An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma

Gao, Xiaoge; Wei, Meng-Xue; Shan, Wenhua; Liu, Qian; Gao, Jian; Liu, Yong; Zhu, Shaolin; Yao, Hong

doi:10.1016/j.phrs.2019.104400

Cited by 7 publications

(2 citation statements)

References 38 publications

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“…Orthotopic mouse liver cancer model was established with mouse liver cancer cell line ML-1 according to previous description [ 19 ]. Briefly, ML-1 cells were collected and injected slowly into the left lobe of liver of anesthetized BALB/c mice with tribromoethyl alcohol.…”

Section: Methodsmentioning

confidence: 99%

Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity

et al. 2023

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Background Galectin-3 (Gal-3), the only chimeric β-galactosides-binding lectin, consists of Gal-3N (N-terminal regulatory peptide) and Gal-3C (C-terminal carbohydrate-recognition domain). Interestingly, Gal-3C could specifically inhibit endogenous full-length Gal-3 to exhibit anti-tumor activity. Here, we aimed to further improve the anti-tumor activity of Gal-3C via developing novel fusion proteins. Methods PK5 (the fifth kringle domain of plasminogen) was introduced to the N-terminus of Gal-3C via rigid linker (RL) to generate novel fusion protein PK5-RL-Gal-3C. Then, we investigated the anti-tumor activity of PK5-RL-Gal-3C in vivo and in vitro by using several experiments, and figured out their molecular mechanisms in anti-angiogenesis and cytotoxicity to hepatocellular carcinoma (HCC). Results Our results show that PK5-RL-Gal-3C can inhibit HCC both in vivo and in vitro without obvious toxicity, and also significantly prolong the survival time of tumor-bearing mice. Mechanically, we find that PK5-RL-Gal-3C inhibits angiogenesis and show cytotoxicity to HCC. In detail, HUVEC-related and matrigel plug assays indicate that PK5-RL-Gal-3C plays an important role in inhibiting angiogenesis by regulating HIF1α/VEGF and Ang-2 both in vivo and in vitro. Moreover, PK5-RL-Gal-3C induces cell cycle arrest at G1 phase and apoptosis with inhibition of Cyclin D1, Cyclin D3, CDK4, and Bcl-2, but activation of p27, p21, caspase-3, -8 and -9. Conclusion Novel fusion protein PK5-RL-Gal-3C is potent therapeutic agent by inhibiting tumor angiogenesis in HCC and potential antagonist of Gal-3, which provides new strategy for exploring novel antagonist of Gal-3 and promotes their application in clinical treatment.

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Section: Methodsmentioning

confidence: 99%

Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity

et al. 2023

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“…The aberrant expression and activation of JNKs are found in Grade 3-4 0 (0.00%) 0 (0.00%) many cancer cell lines and tissue samples (Mohebali et al, 2020;Qu et al, 2020). In primary hepatocellular carcinoma (HCC), compared with the non-neoplastic lesions, the activation of JNK1 in tumor size was significantly increased, and absence of JNK1 impaired hepatocyte proliferation and tumor formation (Chang et al, 2009;Gao et al, 2019). In mice with DEN induced liver cancer, the levels of activated JNK (p-JNK) were decreased by D-JNKI-1 injection for inhibited three months in the treatment group, whereas the levels of p-JNK was continuously expressed high (Davoli et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Significance of Anisomycin-Activated Phospho-c-Jun NH2-Terminal Kinase (p-JNK) in Predicting Breast Cancer Patients’ Survival Time

Chen

Kong

et al. 2021

Front. Cell Dev. Biol.

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This study aims to investigate the prognostic significance of p-JNK in breast cancer patients receiving neoadjuvant chemotherapy (NACT) and analyze the relationship between anisomycin, p-JNK. A total of 104 breast cancer patients had NACT were enrolled in this study. The western blot and immunohistochemistry assays were used to determine the protein expressions of p-JNK in human breast cancer cell lines and patients’ cancer tissues. The chi-square test and Fisher’s exact test were adopted to gauge the associations between breast cancer and clinicopathological variables by p-JNK expression, whereas the univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic value of p-JNK expression. The Kaplan-Meier plots and the log-rank test were adopted to determine patients’ disease-free survival (DFS) and overall survival (OS). Findings indicated that the p-JNK expression had prognostic significance in univariate and multivariate Cox regression survival analyses. Results of log-rank methods showed that: (1) the mean DFS and OS times in patients with high p-JNK expression were significantly longer than those in patients with low p-JNK expression (χ2 = 5.908, P = 0.015 and χ2 = 6.593, P = 0.010, respectively). p-JNK expression is a significant prognostic factor that can effectively predict the survival in breast cancer patients receiving NACT. Treatment with the JNK agonist anisomycin can induce apoptosis, lead to increased p-JNK expression and decreased p-STAT3 expression. Moreover, the p-JNK expression was inversely correlated with p-STAT3 expression.

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Spirooxindole derivatives as kinase-based anticancer agents

Valapil,

Shankaraiah

2024

Spirooxindole

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An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma

Cited by 7 publications

References 38 publications

Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity

Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity

The Prognostic Significance of Anisomycin-Activated Phospho-c-Jun NH2-Terminal Kinase (p-JNK) in Predicting Breast Cancer Patients’ Survival Time

Spirooxindole derivatives as kinase-based anticancer agents

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