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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

1
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
2
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, 690022 Vladivostok, Russia
3
School of Natural Sciences, Far Eastern Federal University, 690091 Vladivostok, Russia
4
Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, 20251 Hamburg, Germany
5
Institute of Clinical Chemistry and Laboratory Medicine, Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
6
Department of Medical Biochemistry and Molecular Biology, University of Greifswald, 17489 Greifswald, Germany
7
Interfacultary Institute of Genetics and Functional Genomics, Department of Functional Genomics, University of Greifswald, 17489 Greifswald, Germany
*
Author to whom correspondence should be addressed.
These authors equally contributed to this work.
Mar. Drugs 2020, 18(5), 251; https://doi.org/10.3390/md18050251
Received: 16 April 2020 / Revised: 3 May 2020 / Accepted: 5 May 2020 / Published: 11 May 2020
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. View Full-Text
Keywords: prostate cancer; thioglucoside conjugates; natural products; sea urchins; glucose uptake prostate cancer; thioglucoside conjugates; natural products; sea urchins; glucose uptake
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Dyshlovoy, S.A.; Pelageev, D.N.; Hauschild, J.; Sabutskii, Y.E.; Khmelevskaya, E.A.; Krisp, C.; Kaune, M.; Venz, S.; Borisova, K.L.; Busenbender, T.; Denisenko, V.A.; Schlüter, H.; Bokemeyer, C.; Graefen, M.; Polonik, S.G.; Anufriev, V.P.; von Amsberg, G. 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, 18, 251.

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