Design and synthesis of NAD(P)H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties

Zhu, Huajian; Lu, Lixue; Zhu, Weibing; Tan, Yuchen; Duan, Yiping; Liu, Jie; Ye, Wen‐Cai; Zhu, Zheying; Xu, Jinyi; Xu, Shengtao

doi:10.1016/j.ejmech.2022.114575

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…Moreover, angiogenesis can be hindered by blocking human microvascular endothelial cells (HMECs) in the S phase ( 17 ), restraining HMEC growth and inducing apoptosis. 23-HBA exhibits a synergistic effect with antitumor drugs such as 5-fluorouracil ( 18 ). It can also inhibit the activity of the ATP binding cassette subfamily B member 1 ATPase ( 19 ), leading to the accumulation of drugs ( 20 ) within cells and effectively reversing P-glycoprotein-mediated multidrug resistance.…”

Section: Introductionmentioning

confidence: 99%

Effect of 23‑hydroxybetulinic acid on lung adenocarcinoma and its mechanism of action

Tan,

Lan,

Zhang

et al. 2024

Exp Ther Med

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The present study aimed to investigate the effect and mechanism of Pulsatilla compounds on lung adenocarcinoma. The representative drug chosen was the compound 23-HBA. GeneCards, Swiss target prediction, DisGeNET and TCMSP were used to screen out related genes, and MTT and flow cytometry assays were used to verify the inhibitory effect of Pulsatilla compounds on the proliferation of lung adenocarcinoma cells. Subsequently, the optimal target, peroxisome proliferator-activated receptor (PPAR)-γ, was selected using bioinformatics analysis, and its properties of low expression in lung adenocarcinoma cells and its role as a tumor suppressor gene were verified by western blot assay. The pathways related to immunity and inflammation, vascular function, cell proliferation, differentiation, development and apoptosis with the highest degree of enrichment and the mechanisms were explored through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Finally, the clinical prognosis in terms of the survival rate of patients in whom the drug is acting on the target was analyzed using the GEPIA database. The results indicated that Pulsatilla compounds can inhibit the proliferation of lung adenocarcinoma cells by blocking the cell cycle at the G 1 phase. Subsequently, the related PPAR-γ gene was verified as a tumor suppressor gene. Further analysis demonstrated that this finding was related to the PPAR signaling pathway and mitochondrial reactive oxygen species (ROS) production. Finally, the clinical prognosis was found to be improved, as the survival rate of patients was increased. In conclusion, Pulsatilla compounds were indicated to inhibit the viability and proliferation of lung adenocarcinoma H1299 cells, and the mechanism of action was related to PPAR-γ, the PPAR signaling pathway and mitochondrial ROS. The present study provides novel insight to further explore the treatment of lung adenocarcinoma.

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Section: Introductionmentioning

confidence: 99%

Effect of 23‑hydroxybetulinic acid on lung adenocarcinoma and its mechanism of action

Tan,

Lan,

Zhang

et al. 2024

Exp Ther Med

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“…In an HCC orthotopic transplantation tumor model, both NQO1 knockout and an NQO1 inhibitor blocked tumor growth and induced apoptosis, suggesting that NQO1 plays an important role in maintaining the proliferation of HCC cells [8]. NQO1-responsive prodrugs and nanocarriers have been developed for cancer treatment [9][10][11][12]. Notably, the ClinicalTrials.gov website (https://www.clinicaltrials.gov) contains 36 NQO1-relevant clinical trials.…”

Section: Introductionmentioning

confidence: 99%

CT radiomics for noninvasively predicting NQO1 expression levels in hepatocellular carcinoma

He,

Shen,

Wang

et al. 2023

PLoS ONE

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Using noninvasive radiomics to predict pathological biomarkers is an innovative work worthy of exploration. This retrospective cohort study aimed to analyze the correlation between NAD(P)H quinone oxidoreductase 1 (NQO1) expression levels and the prognosis of patients with hepatocellular carcinoma (HCC) and to construct radiomic models to predict the expression levels of NQO1 prior to surgery. Data of patients with HCC from The Cancer Genome Atlas (TCGA) and the corresponding arterial phase-enhanced CT images from The Cancer Imaging Archive were obtained for prognosis analysis, radiomic feature extraction, and model development. In total, 286 patients with HCC from TCGA were included. According to the cut-off value calculated using R, patients were divided into high-expression (n = 143) and low-expression groups (n = 143). Kaplan–Meier survival analysis showed that higher NQO1 expression levels were significantly associated with worse prognosis in patients with HCC (p = 0.017). Further multivariate analysis confirmed that high NQO1 expression was an independent risk factor for poor prognosis (HR = 1.761, 95% CI: 1.136−2.73, p = 0.011). Based on the arterial phase-enhanced CT images, six radiomic features were extracted, and a new bi-regional radiomics model was established, which could noninvasively predict higher NQO1 expression with good performance. The area under the curve (AUC) was 0.9079 (95% CI 0.8127–1.0000). The accuracy, sensitivity, and specificity were 0.86, 0.88, and 0.84, respectively, with a threshold value of 0.404. The data verification of our center showed that this model has good predictive efficiency, with an AUC of 0.8791 (95% CI 0.6979–1.0000). In conclusion, there existed a significant correlation between the CT image features and the expression level of NQO1, which could indirectly reflect the prognosis of patients with HCC. The predictive model based on arterial phase CT imaging features has good stability and diagnostic efficiency and is a potential means of identifying the expression level of NQO1 in HCC tissues before surgery.

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“…1 shows the molecular structure of this NQO1-activatable photosensitiser (compound 1 ) and its activation mechanism. The compound contains a distyryl boron dipyrromethene (BODIPY)-based photosensitising unit which is caged with an ester moiety 13 and a NQO1-responsive trimethylquinone unit 14 linked via a self-immolative linker. Upon interactions with NQO1 in the presence of NADPH, the quinone moiety of 1 would first undergo two-electron reduction to give a hydroquinone intermediate, followed by sequential intramolecular cyclisation into a lactone, further cyclisation into a five-membered cyclic urea and 1,6-elimination to release a p -quinone-methide and a carboxylated BODIPY (compound 2 ) as proposed previously.…”

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confidence: 99%

Design and synthesis of a NAD(P)H:quinone oxidoreductase 1-activatable photosensitiser for controlled photodynamic therapy

et al. 2023

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Design and synthesis of NAD(P)H: Quinone oxidoreductase (NQO1)-activated prodrugs of 23-hydroxybetulinic acid with enhanced antitumor properties

Cited by 6 publications

References 35 publications

Effect of 23‑hydroxybetulinic acid on lung adenocarcinoma and its mechanism of action

Effect of 23‑hydroxybetulinic acid on lung adenocarcinoma and its mechanism of action

CT radiomics for noninvasively predicting NQO1 expression levels in hepatocellular carcinoma

Design and synthesis of a NAD(P)H:quinone oxidoreductase 1-activatable photosensitiser for controlled photodynamic therapy

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