Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells

Luo, Dongdong; Yi, Yujiao; Peng, Kai; Liu, Tangrong; Yang, Jiayu; Liu, Shan; Zhao, Wanzhou; Qu, Xian‐Jun; Yu, Wengong; Gu, Yuchao; Wan, Shengbiao

doi:10.1016/j.ejmech.2019.06.006

Cited by 41 publications

(20 citation statements)

References 33 publications

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“…To validate the importance and function of M2BPGi in several differentiated cell lines of HCC, we selected the PLC/PRF/5 cell line to represent poorly differentiated HCC, 23 whereas other cell lines (Huh7 and HepG2) represented well-differentiated HCC. 24 All cell lines were obtained from the JCRB Cell Bank (Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling

et al. 2020

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Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling (Mac-2結合蛋白糖鎖修飾異性体はmTORシグナル伝達経路を活性化することにより肝細胞癌の悪性度を増悪させる) Background: Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, mostly occurs in people with liver cirrhosis. For HCC patients with severe liver fibrosis, treatment option is limited. Therefore, deeper understanding of HCC in fibrotic liver is important for clinical management of HCC. Wisteria floribunda agglutinin (WFA) + Mac-2 binding protein ( M2BPGi) is a novel serum marker for liver fibrosis. Clinical studies reported that an elevated serum level of M2BPGi can predict development

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Section: Methodsmentioning

confidence: 99%

Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling

et al. 2020

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“…To the best of our knowledge, this is the rst report to demonstrate an anti-depressive function of Ori, although this drug has recently been recommended as a potential drug for the treatment of tumors [50][51][52] and neurodegenerative diseases such as AD and PD [26,27,53]. In this study, both prophylactic and therapeutic treatments with Ori (5 mg/kg and 10mg/kg) effectively improved depressive-like behaviors induced by CUMS, with the effects of the former being more pronounced than the latter.…”

Section: Discussionmentioning

confidence: 91%

Oridonin relieves depressive-like behaviors by inhibiting neuroinflammation and autophagy impairment in rats subjected to chronic unpredictable mild stress

Liang¹,

Wang²,

Wang³

et al. 2021

Preprint

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Background: Major depressive disorder (MDD) is a common, chronic, and severe life-threatening disorder with increasing prevalence. Although neuroinflammation is associated with the etiology of depression, the mechanistic interplay between depression, neuroinflammation, and autophagy is yet to be demonstrated. This study investigated the effect of Oridonin on CUMS-induced neuroinflammation, depression, and autophagy impairment. Methods: Male 4-week-old Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) for 4 and 6 weeks respectively, some of which were injected with Oridonin, fluoxetine (FLX) or their combination at different durations of CUMS. After CUMS procedure, sucrose preference test and Forced swim test were used to evaluate depressive-like behaviors. Concomitant neuroinflammation changes and autophagy impairments were examined in the hippocampus.Reults: In this study, we found that chronic stress resulted in depressive-like behaviors and caused neuroinflammation and autophagy impairment. In particular, CUMS treatment significantly increased the levels of cytokines (IL-1β, IL-18 and Caspase-1), reduced autophagy-related protein levels (Beclin-1, p62, Atg5 and LC3B), caused microglia cells activation. Oridonin treatment can prevent and reverse the depressive-like behavior induced by CUMS in prophylactic and therapeutic administration, but there is ceiling effect in the treatment process. Furthermore, 10mg/kg dose of Ori has a stronger and longer lasting antidepressant effect than the 10mg/kg dose of fluoxetine. And the antidepressant effect of Ori in combination with fluoxetine was greater than that of high-dose fluoxetine alone. In addition, Ori treatment significantly normalized autophagy-related protein levels, and reduced levels of cytokines via blocking the interaction between NLRP3 and NEK7. Further, we investigated the role of autophagy in LPS-activated BV2 cells and levels of cytokines. Similarly, Oridonin treatment abolished and reversed levels of cytokines and autophagy-related protein levels.Conclusions: All these results supported our hypothesis that Ori possesses potent anti-depressive action, which might be mediated via inhibition of neuroinflammation and autophagy impairment through blocking the interaction between NLRP3 and NEK7.

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“…Once the volume of the tumor outranges the blood supply, it often leads to core area necrosis (Shi et al, 2019), which suggests a relative hypoxia state in glioma. Our In previous studies, Oridonin was proved to induce Ras, Akt, AMPK, HIF, mTOR signaling pathway inhibition (Jiang et al, 2019;, as well as mitochondrial function restraining (Jiang et al, 2019;Luo et al, 2019). But how Oridonin acts on cellular bioenergy metabolism is still elusive.…”

Section: Discussionmentioning

confidence: 97%

“…In previous studies, Oridonin was proved to induce Ras, Akt, AMPK, HIF, mTOR signaling pathway inhibition (Jiang et al, 2019; Yang, Gao, et al, 2019), as well as mitochondrial function restraining (Jiang et al, 2019; Luo et al, 2019). But how Oridonin acts on cellular bioenergy metabolism is still elusive.…”

Section: Discussionmentioning

confidence: 99%

“…These pathways have been demonstrated to modulate cell metabolism especially in glucose metabolism (Smith et al, 2016). Latest studies demonstrated Oridonin had an impact on mitochondria (Jiang et al, 2019; Luo et al, 2019). In this study, we determined oxidative phosphorylation (OXPHOS) and glycolysis using Seahorse XF96 Extracellular Flux Analyzer in Oridonin treated glioma cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down‐regulating PCK2

Lin

et al. 2021

Phytotherapy Research

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We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA-seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked-down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin-treated U251/U87 cells. Oridonin treatment led to PCK2 down-regulation. Additionally, PCK2 was up-regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti-tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.

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Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells

Cited by 41 publications

References 33 publications

Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling

Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling

Oridonin relieves depressive-like behaviors by inhibiting neuroinflammation and autophagy impairment in rats subjected to chronic unpredictable mild stress

Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down‐regulating PCK2

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