Publications by authors named "Gunhild von Amsberg"

58 Publications

New Deoxyisoaustamide Derivatives from the Coral-Derived Fungus KMM 4689.

Mar Drugs 2021 Jan 12;19(1). Epub 2021 Jan 12.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-letiya Vladivostoka, 159, 690022 Vladivostok, Russia.

Seven new deoxyisoaustamide derivatives (-) together with known compounds (-) were isolated from the coral-derived fungus KMM 4689. Their structures were established using spectroscopic methods, X-ray diffraction analysis and by comparison with related known compounds. The absolute configurations of some alkaloids were determined based on CD and NOESY data as well as biogenetic considerations. The cytotoxic and neuroprotective activities of some of the isolated compounds were examined and structure-activity relationships were pointed out. New deoxyisoaustamides - at concentration of 1 µM revealed a statistical increase of PQ(paraquat)-treated Neuro-2a cell viability by 30-39%.
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http://dx.doi.org/10.3390/md19010032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826743PMC
January 2021

Sea Anemone Actinoporin Demonstrates In Vitro Anticancer Activities and Prevents HT-29 Colorectal Cancer Cell Migration.

Molecules 2020 Dec 17;25(24). Epub 2020 Dec 17.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, 159, Pr. 100 let Vladivostoku, Vladivostok 690022, Russia.

Actinoporins are the most abundant group of sea anemone cytolytic toxins. Their membranolytic activity is of high interest for the development of novel anticancer drugs. However, to date the activity of actinoporins in malignant cells has been poorly studied. Here, we report on recombinant analog of Hct-S3 (rHct-S3), belonging to the combinatory library of actinoporins. rHct-S3 exhibited cytotoxic activity against breast MDA-MB-231 (IC = 7.3 µM), colorectal HT-29 (IC = 6.8 µM), and melanoma SK-MEL-28 (IC = 8.3 µM) cancer cells. The actinoporin effectively prevented epidermal growth factor -induced neoplastic transformation of JB6 Cl41 cells by 34% ± 0.2 and decreased colony formation of HT-29 cells by 47% ± 0.9, MDA-MB-231 cells by 37% ± 1.2, and SK-MEL-28 cells by 34% ± 3.6. Moreover, rHct-S3 decreased proliferation and suppressed migration of colorectal carcinoma cells by 31% ± 5.0 and 99% ± 6.4, respectively. The potent anti-migratory activity was proposed to mediate by decreased matrix metalloproteinases-2 and -9 expression. In addition, rHct-S3 induced programmed cell death by cleavage of caspase-3 and poly (ADP-ribose) polymerase, as well as regulation of Bax and Bcl-2. Our results indicate rHct-S3 to be a promising anticancer drug with a high anti-migratory potential.
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http://dx.doi.org/10.3390/molecules25245979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766076PMC
December 2020

Efficacy and Mechanism of Action of Marine Alkaloid 3,10-Dibromofascaplysin in Drug-Resistant Prostate Cancer Cells.

Mar Drugs 2020 Dec 1;18(12). Epub 2020 Dec 1.

Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.

Efficacy and mechanism of action of marine alkaloid 3,10-dibromofascaplysin (DBF) were investigated in human prostate cancer (PCa) cells harboring different levels of drug resistance. Anticancer activity was observed across all cell lines examined without signs of cross-resistance to androgen receptor targeting agents (ARTA) or taxane based chemotherapy. Kinome analysis followed by functional investigation identified JNK1/2 to be one of the molecular targets of DBF in 22Rv1 cells. In contrast, no activation of p38 and ERK1/2 MAPKs was observed. Inhibition of the drug-induced JNK1/2 activation or of the basal p38 activity resulted in increased cytotoxicity of DBF, whereas an active ERK1/2 was identified to be important for anticancer activity of the alkaloid. Synergistic effects of DBF were observed in combination with PARP-inhibitor olaparib most likely due to the induction of ROS production by the marine alkaloid. In addition, DBF intensified effects of platinum-based drugs cisplatin and carboplatin, and taxane derivatives docetaxel and cabazitaxel. Finally, DBF inhibited AR-signaling and resensitized AR-V7-positive 22Rv1 prostate cancer cells to enzalutamide, presumably due to AR-V7 down-regulation. These findings propose DBF to be a promising novel drug candidate for the treatment of human PCa regardless of resistance to standard therapy.
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http://dx.doi.org/10.3390/md18120609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761490PMC
December 2020

[CARD study: relevance for the treatment of advanced prostate cancer].

Aktuelle Urol 2020 Sep 23. Epub 2020 Sep 23.

Asklepios Klinik Altona, Urologie, Hamburg.

Background:  Various life-prolonging therapy options are available for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

Objective:  The optimal therapy sequence for mCRPC has been discussed for years. With the final results of the CARD study, important prospective data are available to enlighten the discussion about the therapy sequence.

Material And Method:  CARD is a randomised phase IV trial in patients with mCRPC who were previously treated with docetaxel and an anti-androgen receptor (ARTA). The study showed significant efficacy benefits in favour of further treatment with cabazitaxel versus a second ARTA therapy. The study results are presented and discussed in the context of previous study data with regard to their importance for everyday clinical practice.

Results:  The CARD study data confirm cabazitaxel as an effective therapy option for mCRPC patients previously treated with docetaxel and an ARTA. Cabazitaxel was safe to apply. The study results confirm the cross resistance between the two ARTAs Abiraterone and Enzalutamide.

Conclusion: In mCRPC patients eligible for chemotherapy, the therapy sequence should be chosen so that the patients also receive cabazitaxel. A direct therapy sequence with two ARTAs should be avoided or, at least, only considered if other substances are contraindicated.
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http://dx.doi.org/10.1055/a-1247-4155DOI Listing
September 2020

Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma.

Future Oncol 2020 Oct 23;16(29):2307-2328. Epub 2020 Sep 23.

Interdisciplinary GU Oncology, Clinic for Medical Oncology & Clinic for Urology, University Hospital Essen, D-45147, Essen, Germany.

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.
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http://dx.doi.org/10.2217/fon-2020-0403DOI Listing
October 2020

Gracilosulfates A-G, Monosulfated Polyoxygenated Steroids from the Marine Sponge .

Mar Drugs 2020 Aug 30;18(9). Epub 2020 Aug 30.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia.

Seven new polyoxygenated steroids belonging to a new structural group of sponge steroids, gracilosulfates A-G (-), possessing 3--sulfonato, 56 epoxy (or 5(6)-dehydro), and 4,23-dihydroxy substitution patterns as a common structural motif, were isolated from the marine sponge Their structures were determined by NMR and MS methods. The compounds , and inhibited the expression of prostate-specific antigen (PSA) in 22Rv1 tumor cells.
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http://dx.doi.org/10.3390/md18090454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551063PMC
August 2020

Marine alkaloid monanchoxymycalin C: a new specific activator of JNK1/2 kinase with anticancer properties.

Sci Rep 2020 08 6;10(1):13178. Epub 2020 Aug 6.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251, Hamburg, Germany.

Monanchoxymycalin C (MomC) is a new marine pentacyclic guanidine alkaloid, recently isolated from marine sponge Monanchora pulchra by us. Here, anticancer activity and mechanism of action was investigated for the first time using a human prostate cancer (PCa) model. MomC was active in all PCa cell lines at low micromolar concentrations and induced an unusual caspase-independent, non-apoptotic cell death. Kinase activity screening identified activation of mitogen-activated protein kinase (MAPK) c-Jun N-terminal protein kinase (JNK1/2) to be one of the primary molecular mechanism of MomC anticancer activity. Functional assays demonstrated a specific and selective JNK1/2 activation prior to the induction of other cell death related processes. Inhibition of JNK1/2 by pretreatment with the JNK-inhibitor SP600125 antagonized cytotoxic activity of the marine compound. MomC caused an upregulation of cytotoxic ROS. However, in contrast to other ROS-inducing agents, co-treatment with PARP-inhibitor olaparib revealed antagonistic effects indicating an active PARP to be necessary for MomC activity. Interestingly, although no direct regulation of p38 and ERK1/2 were detected, active p38 kinase was required for MomC efficacy, while the inhibition of ERK1/2 increased its cytotoxicity. In conclusion, MomC shows promising activity against PCa, which is exerted via JNK1/2 activation and non-apoptotic cell death.
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http://dx.doi.org/10.1038/s41598-020-69751-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411023PMC
August 2020

Influence of Androgens on Immunity to Self and Foreign: Effects on Immunity and Cancer.

Front Immunol 2020 2;11:1184. Epub 2020 Jul 2.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

It is well-known that sex hormones can directly and indirectly influence immune cell function. Different studies support a suppressive role of androgens on different components of the immune system by decreasing antibody production, T cell proliferation, NK cytotoxicity, and stimulating the production of anti-inflammatory cytokines. Androgen receptors have also been detected in many different cells of hematopoietic origin leading to direct effects of their ligands on the development and function of the immune system. The immunosuppressive properties of androgens could contribute to gender dimorphisms in autoimmune and infectious disease and thereby also hamper immune surveillance of tumors. Consistently, females generally are more prone to autoimmunity, while relatively less susceptible to infections, and have lower incidence and mortality of the majority of cancers compared to males. Some studies show that androgen deprivation therapy (ADT) can induce expansion of naïve T cells and increase T-cell responses. Emerging clinical data also reveal that ADT might enhance the efficacy of various immunotherapies including immune checkpoint blockade. In this review, we will discuss the potential role of androgens and their receptors in the immune responses in the context of different diseases. A particular focus will be on cancer, highlighting the effect of androgens on immune surveillance, tumor biology and on the efficacy of anti-cancer therapies including emerging immune therapies.
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http://dx.doi.org/10.3389/fimmu.2020.01184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346249PMC
July 2020

Urupocidin C: a new marine guanidine alkaloid which selectively kills prostate cancer cells via mitochondria targeting.

Sci Rep 2020 06 17;10(1):9764. Epub 2020 Jun 17.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

New bicyclic guanidine alkaloid, urupocidin C (Ur-C) along with the previously known urupocidin A (Ur-A) were isolated from the rare deep-sea marine sponge Monanchora pulchra, harvested in Northwestern Pacific waters. The unique structure of Ur-C was elucidated using 1D and 2D NMR spectroscopy as well as mass spectra. We discovered a promising selectivity of both alkaloids for human prostate cancer (PCa) cells, including highly drug-resistant lines, compared to non-malignant cells. In cancer cells, marine derived compounds were able to induce G1- and S-cell cycle arrest as well as caspase-mediated cell death. For the first time we have identified mitochondrial targeting as a central mechanism of anticancer action for these and similar molecules. Thus, treatment with the isolated alkaloids resulted in mitochondrial membrane permeabilization consequently leading to the release of cytotoxic mitochondrial proteins to cellular cytoplasm, ROS upregulation, consequent activation of caspase-9 and -3, followed by PARP cleavage, DNA fragmentation, and apoptosis. Moreover, synergistic effects were observed when Ur-A and Ur-C were combined with clinically approved PARP inhibitor olaparib. Finally, these alkaloids exhibited additive effects in combination with docetaxel and androgen receptor inhibitor enzalutamide, both applied in PCa therapy. In conclusion, urupocidin-like compounds are promising lead molecules for the development of new drugs for the treatment of advanced PCa.
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http://dx.doi.org/10.1038/s41598-020-66428-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299949PMC
June 2020

Leptogorgins A-C, Humulane Sesquiterpenoids from the Vietnamese Gorgonian sp.

Mar Drugs 2020 Jun 13;18(6). Epub 2020 Jun 13.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-let Vladivostoku 159, 690022 Vladivostok, Russia.

Leptogorgins A-C (-), new humulane sesquiterpenoids, and leptogorgoid A (), a new dihydroxyketosteroid, were isolated from the gorgonian sp. collected from the South China Sea. The structures were established using MS and NMR data. The absolute configuration of was confirmed by a modification of Mosher's method. Configurations of double bonds followed from NMR data, including NOE correlations. This is the first report of humulane-type sesquiterpenoids from marine invertebrates. Sesquiterpenoids leptogorgins A () and B () exhibited a moderate cytotoxicity and some selectivity against human drug-resistant prostate cancer cells 22Rv1.
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http://dx.doi.org/10.3390/md18060310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344390PMC
June 2020

[Vorwort].

Oncol Res Treat 2020 19;43 Suppl 2. Epub 2020 May 19.

Urologische Klinik und Poliklinik der Technischen Universität München, Universitätsklinikum rechts der Isar, München, Deutschland.

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http://dx.doi.org/10.1159/000507053DOI Listing
January 2021

Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer.

Mar Drugs 2020 May 11;18(5). Epub 2020 May 11.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

The phenomenon of high sugar consumption by tumor cells is known as Warburg effect. It results from a high glycolysis rate, used by tumors as preferred metabolic pathway even in aerobic conditions. Targeting the Warburg effect to specifically deliver sugar conjugated cytotoxic compounds into tumor cells is a promising approach to create new selective drugs. We designed, synthesized, and analyzed a library of novel 6-S-(1,4-naphthoquinone-2-yl)-d-glucose chimera molecules (SABs)-novel sugar conjugates of 1,4-naphthoquinone analogs of the sea urchin pigments spinochromes, which have previously shown anticancer properties. A sulfur linker (thioether bond) was used to prevent potential hydrolysis by human glycoside-unspecific enzymes. The synthesized compounds exhibited a Warburg effect mediated selectivity to human prostate cancer cells (including highly drug-resistant cell lines). Mitochondria were identified as a primary cellular target of SABs. The mechanism of action included mitochondria membrane permeabilization, followed by ROS upregulation and release of cytotoxic mitochondrial proteins (AIF and cytochrome C) to the cytoplasm, which led to the consequent caspase-9 and -3 activation, PARP cleavage, and apoptosis-like cell death. These results enable us to further clinically develop these compounds for effective Warburg effect targeting.
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http://dx.doi.org/10.3390/md18050251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281150PMC
May 2020

Evaluation of PD-L1 expression on circulating tumor cells (CTCs) in patients with advanced urothelial carcinoma (UC).

Oncoimmunology 2020 23;9(1):1738798. Epub 2020 Mar 23.

Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Immune checkpoint inhibition (ICI) of the PD-1/PD-L1 axis shows durable responses in a subset of patients with metastatic urothelial carcinoma (UC). However, PD-L1 expression in tumor biopsies does not necessarily correlate with response to PD-1/PD-L1 inhibitors. Thus, a reliable predictive biomarker is urgently needed. Here, the expression of PD-L1 on circulating tumor cells (CTCs) in blood from patients with advanced UC was analyzed. For this purpose, an assay to test PD-L1 expression on CTCs using the CellSearch® system was established using cells of five UC cell lines spiked into blood samples from healthy donors and applied to a heterogeneous cohort of UC patients. Enumeration of CTCs was performed in blood samples from 49 patients with advanced UC. PD-L1 expression in ≥1 CTC was found in 10 of 16 CTC-positive samples (63%). Both intra- and inter-patient heterogeneity regarding PD-L1 expression of CTCs were observed. Furthermore, vimentin-expressing CTCs were detected in 4 of 15 CTC-positive samples (27%), independently of PD-L1 analysis. Both CTC detection and presence of CTCs with moderate or strong PD-L1 expression correlated with worse overall survival. Analyses during disease course of three individual patients receiving ICI suggest that apart from CTC numbers also PD-L1 expression on CTCs might potentially indicate disease progression. This is the first study demonstrating the feasibility to detect CTC-PD-L1 expression in patients with advanced UC using the CellSearch® system. This assay is readily available for clinical application and could be implemented in future clinical trials to evaluate its relevance for predicting and monitoring response to ICI.
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http://dx.doi.org/10.1080/2162402X.2020.1738798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199812PMC
March 2020

[Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial].

Urologe A 2020 Jun;59(6):723-724

Professur für Uroonkologie der II. Medizinischen Klinik des Onkologischen Zentrums und der Martini-Klinik, Universtitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.

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http://dx.doi.org/10.1007/s00120-020-01176-yDOI Listing
June 2020

Polyphenolic Compounds from Lespedeza Bicolor Root Bark Inhibit Progression of Human Prostate Cancer Cells via Induction of Apoptosis and Cell Cycle Arrest.

Biomolecules 2020 03 14;10(3). Epub 2020 Mar 14.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

From a root bark of Turch we isolated two new (7 and 8) and six previously known compounds (1-6) belonging to the group of prenylated polyphenols. Their structures were elucidated using mass spectrometry, nuclear magnetic resonance and circular dichroism spectroscopy. These natural compounds selectively inhibited human drug-resistant prostate cancer in vitro. Prenylated pterocarpans 1-3 prevented the cell cycle progression of human cancer cells in S-phase. This was accompanied by a reduced expression of mRNA corresponding to several human cyclin-dependent kinases (CDKs). In contrast, compounds 4-8 induced a G1-phase cell cycle arrest without any pronounced effect on CDKs mRNA expression. Interestingly, a non-substituted hydroxy group at C-8 of ring D of the pterocarpan skeleton of compounds 1-3 seems to be important for the CDKs inhibitory activity.
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http://dx.doi.org/10.3390/biom10030451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175281PMC
March 2020

Biologically Active Echinulin-Related Indolediketopiperazines from the Marine Sediment-Derived Fungus .

Molecules 2019 Dec 23;25(1). Epub 2019 Dec 23.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-letiya Vladivostoka, 159, Vladivostok 690022, Russia.

Seven known echinulin-related indolediketopiperazine alkaloids (-) were isolated from the Vietnamese sediment-derived fungus . Using chiral HPLC, the enantiomers of cryptoechinuline B () were isolated as individual compounds for the first time. (+)-Cryptoechinuline B () exhibited neuroprotective activity in 6-OHDA-, paraquat-, and rotenone-induced in vitro models of Parkinson's disease. (-)-Cryptoechinuline B () and neoechinulin C () protected the neuronal cells against paraquat-induced damage in a Parkinson's disease model. Neoechinulin B () exhibited cytoprotective activity in a rotenone-induced model, and neoechinulin () showed activity in the 6-OHDA-induced model.
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http://dx.doi.org/10.3390/molecules25010061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983058PMC
December 2019

Piltunines A-F from the Marine-Derived Fungus KMM 4668.

Mar Drugs 2019 Nov 18;17(11). Epub 2019 Nov 18.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-letiya Vladivostoka, 159, Vladivostok 690022, Russia.

Six new carotane sesquiterpenoids piltunines A-F (-) together with known compounds (-) were isolated from the marine-derived fungus KMM 4668. Their structures were established using spectroscopic methods. The absolute configurations of - were determined based on circular dichroism (CD) and nuclear Overhauser spectroscopy (NOESY) data as well as biogenetic considerations. The cytotoxic activity of some of the isolated compounds and their effects on regulation of reactive oxygen species (ROS) and nitric oxide (NO) production in lipopolysaccharide-stimulated macrophages were examined.
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http://dx.doi.org/10.3390/md17110647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891813PMC
November 2019

Successful Targeting of the Warburg Effect in Prostate Cancer by Glucose-Conjugated 1,4-Naphthoquinones.

Cancers (Basel) 2019 Oct 30;11(11). Epub 2019 Oct 30.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.
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http://dx.doi.org/10.3390/cancers11111690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896172PMC
October 2019

Biologically Active Metabolites from the Marine Sediment-Derived Fungus .

Mar Drugs 2019 Oct 11;17(10). Epub 2019 Oct 11.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-letiya Vladivostoka, 159, Vladivostok 690022, Russia.

Four new compounds were isolated from the Vietnamese marine sediment-derived fungus , one aspyrone-related polyketide aspilactonol G (), one meroterpenoid 12-epi-aspertetranone D (), two drimane derivatives (,), together with five known metabolites (,,,,,). The structures of compounds - were established by NMR and MS techniques. The absolute stereoconfigurations of compounds and were determined by a modified Mosher's method. The absolute configurations of compounds and were established by a combination of analysis of ROESY data and coupling constants as well as biogenetic considerations. Compounds and exhibited cytotoxic activity toward human prostate cancer 22Rv1, human breast cancer MCF-7, and murine neuroblastoma Neuro-2a cells.
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http://dx.doi.org/10.3390/md17100579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835654PMC
October 2019

Detection of Androgen Receptor Variant 7 ( mRNA Levels in EpCAM-Enriched CTC Fractions for Monitoring Response to Androgen Targeting Therapies in Prostate Cancer.

Cells 2019 09 11;8(9). Epub 2019 Sep 11.

Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Expression of the androgen receptor splice variant 7 ( in circulating tumor cells (CTCs) has been associated with resistance towards novel androgen receptor (AR)-targeting therapies. While a multitude of ARV7 detection approaches have been developed, the simultaneous enumeration of CTCs and assessment of status and the integration of validated technologies for CTC enrichment/detection into their workflow render interpretation of the results more difficult and/or require shipment to centralized labs. Here, we describe the establishment and technical validation of a novel detection method integrating the CellSearch technology, the only FDA-cleared CTC-enrichment method for metastatic prostate cancer available so far. A highly sensitive and specific qPCR-based assay was developed, allowing detection of and transcripts from as low as a single cell, even after 24 h of sample storage. Clinical feasibility was demonstrated on blood samples from 26 prostate cancer patients and assay sensitivity and specificity was corroborated. Our novel approach can now be included into prospective clinical trials aimed to assess the predictive values of CTC/ARV7 measurements in prostate cancer.
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http://dx.doi.org/10.3390/cells8091067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770695PMC
September 2019

Total Syntheses and Preliminary Biological Evaluation of Brominated Fascaplysin and Reticulatine Alkaloids and Their Analogues.

Mar Drugs 2019 Aug 25;17(9). Epub 2019 Aug 25.

Department of organic chemistry and Laboratory of biologically active compounds, School of Natural Sciences, Far Eastern Federal University, 8 Sukhanov Str., Vladivostok 690950, Russia.

A simple approach toward the synthesis of the marine sponge derived pigment fascaplysin was used to obtain the marine alkaloids 3-bromofascaplysin and 3,10-dibromofascaplysin. These compounds were used for first syntheses of the alkaloids 14-bromoreticulatate and 14-bromoreticulatine. Preliminary bioassays showed that 14-bromoreticulatine has a selective antibiotic (to ) activity and reveals cytotoxicity toward human melanoma, colon, and prostate cancer cells. 3,10-Dibromofascaplysin was able to target metabolic activity of the prostate cancer cells, without disrupting cell membrane's integrity and had a wide therapeutic window amongst the fascaplysin alkaloids.
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http://dx.doi.org/10.3390/md17090496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780422PMC
August 2019

New Trisulfated Steroids from the Vietnamese Marine Sponge and Their PSA Expression and Glucose Uptake Inhibitory Activities.

Mar Drugs 2019 Jul 27;17(8). Epub 2019 Jul 27.

Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam.

Seven new unusual polysulfated steroids-topsentiasterol sulfate G (), topsentiasterol sulfate I (), topsentiasterol sulfate H (), bromotopsentiasterol sulfate D (), dichlorotopsentiasterol sulfate D (), bromochlorotopsentiasterol sulfate D (), and 4-hydroxyhalistanol sulfate C (), as well as three previously described-topsentiasterol sulfate D (), chlorotopsentiasterol sulfate D () and iodotopsentiasterol sulfate D () have been isolated from the marine sponge . Structures of these compounds were determined by detailed analysis of 1D- and 2D-NMR and HRESIMS data, as well as chemical transformations. The effects of the compounds on human prostate cancer cells PC-3 and 22Rv1 were investigated.
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http://dx.doi.org/10.3390/md17080445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723502PMC
July 2019

Naphto-Γ-pyrones from the marine-derived fungus .

Nat Prod Res 2021 Jan 26;35(1):131-134. Epub 2019 Jun 26.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russian Federation.

Nine naphto-γ-pyrones rubrofusarine B (), TMC 256 A1 (), fansecinones A () and B (), aurasperones A (), B () and F (), dianhydro-aurasperone C () and asperpyrone B () were isolated from the marine-derived fungus KMM 4694. Their structures were established based on spectroscopic methods. The effect of the substances on viability and colony formation of human drug-resistant prostate cancer 22Rv1 cell was evaluated.
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http://dx.doi.org/10.1080/14786419.2019.1610954DOI Listing
January 2021

[50 years of systemic therapy of urinary bladder cancer].

Aktuelle Urol 2019 Aug 26;50(4):358-365. Epub 2019 Jun 26.

Technische Universität München, Klinikum rechts der Isar, Urologische Klinik und Poliklinik, München.

This review summarises the treatment strategies of the last five decades for metastatic urothelial cancer. The introduction of combination chemotherapy in the mid-1980s led to clinically significant response rates and prolonged survival. Two years ago, the results of a phase-3 clinical trial with the PD1 inhibitor pembrolizumab for second-line treatment of metastatic urothelial carcinoma were published. These data were the first to show an overall survival benefit in comparison with a conventional chemotherapy with vinflunine, docetaxel or paclitaxel. Currently, PD1/PD-L1 inhibitors are also tested within randomized phase-3-trials for first-line treatment using different approaches either as a monotherapy or a combination with conventional chemotherapy or CTLA-4 inhibitors. Whereas data from single-arm phase-2 clinical trials have already been published, first phase-3 data are expected in 2019.
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http://dx.doi.org/10.1055/a-0945-8340DOI Listing
August 2019

Prostate cancer prognosis in men with other malignancies prior to radical prostatectomy.

Urol Oncol 2019 09 30;37(9):575.e1-575.e7. Epub 2019 Apr 30.

Martini-Klinik, Prostate Cancer Center, Medical University Hamburg Eppendorf, Hamburg, Germany. Electronic address:

Objectives: Cancer survivors are often diagnosed with subsequent prostate cancer. To improve medical care of these patients, we examined the oncological outcomes in men with prostate cancer and a cancer history.

Patients And Methods: We retrospectively analyzed data from 25,422 prostate cancer patients, who underwent a radical prostatectomy between 1992 and 2016. Patients with other malignancies were identified using medical records and self-administrated questionnaires. Cox regression and Kaplan Meier analysis of a propensity score-matched patient cohort were performed to examine biochemical recurrence-free survival, metastasis-free survival, overall survival and prostate cancer-specific survival. Competing risk analysis was used to estimate other-cause mortality, other cancer-specific mortality, and prostate cancer-specific mortality. Statistical analysis was performed using R.

Results: Of all patients, 6.4% were diagnosed with other malignancy prior to radical prostatectomy. Patients with tumor history were older (median: 66 years vs. 64 years., P< 0,001) and showed a higher tumor volume (median: 4.0 ml vs. 3.6 ml, P = 0.02) than patients without. The risk of biochemical recurrence and metastasis development after radical prostatectomy was similar. All-cause mortality was significantly increased (hazard ratio 2.0; 95% confidence interval 1.7-2.4), while prostate cancer-specific mortality was lower (hazard ratio 0.4; 95% confidence interval 0.23-0.87) in patients with additional malignancy. In a propensity score-matched cohort overall survival was significantly adverse (P< 0.001) and prostate cancer-specific survival was higher (P= 0.003) in patients with other malignancy prior to surgery.

Conclusion: A higher other-cause mortality in men with tumor history should be concerned in the decision-making for medical care of prostate cancer patients in favor of reserved care strategies.
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http://dx.doi.org/10.1016/j.urolonc.2019.04.007DOI Listing
September 2019

Response to olaparib in a germline mutated prostate cancer and genetic events associated with resistance.

Cold Spring Harb Mol Case Stud 2019 04 1;5(2). Epub 2019 Apr 1.

Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.

Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.
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http://dx.doi.org/10.1101/mcs.a003657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549578PMC
April 2019

Citriperazines A-D produced by a marine algae-derived fungus sp. KMM 4672.

Nat Prod Res 2020 Apr 19;34(8):1118-1123. Epub 2019 Jan 19.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia.

Four new diketopiperazine alkaloids, citriperazines A-D were isolated from algae-derived sp. KMM 4672. The structures of compounds were determined using spectroscopic methods. The absolute configurations of compounds and were established by comparison of calculated and experimental ECD spectra. The cytotoxicity of compounds - against several human prostate cell lines was evaluated.
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http://dx.doi.org/10.1080/14786419.2018.1552696DOI Listing
April 2020

Auroglaucin-related neuroprotective compounds from Vietnamese marine sediment-derived fungus .

Nat Prod Res 2020 Sep 9;34(18):2589-2594. Epub 2019 Jan 9.

G.B. Elyakov Pacific Institute of bioorganic chemistry, Vladivostok, Russia.

Two new auroglaucin-derived compounds, niveoglaucins A () and B (), together with four known related compounds were isolated from extract of the marine sediment-derived strain of . The structures of these compounds were determined by 1D and 2D NMR spectroscopy and high resolution MS. The plausible biosynthetic pathway was proposed for new compounds and . The neuroprotective activity in 6-OHDA-induced Parkinson's disease cell model was shown for niveoglaucin A ().
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http://dx.doi.org/10.1080/14786419.2018.1547293DOI Listing
September 2020

Cost-effectiveness analyses and cost analyses in castration-resistant prostate cancer: A systematic review.

PLoS One 2018 5;13(12):e0208063. Epub 2018 Dec 5.

Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Treatment of metastatic prostate cancer is associated with high personal and economic burden. Recently, new treatment options for castration-resistant prostate cancer became available with promising survival advantages. However, cost-effectiveness of those new treatment options is sometimes ambiguous or given only under certain circumstances. The aim of this study was to systematically review studies on the cost-effectiveness of treatments and costs of castration-resistant prostate cancer (CRPC) and metastasizing castration-resistant prostate cancer (mCRPC) on their methodological quality and the risk of bias.

Methods: A systematic literature search was performed in the databases PubMed, CINAHL Complete, the Cochrane Library and Web of Science Core Collection for costs-effectiveness analyses, model-based economic evaluations, cost-of-illness analyses and budget impact analyses. Reported costs were inflated to 2015 US$ purchasing power parities. Quality assessment and risk of bias assessment was performed using the Consolidated Health Economic Evaluation Reporting Standards checklist and the Bias in Economic Evaluations checklist, respectively.

Results: In total, 38 articles were identified by the systematic literature search. The methodological quality of the included studies varied widely, and there was considerable risk of bias. The cost-effectiveness treatments for CRPC and mCRPC was assessed with incremental cost-effectiveness ratios ranging from dominance for mitoxantrone to $562,328 per quality-adjusted life year gained for sipuleucel-T compared with prednisone alone. Annual costs for the treatment of castration-resistant prostate cancer ranged from $3,067 to $77,725.

Conclusion: The cost-effectiveness of treatments of CRPC strongly depended on the willingness to pay per quality-adjusted life year gained/life-year saved throughout all included costs-effectiveness analyses and model-based economic evaluations. High-quality cost-effectiveness analyses based on randomized controlled trials are needed in order to make informed decisions on the management of castration-resistant prostate cancer and the resulting financial impact on the healthcare system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208063PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281264PMC
May 2019

Asperindoles A⁻D and a -Terphenyl Derivative from the Ascidian-Derived Fungus sp. KMM 4676.

Mar Drugs 2018 Jul 9;16(7). Epub 2018 Jul 9.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Prospect 100-letiya Vladivostoka, 159, Vladivostok 690022, Russia.

Four new indole-diterpene alkaloids asperindoles A⁻D (⁻) and the known -terphenyl derivative 3″-hydroxyterphenyllin () were isolated from the marine-derived strain of the fungus sp., associated with an unidentified colonial ascidian. The structures of ⁻ were established by 2D NMR and HRESIMS data. The absolute configurations of all stereocenters of ⁻ were determined by the combination of ROESY data, coupling constants analysis, and biogenetic considerations. Asperindoles C and D contain a 2-hydroxyisobutyric acid (2-HIBA) residue, rarely found in natural compounds. Asperindole A exhibits cytotoxic activity against hormone therapy-resistant PC-3 and 22Rv1, as well as hormone therapy-sensitive human prostate cancer cells, and induces apoptosis in these cells at low-micromolar concentrations.
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http://dx.doi.org/10.3390/md16070232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070833PMC
July 2018