Seliciclib is a cyclin-dependent kinase (CDK) inhibitor that has been assayed in phase II clinical trials as an anticancer agent. This paper describes the synthesis of novel derivatives of seliciclib ...with improved potency, metabolic stability, aqueous solubility, and anti-proliferative activity. The new derivatives showed a novel CDKs selectivity profile. Replacement of ethyl alcohol at position 2 of purine with dimethylaminopropyl and fluorination of benzyl at position 6 of purine of seliciclib resulted in the formation of a derivative that potently and selectively inhibited CDK9 (26 nM vs. CDK9 and > 60-fold selectivity vs. CDK2/5/7). In comparison to seliciclib, this derivative shows lower metabolic clearance (25% lower in Cl
int
), higher aqueous solubility and is more cytotoxic in androgen-independent prostate cancer cells.
Graphic abstract
Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited ...for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual‐nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual‐chelator conjugates, featuring interlinked cyclen‐ and triazacyclononane‐based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g., 177Lu, 90Y, or 213Bi) and PET (e.g., 68Ga) radiometals in the same molecular framework by exploiting the orthogonal metal ion selectivity of these chelators (DOTPI: large cations, such as lanthanide(III) ions; TRAP: small trivalent ions, such as GaIII). Such DOTPI–TRAP conjugates were decorated with 3 Gly‐urea‐Lys (KuE) motifs for targeting prostate‐specific membrane antigen (PSMA), employing Cu‐catalyzed (CuAAC) as well as strain‐promoted (SPAAC) click chemistry. These were labeled with 177Lu or 213Bi and 68Ga and used for in vivo imaging of LNCaP (human prostate carcinoma) tumor xenografts in SCID mice by PET, thus proving practical applicability of the concept.
Take two: Dual‐nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, derived from common and widely available metal radionuclides, enable a precise PET‐based dosimetry for improvement of individual therapeutic outcome and increased patient safety in molecular radiotherapy.
SERS microscopy is a novel staining technique in immunohistochemistry, which is based on antibodies labeled with functionalized noble metal colloids called SERS labels or nanotags for optical ...detection. Conventional covalent bioconjugation of these SERS labels cannot prevent blocking of the antigen recognition sites of the antibody. We present a rational chemical design for SERS label-antibody conjugates which addresses this issue. Highly sensitive, silica-coated gold nanoparticle clusters as SERS labels are non-covalently conjugated to primary antibodies by using the chimeric protein A/G, which selectively recognizes the Fc part of antibodies and therefore prevents blocking of the antigen recognition sites. In proof-of-concept two-color imaging experiments for the co-localization of p63 and PSA on non-neoplastic prostate tissue FFPE specimens, we demonstrate the specificity and signal brightness of these rationally designed primary antibody-protein A/G-gold nanocluster conjugates.
Pollution status of six anticancer agents in the river water and effluents of sewage treatment plants (STPs) in Japan was surveyed with comparative analysis of the levels of four microbial and one ...psychotropic pharmaceuticals widely used for therapeutic medication. The area of survey is located in the Kanzaki–Ai River basin which is a major subcatchment of the Yodo River basin and is centered on a highly populated area that includes the middle and downstream reaches of the Yodo River. Selected cancer agents were bicalutamide, capecitabine, cyclophosphamide, doxifluridine, tamoxifen, and tegafur. A combination of strong anion solid-phase extraction cartridge under pH 11 for adsorption and optimization of liquid chromatography–tandem mass spectroscopy (LC–MS/MS) system was necessary to ensure high recovery rates (63–124 % for river water and 52–115 % for STP effluent). The year-round survey of these compounds in four seasons showed that all anticancer compounds were detected at median concentrations ranged from not detected to 32 ng/L in the river water and from not detected to 245 ng/L in the effluents of sewage treatment plants not using ozonation. In the case of bicalutamide (an active antiandrogen used to treat prostate cancer), the maximum concentration detected was 254 ng/L in river water and 1032 ng/L in non-ozonated sewage treatment plant effluents. Based on the mass balance, sewage treatment plants were the primary sources of anticancer compounds as well as the other pharmaceuticals in the river, and the attenuation effect of the river water was small. Ozonation at sewage treatment plants was effective in removing these compounds. To the best of our knowledge, this study is the first to report the existence of bicalutamide, doxifluridine, and tegafur in the river environment.
Sarcosine is a potential prostate cancer marker. In this study, we developed a method of three‐phase solvent bar liquid‐phase microextraction combined with high‐performance liquid chromatography to ...determine sarcosine after derivatization with 4‐dimethylarminoazobenzene‐4‐sulfonyl chloride from human urine. The effects of different extraction conditions on extraction efficiency were investigated and optimized. Under optimum experimental conditions, a calibration graph exhibited linearity over the range of 0.05–25 μmol/L with a correlation coefficient (r2) of 0.9990. The enrichment factor was 168, and the detection limit was 0.02 μmol/L. The method was successfully used to analyze sarcosine in human urine and non‐invasive detection, and good spiked recoveries ranging from 90.5 to 93.6% were obtained. The proposed method exhibited high sensitivity, high enrichment factor, good precision, and a simple setup. It may contribute to the early accurate diagnosis and the progression monitoring of prostatic carcinoma.
An electrochemical method for discriminating healthy and malignant tissues in prostate biopsies using the voltammetry of immobilized particles methodology is described. The method involves the ...sampling with graphite bars 0.5 mm in diameter on paraffin-impregnated cross sections of prostate tissues used in ordinary cytological evaluation after local staining with methylene blue (MB). The subsequent record of the voltammetric response of sample-modified graphite electrodes displays clearly different MB-centered features for healthy and malignant regions due to the different association of the dye to the respective cells.
Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is an innovative molecular imaging technique in which contrast agents are labeled by saturating their exchangeable proton ...spins by radio‐frequency irradiation. Salicylic acid and its analogues are a promising class of highly sensitive, diamagnetic CEST agents. Herein, polymeric agents grafted with salicylic acid moieties and a known high‐affinity ligand targeting prostate‐specific membrane antigen in approximately 10:1 molar ratio were synthesized to provide sufficient MRI sensitivity and receptor specificity. The proton‐exchange properties of the contrast agent in solution and in an experimental murine model are reported to demonstrate the feasibility of receptor‐targeted CEST MRI of prostate cancer. Furthermore, the CEST imaging data were validated with an 111In‐labeled analogue of the agent by in vivo single photon emission computed tomographic imaging and tissue biodistribution studies.
Receptor‐targeted imaging agent: Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) to detect tumor‐specific receptor expression is largely unexplored because of its low sensitivity. A rationally designed, salicylic acid‐based, metal‐free, polymeric contrast agent showed the feasibility of CEST MRI of prostate‐specific membrane antigen (PSMA) expression in vivo in a proof‐of‐concept experiment (see figure).
Background
Autosomal dominant polycystic kidney disease (ADPKD) can involve prostate and seminal vesicles but the potential interrelationship of these findings and associations with PKD gene mutation ...locus and type is unknown.
Purpose
To determine the interrelationship of seminal megavesicles (seminal vesicles with lumen diameter > 10mm) and prostatic cysts in ADPKD and to determine whether there are associations with PKD gene mutations.
Study Type
Retrospective, case control.
Population
Male ADPKD subjects (n = 92) with mutations in PKD1 (n = 71; 77%) or PKD2 (n = 21; 23%), and age/gender‐matched controls without ADPKD (n = 92).
Field Strength/Sequence
1.5T, axial/coronal T2‐weighted MR images.
Assessment
Reviewers blinded to genotype independently measured seminal vesicle lumen diameter and prevalence of cysts in prostate, kidney, and liver.
Statistical Tests
Nonparametric tests for group comparisons and univariate and multivariable logistic regression analyses to identify associations of megavesicles and prostate median cysts with mutations and renal/hepatic cyst burden.
Results
Seminal megavesicles were found in 23 of 92 ADPKD (25%) subjects with PKD1 (22/71, 31%) or PKD2 (n = 1/21, 5%) mutations, but in only two control subjects (P < 0.0001). Prostate median cysts were found in 17/92 (18%) ADPKD subjects, compared with only 6/92 (7%) controls (P = 0.01), and were correlated with seminal vesicle diameters (ρ = 0.24, P = 0.02). Nonmedian prostate cyst prevalence was identical between ADPKD and controls (7/92, 8%). After adjusting for age, estimated glomerular filtration rate, and height‐adjusted total kidney volume, ADPKD subjects with megavesicles were 10 times more likely to have a PKD1 than a PKD2 mutation. Among PKD1 subjects, seminal megavesicles occurred more frequently with nontruncating mutations with less severe kidney involvement.
Data Conclusion
ADPKD is associated with prostate median cysts near ejaculatory ducts. These cysts correlate with seminal megavesicles (dilated to >10 mm) which predict a 10‐fold greater likelihood of PKD1 vs. PKD2 mutation. Cysts elsewhere in the prostate are not related to ADPKD.
Level of Evidence: 2
Technical Efficacy: Stage 2
J. Magn. Reson. Imaging 2019;49:894–903.
A new 3D nanofluidic biochip for the study of cancer cell migration and invasion is proposed. In this design, femtosecond laser‐assisted etching is applied to create embedded microfluidic channels, ...with a base thickness of less than 100 µm for high‐resolution imaging using inverted microscopes. The glass deformation is thermally controlled during fabrication to create pillar‐like formations separated by narrow constricted channels with widths of less than 1 µm spanning lengths of more than tens of microns, mimicking the 3D intravasation–extravasation configuration. Time‐lapse microscopy is used to observe the behavior of prostate cancer (PC3) cells in chemoattractant‐free media over long time intervals as the cells invade the narrow spaces. The PC3 cells are observed to be capable of breaching the fabricated submicrometric intravasation‐like barriers while retaining their viability and proliferation activity. The cells are further able to penetrate the extravasation‐like confining spaces, confirming their dynamic adaptability as they pass through constricted channels with volumes much less than that of the cell nucleus.
This work describes a novel approach to fabricating 3D glass nanofluidic devices with hierarchical architectures and narrow constrictive spaces for the observation of cancer cell migration in chemoattractant‐free environments. This device is used to demonstrate the capability of prostate cancer cells to penetrate two arrays of narrow constrictions mimicking intravasation–extravasation events in an in vivo environment.
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•p-Nitrophenol interacts with FKBP51, a positive regulator of AR signaling.•Structural analysis reveals p-nitrophenol occupies the FK1 pocket of FKBP51.•p-Nitrophenol suppresses AR ...signaling possibly through blocking the FK1 pocket.
The compound p-nitrophenol, which shows the anti-androgenic activity, can easily become anthropogenic pollutants and pose a threat to the environment and human health. Previous work indicates that the anti-androgenic mechanism of p-nitrophenol is complex and may involve several components in the AR signaling pathway, but the molecular details of how p-nitrophenol inhibits AR signaling are still not quite clear. Here, we characterized p-nitrophenol binds to the FK1 domain of an AR positive regulator FKBP51 with micromolar affinity and structural analysis of FK1 domain in complex with p-nitrophenol revealed that p-nitrophenol occupies a hydrophobic FK1 pocket that is vital for AR activity enhancement. Molecular dynamics simulation indicated that p-nitrophenol is stably bound to the FK1 pocket and the hotspot residues that involved p-nitrophenol binding are mainly hydrophobic and overlap with the AR interaction site. Furthermore, we showed that p-nitrophenol inhibits the androgen-dependent growth of human prostate cancer cells, possibly through down-regulating the expression levels of AR activated downstream genes. Taken together, our data suggests that p-nitrophenol suppresses the AR signaling pathway at least in part by blocking the interaction between AR and its positive regulator FKBP51. We believe that our findings could provide new guidelines for assessing the potential health effects of p-nitrophenol.
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