Icaritin induces ovarian cancer cell apoptosis through activation of p53 and inhibition of Akt/mTOR pathway

Gao, Lvfen; Ouyang, Yong; Li, Ruobin; Zhang, Xian; Gao, Xuesong; Lin, Shaoqiang; Wang, Xiaoyu

doi:10.1016/j.lfs.2018.03.059

Cited by 29 publications

(19 citation statements)

References 34 publications

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“…During the overall study period, major cancers, such as colorectal cancer (18%, 18/99) [19,20,21,29,41,42,47,48,49,51,52,56,58,60,79,87,108,111], lung cancer (17%, 17/99) [18,25,35,40,43,44,49,64,71,72,73,78,84,104,106,110,112], and breast cancer (14%, 14/99) [26,28,46,55,61,65,71,77,85,86,88,89,91,102] were used more frequently for PDX models. The others were ovarian cancer (9%, 9/99) [49,67,70,71,80,95,97,100,101], brain tumors (6%, 6/99) [57,59,63,83,101,103], pancreatic cancer (6%, 6/99) [22,24,27,39,…”

Section: Resultsmentioning

confidence: 99%

Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors

Koga

Ochiai

2019

Cells

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Patient-derived xenograft (PDX) models are used as powerful tools for understanding cancer biology in PDX clinical trials and co-clinical trials. In this systematic review, we focus on PDX clinical trials or co-clinical trials for drug development in solid tumors and summarize the utility of PDX models in the development of anti-cancer drugs, as well as the challenges involved in this approach, following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Recently, the assessment of drug efficacy by PDX clinical and co-clinical trials has become an important method. PDX clinical trials can be used for the development of anti-cancer drugs before clinical trials, with their efficacy assessed by the modified response evaluation criteria in solid tumors (mRECIST). A few dozen cases of PDX models have completed enrollment, and the efficacy of the drugs is assessed by 1 × 1 × 1 or 3 × 1 × 1 approaches in the PDX clinical trials. Furthermore, co-clinical trials can be used for personalized care or precision medicine with the evaluation of a new drug or a novel combination. Several PDX models from patients in clinical trials have been used to assess the efficacy of individual drugs or drug combinations in co-clinical trials.

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Section: Resultsmentioning

confidence: 99%

Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors

Koga

Ochiai

2019

Cells

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“…It has a wide range of biological and pharmacological functions, including antioxidative, anticancer, and enhancing immunity [10][11][12]. Its anticancer activities were reported in breast cancer, lung cancer, esophageal cancer, glioblastoma, leukemia, and HCC [13][14][15][16][17]. Previous studies found that icaritin inhibited the growth of liver cancer cells by promoting HCC cell apoptosis through activating the caspase pathway and inhibiting the interleukin-6/Janus kinase (JNK)2/signal transducer and activator of transcription 3 signaling pathway, while the safety of daily doses of oral icaritin (1600 mg) was documented in clinical studies [18,19].…”

Section: Introductionmentioning

confidence: 99%

Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma

Liu

Xue

et al. 2021

BMC Cancer

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Background Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway. Methods Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting. Results Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis. Conclusion Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer.

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“…The necrotic areas expanded after treatment with the compounds, as shown in Figure 5F. TUNEL staining of tumor slices showed that the number of apoptotic tumor cells (White arrow) were increased (Figure 5G, p < 0.01) (42). The results indicated that apoptosis of tumor cells was induced by CAPE and CAPE- p NO 2 .…”

Section: Resultsmentioning

confidence: 92%

“…Images were obtained using a fluorescence microscope (Olympus, U-RFLT50, Tokyo, Japan). The fluorescence intensity of images was analyzed using Image-Pro Plus software (Media Cybernetics, Inc., Rockville, MD, USA) (42).…”

Section: Methodsmentioning

confidence: 99%

CAPE-pNO2 Inhibited the Growth and Metastasis of Triple-Negative Breast Cancer via the EGFR/STAT3/Akt/E-Cadherin Signaling Pathway

Huang

Zhang

et al. 2019

Front. Oncol.

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Overexpressed epidermal growth factor receptor (EGFR) and overactivated epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) can enhance tumorigenesis and tumor recurrence and metastasis. Caffeic acid p -nitro-phenethyl ester (CAPE- p NO 2 ) has various pharmacological activities in our previous research, but its effect on metastasis and growth of TNBC has not been studied. In this study, Caffeic acid phenethyl ester (CAPE) was as a positive control. in vitro , MTT, Transwell, wound healing, colony formation and cell adhesion assays were performed to examine the effect on viability, invasion, migration, colony formation and adhesion of MDA-MB-231 cells by CAPE- p NO 2 , the results indicated that CAPE- p NO 2 significantly dose-dependently inhibited metastasis of MDA-MB-231 cells ( p < 0.05). in vivo , TNBC xenograft mice were established by subcutaneously injected with MDA-MB-231 cells, and they were used to estimate the effect on metastasis and growth of CAPE- p NO 2 after 38 days of treatment. HE staining and TUNEL staining were carried out in tumor tissues, results showed that CAPE- p NO 2 obviously suppressed the tumor growth, induced cells apoptosis ( p < 0.01) and decreased pulmonary and splenic metastatic tumor cells. The results of IHC demonstrated that the VEGFA and Ki-67 proteins expression were downregulated ( p < 0.01) in tumor tissues. Furthermore, western blot analysis was used to quantify key metastasis- and growth-associated proteins expression in vitro and in vivo , the results suggested that CAPE- p NO 2 downregulated the proteins expression of p-EGFR, p-STAT3, p-Akt, MMP-2, MMP-9, Survivin, and key EMT-related proteins (Vimentin and N-cadherin) ( p < 0.01), and increased the expression of E-cadherin ( p < 0.01) in vivo and in vitro . Besides, CAPE- p NO 2 had a similar effect as erlotinib in regulating the EGFR downstream proteins in EGF-induced MDA-MB-231cells. Collectively, these results indicated that CAPE- p NO 2 possessed inhibitory effect on the growth and metastasis of TNBC may via the EGFR/STAT3/Akt/E-cadherin signaling pathway, and CAPE- p NO 2 is better than CAPE in inhibiting growth and metastasis.

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Icaritin induces ovarian cancer cell apoptosis through activation of p53 and inhibition of Akt/mTOR pathway

Cited by 29 publications

References 34 publications

Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors

Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors

Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma

CAPE-pNO2 Inhibited the Growth and Metastasis of Triple-Negative Breast Cancer via the EGFR/STAT3/Akt/E-Cadherin Signaling Pathway

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