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

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 c...

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Autores principales: Dyshlovoy, Sergey A., Pelageev, Dmitry N., Hauschild, Jessica, Sabutskii, Yurii E., Khmelevskaya, Ekaterina A., Krisp, Christoph, Kaune, Moritz, Venz, Simone, Borisova, Ksenia L., Busenbender, Tobias, Denisenko, Vladimir A., Schlüter, Hartmut, Bokemeyer, Carsten, Graefen, Markus, Polonik, Sergey G., Anufriev, Victor Ph., von Amsberg, Gunhild
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281150/
https://www.ncbi.nlm.nih.gov/pubmed/32403427
http://dx.doi.org/10.3390/md18050251
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author Dyshlovoy, Sergey A.
Pelageev, Dmitry N.
Hauschild, Jessica
Sabutskii, Yurii E.
Khmelevskaya, Ekaterina A.
Krisp, Christoph
Kaune, Moritz
Venz, Simone
Borisova, Ksenia L.
Busenbender, Tobias
Denisenko, Vladimir A.
Schlüter, Hartmut
Bokemeyer, Carsten
Graefen, Markus
Polonik, Sergey G.
Anufriev, Victor Ph.
von Amsberg, Gunhild
author_facet Dyshlovoy, Sergey A.
Pelageev, Dmitry N.
Hauschild, Jessica
Sabutskii, Yurii E.
Khmelevskaya, Ekaterina A.
Krisp, Christoph
Kaune, Moritz
Venz, Simone
Borisova, Ksenia L.
Busenbender, Tobias
Denisenko, Vladimir A.
Schlüter, Hartmut
Bokemeyer, Carsten
Graefen, Markus
Polonik, Sergey G.
Anufriev, Victor Ph.
von Amsberg, Gunhild
author_sort Dyshlovoy, Sergey A.
collection PubMed
description 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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spelling pubmed-72811502020-06-15 Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer Dyshlovoy, Sergey A. Pelageev, Dmitry N. Hauschild, Jessica Sabutskii, Yurii E. Khmelevskaya, Ekaterina A. Krisp, Christoph Kaune, Moritz Venz, Simone Borisova, Ksenia L. Busenbender, Tobias Denisenko, Vladimir A. Schlüter, Hartmut Bokemeyer, Carsten Graefen, Markus Polonik, Sergey G. Anufriev, Victor Ph. von Amsberg, Gunhild Mar Drugs Article 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. MDPI 2020-05-11 /pmc/articles/PMC7281150/ /pubmed/32403427 http://dx.doi.org/10.3390/md18050251 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dyshlovoy, Sergey A.
Pelageev, Dmitry N.
Hauschild, Jessica
Sabutskii, Yurii E.
Khmelevskaya, Ekaterina A.
Krisp, Christoph
Kaune, Moritz
Venz, Simone
Borisova, Ksenia L.
Busenbender, Tobias
Denisenko, Vladimir A.
Schlüter, Hartmut
Bokemeyer, Carsten
Graefen, Markus
Polonik, Sergey G.
Anufriev, Victor Ph.
von Amsberg, Gunhild
Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
title Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
title_full Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
title_fullStr Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
title_full_unstemmed Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
title_short Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
title_sort inspired by sea urchins: warburg effect mediated selectivity of novel synthetic non-glycoside 1,4-naphthoquinone-6s-glucose conjugates in prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281150/
https://www.ncbi.nlm.nih.gov/pubmed/32403427
http://dx.doi.org/10.3390/md18050251
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