Journal Article

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

Schlüter, Hartmut, Polonik, Sergey G., Anufriev, Victor Ph, Krisp, Christoph, Kaune, Moritz, Hauschild, Jessica, Sabutskii, Yurii E., Denisenko, Vladimir A., Venz, Simone, von Amsberg, Gunhild, Pelageev, Dmitry N., Busenbender, Tobias, Graefen, Markus, Dyshlovoy, Sergey A., Borisova, Ksenia L., Bokemeyer, Carsten, Khmelevskaya, Ekaterina A.

2020

Overview

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.

• Publisher: MDPI,MDPI AG
• Subject: Animals / Antineoplastic Agents - chemical synthesis / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Apoptosis - drug effects / Cell Line, Tumor / Drug Screening Assays, Antitumor / Glucose - chemical synthesis / Glucose - pharmacology / glucose uptake / Humans / Male / Membrane Potential, Mitochondrial - drug effects / Mitochondrial Membranes - drug effects / Naphthoquinones - chemical synthesis / Naphthoquinones - pharmacology / Naphthoquinones - therapeutic use / natural products / Pigments, Biological - chemistry / prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - pathology / sea urchins / Sea Urchins - chemistry / thioglucoside conjugates / Warburg Effect, Oncologic - drug effects