5% (6/7) men by day 9 (P <0.04), with an associated PSA response in 100% men (P < 0.03). TTV reduced in all men by 74.5% (IQR 27- 97) (P <0.02). Following day 9, PSMA response heterogeneity was noted, with persistently high or increasing SUV max in 37.5% (3/8) and marked reduction in 62.5% (5/8). Cohort 2: A median 45% (IQR 12.7-66) increase in intensity of PSMA SUV was recorded by day 9 post AB. All men demonstrated an increase in SUV max and mean on PSMA PET compared to baseline (P < 0.04). This increase at day 9 plateaued by day 28. PSA responses were more delayed in cohort 2 (-15% (IQR 70 -138), with 2/7 men demonstrating PSA progression. Conclusion: There is rapid dichotomous response on 68GaPSMA PET imaging to androgen blockade dependent on the presence of a hormone sensitive or castrate resistant PCa phenotype. This has important implications for interpretation of PSMA PET , and in the timing and sequencing of PSMA targeted therapy.
New Search Next
- Albumin-Binding PSMA Ligands: Implications for Expanding the Therapeutic Window. [Journal Article]
- JNJ Nucl Med 2018 Dec 14
- Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting PSMA, 30% of patients never respond to therapy. One possible explanation is ins...
Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting PSMA, 30% of patients never respond to therapy. One possible explanation is insufficient dose delivery to the tumor, which is related to suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors, but also in kidneys. We aimed to use structural modifications to increase the tumor-to-kidney ratio through increased albumin binding and tumor uptake and reduction of kidney activity. Methods: Four structurally-related trifunctional PSMA-targeting small molecules were prepared by either varying the albumin binding group or by inserting a PEG8 linker into a common structure. The compounds were ranked by PSMA affinity and albumin affinity, radiolabeled with 68Ga and 177Lu, and tissue kinetics determined in male BALB/C nu/nu mice bearing LNCaP xenograft tumors. Results: Each of the compounds binds PSMA with IC50 < 10 nM. The albumin binding group had a minimal effect on PSMA affinity, but changed albumin affinity by an order of magnitude. However, the addition of a PEG8 spacer weakened affinity for albumin in each case. Increased affinity for albumin corresponded with delayed blood clearance and modified uptake kinetics in the tumor and kidney. Uptake of 177Lu-RPS-072 (34.9 ± 2.4 %ID/g) and 177Lu-RPS-077 (27.4 ± 0.6 %ID/g) increased up to 24 h post injection, and washout by 96 h was not significant. As a result, the area under the curve (AUC) in the tumor was in the order 177Lu-RPS-072>177Lu-RPS-077>177Lu-RPS-063>177Lu-RPS-071. Increased linker length corresponded with more rapid clearance from kidneys. Consequently, the ratio of tumor AUC and kidney AUC was 4.7 ± 0.3 for 177Lu-RPS-072. Conclusion: The AUC in the tumor and tumor-to-kidney ratio of 177Lu-RPS-072 are superior to any small molecule investigated in a LNCaP xenograft model to date. In comparison to other PSMA-targeting radioligands that have been evaluated in a PC3-PIP model, activity in kidneys is reduced and activity in tumors compares favorably when the different PSMA expression levels in LNCaP and PC3-PIP cells are taken into account. RPS-072 therefore exhibits an increased therapeutic index, shows the potential to increase the dose delivered to tumors and is a highly promising candidate for targeted radioligand therapy.