During the chemotherapy of cancer, drug resistance is the first issue that chemotherapeutic drugs cannot be effectively used for the treatment of cancers repeatedly for a long term, and the main reason for this is that tumor cell detoxification is mediated by GSH (glutathione) catalyzed by GST (glutathione-S-transferase). In this study, a GST inhibitor, ethacrynic acid (ECA), was designed to be coupled with methoxy poly(ethylene glycol)-poly(lactide) (MPEG–PLA) by disulfide bonds to prepare methoxy poly(ethylene glycol)-poly(lactide)-disulphide bond-mthacrynic acid (MPEG–PLA–SS–ECA) as a carrier material of the nanoparticles. Nanoparticles of pingyangmycin (PYM) and carboplatin (CBP) were prepared, respectively, and their physicochemical properties were investigated. The ECA at the disulfide could be released in the presence of GSH, the pingyangmycin, carboplatin and ECA were all uniformly released, and the nanoparticles could release all the drugs completely within 10 days. The half maximal inhibitory concentration (IC50) of the prepared MPEG–PLA–SS–ECA/CBP and MPEG–PLA–SS–ECA/PYM nanoparticles in drug-resistant oral squamous cell carcinoma cell lines SCC15/CBP and SCC15/PYM cells was 12.68 μg·mL−1and 12.76 μg·mL−1, respectively; the resistant factor RF of them in the drug-resistant cells were 1.51 and 1.24, respectively, indicating that MPEG–PLA–SS–ECA nanoparticles can reverse the drug resistance of these two drug-resistant cells.Keywords:nanoparticle;GST inhibitor;redox-sensitive;self-assembly
Root-knot nematodes ( Meloidogyne incognita ) present a significant threat to global agriculture, and the development of multi-drug resistance in these nematodes exacerbates this problem. Benzothiazole, a heterocyclic compound has been reported as a potential nematicide, however, its mode of action is not fully understood. This study aims to elucidate the nematicidal mechanism of benzothiazole against M. incognita . In the toxicity assays, benzothiazole exhibited rapid and effective nematocidal activity, significantly compromising egg masses and inhibiting egg hatching while killing newly hatched second-stage juveniles (J2s) of M. incognita . Microscopic observations revealed that after 48 h of incubation, a marked reduction in protein and carbohydrate levels within the J2s was observed. Notably, benzothiazole at a concentration of 14 mmol/L significantly inhibits glutathione S-transferase (GST) enzyme activity, leading to the accumulation of reactive oxygen species (ROS), ultimately resulting in rapid nematode death. Molecular docking and dynamics simulations demonstrated that benzothiazole forms a stable complex with GST, thereby disrupting its antioxidant function. Furthermore, in pot experiments, benzothiazole effectively reduced the gall formations of M. incognita on tomato roots. Overall, this novel inhibitory mechanism of glutathione S-transferase (GST) differs from that of the neurotoxicant abamectin, which targets glutamate-gated chloride channels (GluCl). This mechanism holds significant promise for the development of environmentally friendly nematicides. It offers a potential solution to the growing problem of multidrug resistance in root-knot nematodes and could help mitigate the substantial economic losses caused by these pests in global agriculture.
Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH) and glutathione S-transferase pi (GST-pi), has significantly limited the application of CHL. To overcome this issue, we first designed a GSH-responsive small-molecule prodrug (EA-SS-CHL) by combining CHL and ethacrynic acid (EA). Subsequently, drug-loaded nanoparticles (ECPP) were formed by the self-assembly between EA-SS-CHL and amphiphilic PEG-PDLLA to improve the water solubility of the prodrug and its ability to target tumor sites. Upon exposure to high intracellular GSH concentration, EA-SS-CHL gradually degrades, leading to the release of EA and CHL. The presence of EA facilitates the depletion of GSH and inhibition of GST-pi, ultimately attenuating the detoxification of the intracellular defense system to CHL. Cytotoxicity studies and apoptosis assays demonstrate that ECPP exhibits higher therapeutic efficiency than CHL. Additionally, in vivo tumor suppression effects and biocompatibility provide further evidence for the superiority of ECPP. This work presents a promising strategy to enhance the efficacy of CHL in cancer therapy.
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