Abstract

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.

Highlights

  • IntroductionInexorable efforts have been made to develop targeted therapies allowing the release of cytotoxic activity in the region of interest while sparing healthy tissue

  • Chemotherapy remains an important treatment component for the vast majority of cancer patients.a lack of selectivity for tumor cells over normal cells frequently results in insufficient drug concentrations in the malignant tissue, systemic toxicity, and the development of drug resistance.inexorable efforts have been made to develop targeted therapies allowing the release of cytotoxic activity in the region of interest while sparing healthy tissue

  • In continuation of the research on synthesis of bioactive 1,4-naphthoquinones, capable of selective activity towards human drug-resistance prostate cancer cells, we designed the chimera molecules consisting of cytotoxic 1,4-naphthoquinone pharmacophore and 6-thioglucose moiety

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Summary

Introduction

Inexorable efforts have been made to develop targeted therapies allowing the release of cytotoxic activity in the region of interest while sparing healthy tissue. Antibody drug conjugates (ADCs) consisting of an antibody linked to a biological active payload are under intensive investigation and first drugs are available in clinics, e.g., gemtuzumab ozogamicin in acute myeloid leukemia or brentuximab vedotin in relapsed Hodgkins lymphoma [2]. PSMA-ligand therapy with PSMA-linked α- or β-emitters are evaluated in clinical trials in prostate cancer and are applied to patients in every day0 s routine on individual bases [4]. Additional targeted therapies in prostate cancer include androgen-receptor (AR) targeting drugs such as abiraterone acetate, apalutamide, or enzalutamide as well as PARP-inhibitors in patients with DNA-repair defects [5]

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