Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT

Mao, Jie; Yang, Hongbao; Cui, Tongtong; Pan, Pan; Kabir, Nadia; Chen, Duo; Ma, Jingui; Chen, Xingyi; Chen, Yijun; Yang, Yong

doi:10.1016/j.ejphar.2018.05.027

Cited by 52 publications

(32 citation statements)

References 34 publications

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“… 36 The results of the study carried out by Mao et al. 37 showed that silibinin can trigger the expression changes of downstream Mcl-1 and Bcl-2 genes through inhibiting the phosphorylation of Akt and STAT3, and then strengthen the effect of sorafenib. All these results have confirmed the importance of targeted Akt in HCC.…”

Section: Discussionmentioning

confidence: 99%

A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma

Zhang

Wang

Zhou

et al. 2018

Molecular Therapy - Nucleic Acids

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Currently, sorafenib-based therapy is the standard treatment for advanced hepatocellular carcinoma (HCC), and there is a strong rationale for investigating its use in combination with other agents to achieve better therapeutic effects. Aurora-A, a member of a family of mitotic serine/threonine kinases, is frequently overexpressed in human cancers and therefore represents a target for therapy. Here, we investigated a novel Aurora-A inhibitor, MLN8237, together with sorafenib in HCC cells in vitro and in vivo, and elucidated the possible molecular mechanism. Here, it was found that MLN8237 was strongly synergistic with sorafenib in inhibition of HCC progression by altering cell growth, cell-cycle regulation, apoptosis, migration, invasion, and angiogenesis. Mechanism dissection suggests that the combination of MLN8237 and sorafenib led to significant inhibition of the activation of phospho-Akt (p-Akt) and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) and their downstream genes including CDK4, cyclinD1, and VEGFA. The activators of p-Akt and p-p38 MAPK signaling partially reversed the synergistic inhibitory effects of sorafenib and MLN8237 on HCC progression. Subsequent in vivo studies further confirmed the synergistic effects of sorafenib and MLN8237. Collectively, the newly developed sorafenib-MLN8237 combination may be a novel therapy to better inhibit HCC progression.

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Section: Discussionmentioning

confidence: 99%

A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma

Zhang

Wang

Zhou

et al. 2018

Molecular Therapy - Nucleic Acids

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“…Hepatocellular carcinoma stem cells↓; Glioblastoma stem cells↓; Head and neck squamous cell carcinomas stem cells↓; Breast cancer stem cells↓; Colon cancer stem cell↓; Lung cancer stem cells↓…”

Section: Introductionmentioning

confidence: 99%

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

et al. 2019

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Traditional Chinese medicine (TCM) has been practiced for thousands of years and at the present time is widely accepted as an alternative treatment for cancer. In this review, we sought to summarize the molecular and cellular mechanisms underlying the chemopreventive and therapeutic activity of TCM, especially that of the Chinese herbal medicine‐derived phytochemicals curcumin, resveratrol, and berberine. Numerous genes have been reported to be involved when using TCM treatments and so we have selectively highlighted the role of a number of oncogene and tumor suppressor genes in TCM therapy. In addition, the impact of TCM treatment on DNA methylation, histone modification, and the regulation of noncoding RNAs is discussed. Furthermore, we have highlighted studies of TCM therapy that modulate the tumor microenvironment and eliminate cancer stem cells. The information compiled in this review will serve as a solid foundation to formulate hypotheses for future studies on TCM‐based cancer therapy.

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“…Other polyphenols have also been shown to potentiate the in vitro anticancer effects of Sf on various tumor cell types (e.g., [10,11,39,40]). The effects of such combinations on the intracellular ROS levels were scarcely studied.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have demonstrated that the cooperative effects of Sf/polyphenol combinations on ERK1/2 and STAT3 in HCC cells; differ depending on the type of phenolic compound. Thus, combined treatments with Sf and silibinin or the curcumin analog ASC-J9r were shown to cooperatively reduce phosphorylation of ERK1/2 and/or STAT3 [ 11 , 44 ] while the Sf/chrysin combination induced sustained ERK1/2 phosphorylation [ 45 ]. Moreover, overexpression of Mek1 enhanced, whereas inhibition of Mek1 by U0126 reduced the synergistic reduction of cell viability by Sf/chrysin [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…The main strategy has been to combine Sf with other cytotoxic agents (eg [ 7 – 9 ]). Combinations of Sf with non-toxic botanicals such as curcumin and silibinin have also been reported [ 10 , 11 ]. More recently, we have shown that carnosic acid (CA), a polyphenolic antioxidant from the food preservative Rosemary Extract [ 12 ], used alone, or together with a vitamin D2 analog, can markedly enhance the cytotoxic actions of a low concentration of Sf in two cell lines derived from HCC, Huh7 and HepG2, but not in the Hu1545 cell line derived from normal hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

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Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells

et al. 2020

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Hepatocellular carcinoma (HCC) has increasing worldwide incidence but when unresectable lacks curative options. Treatment with a kinase inhibitor Sorafenib (Sf), while initially effective, results in only short increases in patient survival, thus there is a need for improved treatment regimens. Numerous treatment regimens have been explored wherein Sf is combined with other agents, such as non-toxic botanicals like Curcumin or Silibinin. Recently, we have shown that carnosic acid (CA), a component of the food preservative Rosemary Extract, can markedly enhance the cytotoxic actions of Sf in several cell lines derived from HCC, but not in the cell line Hu1545 derived from normal hepatocytes. CA has been shown to enhance Sf-induced cell death in the neoplastic cell lines, principally due to the composite of increased apoptosis and cytotoxic autophagy. In the present study we focused on the mechanisms that underlie the reduced proliferation and survival of HCC cells when CA is added to Sf and how this relates to the increase in Sf-induced DNA damage as well as to the elevation of cytoplasmic levels of reactive oxygen species (ROS). Importantly, the elevation of ROS levels induced by Sf was increased by adding CA. We found that CA enhanced Sf-induced prolongation of cell cycle, and the overall decrease in cell growth was associated with reduced activation of both STAT3 transcription factor (TF) and extracellular signal-regulated protein kinase (Erk)1/2. Our data suggest that a regimen incorporating CA, an inexpensive and non-toxic food additive, in the treatment of advanced HCC merits clinical evaluation.

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Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT

Cited by 52 publications

References 34 publications

A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma

A Novel Aurora-A Inhibitor (MLN8237) Synergistically Enhances the Antitumor Activity of Sorafenib in Hepatocellular Carcinoma

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells

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