Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
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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. / 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; Amsberg, Gunhild von.
in: MAR DRUGS, Jahrgang 18, Nr. 5, 11.05.2020.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Inspired by Sea Urchins: Warburg Effect Mediated Selectivity of Novel Synthetic Non-Glycoside 1,4-Naphthoquinone-6S-Glucose Conjugates in Prostate Cancer
AU - Dyshlovoy, Sergey A
AU - Pelageev, Dmitry N
AU - Hauschild, Jessica
AU - Sabutskii, Yurii E
AU - Khmelevskaya, Ekaterina A
AU - Krisp, Christoph
AU - Kaune, Moritz
AU - Venz, Simone
AU - Borisova, Ksenia L
AU - Busenbender, Tobias
AU - Denisenko, Vladimir A
AU - Schlüter, Hartmut
AU - Bokemeyer, Carsten
AU - Graefen, Markus
AU - Polonik, Sergey G
AU - Anufriev, Victor Ph
AU - Amsberg, Gunhild von
PY - 2020/5/11
Y1 - 2020/5/11
N2 - 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.
AB - 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.
U2 - 10.3390/md18050251
DO - 10.3390/md18050251
M3 - SCORING: Journal article
C2 - 32403427
VL - 18
JO - MAR DRUGS
JF - MAR DRUGS
SN - 1660-3397
IS - 5
ER -