Efficient delivery of ursolic acid by poly(N-vinylpyrrolidone)-block-poly (&amp;epsilon;-caprolactone) nanoparticles for inhibiting the growth of hepatocellular carcinoma in vitro and in vivo

Zhang, Hao; Zheng, Donghui; Jing, Ding; Xu, Huae; Li, Xin; Sun, Wei

doi:10.2147/ijn.s77125

Cited by 18 publications

(9 citation statements)

References 35 publications

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“…More importantly, our in vivo data were consistent with the findings from that in vitro, confirming the effect of UA on liver cancer growth inhibition and regulation of IGFBP1, FOXO3a expression, and p38 MAPK phosphorylation. The doses used for UA in the current study were similar to other reports demonstrating the significant effects in inhibiting growth of several cancer types including HCC [ 34 – 36 ]. Nevertheless, more experiments are needed to further elucidate the important role and the correlation between IGFBP1 and FOXO3a in this process using cells stable transfected with shRNAs or exogenous expressed IGFBP1 and/or FOXO3a genes in animal model.…”

Section: Discussionsupporting

confidence: 81%

“…Xenografts were allowed to grow for over one week when the initial measurement was made with calipers and with bioluminescence imaging (BLI) using the IVIS-200 Imaging System (Xenogen Corporation, Berkeley, CA). The mice were randomly divided into control, low (25 g/kg), and high doses (50 g/kg) of UA treatment groups, which based on other studies [ 34 – 36 ]. The UA was given via gavages daily for up to 30 days ( n = 12/group).…”

Section: Methodsmentioning

confidence: 99%

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Inter-regulation of IGFBP1 and FOXO3a unveils novel mechanism in ursolic acid-inhibited growth of hepatocellular carcinoma cells

Li¹,

Tang²,

Wu³

et al. 2016

J Exp Clin Cancer Res

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BackgroundUrsolic acid (UA), a natural pentacyclic triterpenoid, exerts anti-tumor effects in various cancer types including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying this remain largely unknown.MethodsCell viability and cell cycle were examined by MTT and Flow cytometry assays. Western blot analysis was performed to measure the phosphorylation and protein expression of p38 MAPK, insulin-like growth factor (IGF) binding protein 1 (IGFBP1) and forkhead box O3A (FOXO3a). Quantitative real-time PCR (qRT-PCR) was used to examine the mRNA levels of IGFBP1 gene. Small interfering RNAs (siRNAs) method was used to knockdown IGFBP1 gene. Exogenous expressions of IGFBP1 and FOXO3a were carried out by transient transfection assays. IGFBP1 promoter activity was measured by Secrete-Pair™ Dual Luminescence Assay Kit. In vivo nude mice xenograft model and bioluminescent imaging system were used to confirm the findings in vitro.ResultsWe showed that UA stimulated phosphorylation of p38 MAPK. In addition, UA increased the protein, mRNA levels, and promoter activity of IGFBP1, which was abrogated by the specific inhibitor of p38 MAPK (SB203580). Intriguingly, we showed that UA increased the expression of FOXO3a and that overexpressed FOXO3a enhanced phosphorylation of p38 MAPK, all of which were not observed in cells silencing of endogenous IGFBP1 gene. Moreover, exogenous expressed IGFBP1 strengthened UA-induced phosphorylation of p38 MAPK and FOXO3a protein expression, and more importantly, restored the effect of UA-inhibited growth in cells silencing of endogenous IGFBP1 gene. Consistent with these, UA suppressed tumor growth and increased phosphorylation of p38 MAPK, protein expressions of IGFBP1 and FOXO3a in vivo.ConclusionCollectively, our results show that UA inhibits growth of HCC cells through p38 MAPK-mediated induction of IGFBP1 and FOXO3a expression. The interactions between IGFBP1 and FOXO3a, and feedback regulatory loop of p38 MAPK by IGFBP1 and FOXO3a resulting in reciprocal pathways, contribute to the overall effects of UA. This in vitro and in vivo study corroborates a potential novel mechanism by which UA controls HCC growth and implies that the rational targeting IGFBP1 and FOXO3a can be potential for the therapeutic strategy against HCC.

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Section: Discussionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Inter-regulation of IGFBP1 and FOXO3a unveils novel mechanism in ursolic acid-inhibited growth of hepatocellular carcinoma cells

Li¹,

Tang²,

Wu³

et al. 2016

J Exp Clin Cancer Res

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“…UA inhibits the growth of gastric cancer cells and colon cancer cells [ 8 – 10 ]. In animal models, UA inhibited tumorigenesis [ 11 ] and suppressed tumor invasion and metastasis [ 12 , 13 ]. We found that UA induces apoptosis via down-regulation of cyclooxygenase-2 (COX-2) in gastric cancer cells [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 mediated synergistic effect of ursolic acid in combination with paclitaxel against human gastric carcinoma

Zhu

Zhang

et al. 2017

Oncotarget

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Ursolic acid (UA) induces apoptosis in gastric cancer cells by inhibiting cyclooxygenase-2 (COX-2). Paclitaxel (PTX) is an important chemotherapy agent used to treat solid tumors. We evaluated the in vitro antitumor activity of UA in combination with PTX against gastric cancer cells and investigated the mechanisms underlying the combined effects. A cytotoxicity test and flow cytometry were utilized to study the effects of UA and PTX on proliferation and apoptosis, respectively. To further elucidate the mechanism, Western blot analysis was used to assess changes in the expression of a series of related proteins, including COX-2, proliferating cell nuclear antigen (PCNA), Bcl-2, and Bax. UA and PTX dose- and time-dependently inhibited BGC-823 and SGC-7901 gastric cancer cell proliferation. Combined delivery of UA and PTX synergistically reduced cell proliferation and induced apoptosis in these cells by lowering COX-2, PCNA, and Bcl-2 expression and by increasing Bax expression. These results indicate that the synergistic inhibition of proliferation and induction of apoptosis by UA and PTX may be induced by reducing COX-2 expression in gastric cancer cells.

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“…UA, found in the leaves and fruits of many plants, induces cytotoxicity in cancer cells while remaining nontoxic to normal cells (Shanmugam et al, 2013;Weng et al, 2014). Derivatives of UA have also demonstrated increased antitumor efficacy in vivo (Wang et al, 2011;Yoon et al, 2016;Zhang et al, 2015). This paper demonstrates that UA induces JNKdependent and caspase independent cytotoxicity in a human GBM model.…”

Section: Discussionmentioning

confidence: 66%

Ursolic acid inhibits cell migration and promotes JNK-dependent lysosomal associated cell death in Glioblastoma multiforme cells

Conway

Zizyte

Mondala

et al. 2020

Preprint

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Running title: Ursolic Acid is Pro-Apoptotic and Anti-Invasive in GBM Abbreviations: UA, Ursolic acid; GBM, Glioblastoma Multiforme; TMZ, temozolomide; 3-MA, 3methyladenine. AbstractUrsolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM), however, the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrated that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM cell migration in a time dependent manner that is independent of the JNK signalling pathway. The cytotoxic insult induced by UA resulted in the formation of acidic vesicle organelles (AVOs), speculating activation of autophagy. However, inhibitor and spectrophotometric analysis demonstrated that autophagy was not responsible for the formation of the AVOs and confocal microscopy identified the AVO's as lysosomes. Further investigation using isosurface visualisation of confocal imaging determined co-localisation of lysosomes with the previously identified acidic vesicles, thus providing evidence that lysosomes are likely to be playing a role in UA induced cell death.Collectively, our data identifies that UA rapidly induces a lysosomal associated mechanism of cell death in addition to UA acting as an inhibitor of GBM cell migration.

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Efficient delivery of ursolic acid by poly(N-vinylpyrrolidone)-block-poly (ε-caprolactone) nanoparticles for inhibiting the growth of hepatocellular carcinoma in vitro and in vivo

Cited by 18 publications

References 35 publications

Inter-regulation of IGFBP1 and FOXO3a unveils novel mechanism in ursolic acid-inhibited growth of hepatocellular carcinoma cells

Inter-regulation of IGFBP1 and FOXO3a unveils novel mechanism in ursolic acid-inhibited growth of hepatocellular carcinoma cells

Cyclooxygenase-2 mediated synergistic effect of ursolic acid in combination with paclitaxel against human gastric carcinoma

Ursolic acid inhibits cell migration and promotes JNK-dependent lysosomal associated cell death in Glioblastoma multiforme cells

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