| Autor: |
Sergey A. Dyshlovoy, Dmitry N. Pelageev, Jessica Hauschild, Yurii E. Sabutskii, Ekaterina A. Khmelevskaya, Christoph Krisp, Moritz Kaune, Simone Venz, Ksenia L. Borisova, Tobias Busenbender, Vladimir A. Denisenko, Hartmut Schlüter, Carsten Bokemeyer, Markus Graefen, Sergey G. Polonik, Victor Ph. Anufriev, Gunhild von Amsberg |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Marine Drugs, Vol 18, Iss 5, p 251 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
1660-3397 |
| DOI: |
10.3390/md18050251 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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