Targeting STAT3 with silibinin to improve cancer therapeutics

Bosch-Barrera, Joaquim; Queralt, Bernardo; Menendez, Javier A.

doi:10.1016/j.ctrv.2017.06.003

Cited by 92 publications

(60 citation statements)

References 108 publications

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“…There has not shown any apparent signs of toxicity or adverse effects in various acute and chronic animal tests (Raina and Agarwal, 2007). Given the traditional use of SB in the clinic and the high anti-cancer efficacy of SB, the mechanism underlying its anti-cervical cancer activity deserves further investigation (Bosch-Barrera et al, 2017).…”

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confidence: 99%

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

You

et al. 2020

Front. Pharmacol.

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Cervical cancer is the fourth leading cancer type and the second most common gynecological malignancy among women worldwide. Silibinin (SB), a chief bioactive natural polyphenolic flavonoid of Silybum marianum L., has been used clinically for its hepatocyte protective effects. It also has anticancer effects via the induction of apoptosis and cell cycle arrest. However, the effects of SB on cervical cancer cells through mitochondrial fission have not been studied. Here, we showed that SB markedly suppressed cervical cell proliferation by inducing G2/M cell cycle arrest via the activation of dynamin-related protein 1 (Drp1), which in turn mediated the mitochondrial fission dysfunction both in vitro and in vivo. SB decreased the ATP content, mitochondrial membrane potential, and mtDNA copy number, as well as reduced the reactive oxygen species levels in cervical cells. Furthermore, SB induced excessive mitochondrial fragmentation and reduced tubule formation. Further study showed that knockdown of Drp1 abolished the SB-induced G2/M cell cycle arrest in cervical cancer cells by inhibiting the mitochondrial fission pathway. More importantly, SB inhibited Hela cell growth in vivo model. In conclusion, we are the first to demonstrate that SB induces cervical cancer cell G2/M cell cycle arrest by activating Drp1-dependent mitochondrial fission dysfunction. This study suggests the strategy of inducing Drp1-dependent mitochondrial fission for cervical cancer prevention and treatment.

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confidence: 99%

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

You

et al. 2020

Front. Pharmacol.

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“…Curcumin and silibinin have shown anticancer properties by modulating several signalling pathways [34,36,[53][54][55] . More importantly, it is documented that curcumin and silibinin have the ability to repress proteins that are involved in EMT and metastasis [45,47,56] .…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, the expression of another mesenchymal marker, Vimentin, did not change in the neuroblastoma cells treated with or without curcumin or silibinin (data not shown). Curcumin and silibinin are natural compounds that have many anti-cancer properties including induction of MET [34][35][36] . As neuroblastoma cells, especially high-risk ones, are aggressive and resistant to treatment, the combinatorial effect of curcumin or silibinin with doxorubicin was examined to understand their therapeutic potential.…”

Section: Curcumin and Silibinin Reduce The Expression Of Mesenchymal mentioning

confidence: 99%

“…Curcumin and silibinin are natural components that have exhibited anti-cancer activities and can induce MET in many adult cancers with less or no toxicity [32,33] . These natural active ingredients have been implicated in suppressing various growth and pro-invasive signalling pathways as well as inducing cell death in a variety of cancer cells [34][35][36] . In non-N-Myc amplified SH-SY-5Y neuroblastoma cells, curcumin was shown to induce cell death in vitro [37] .…”

Section: Introductionmentioning

confidence: 99%

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Combinatorial treatment of curcumin or silibinin with doxorubicin sensitises high-risk neuroblastoma

Fonseka¹,

Gangoda²,

Pathan³

et al. 2020

JCMT

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Aim: Neuroblastoma is a pediatric cancer of the sympathetic nervous system. Using various parameters including stage of the disease, amplification status of N-Myc, DNA index and histopathology, neuroblastoma can be stratified into low-and high-risk groups. Recent advances in treatment have significantly improved the survival rate of lowrisk neuroblastoma patients. However, the overall survival rate of high-risk neuroblastoma group, especially N-Myc amplified patients, is poor. Moreover, the survivors of both low-and high-risk neuroblastoma manifest adverse side effects to chemotherapy and thus their quality of life is impaired. Considering all these factors, there is an urgent need to develop therapeutic strategies with natural compounds to improve the survival rate and to reduce the side effects. In this study, we hypothesised that the mesenchymal nature of neuroblastoma cells is a reason, at least in part, for the aggressive and treatment resistant phenotype. Method: In order to validate our hypothesis, we used publicaly available RNA-Seq data, in vitro assays and xenograft mouse models. Results: Using a combinatorial treatment of mesenchymal-to-epithelial inducers (curcumin or silibinin) with doxorubicin significantly increased the cell death in a panel of neuroblastoma cells in vitro. Follow up analysis in vivo, confirmed the therapeutic benefit of utilising the combination of curcumin with doxorubicin. The combinatorial therapy significantly reduced the tumor burden and increased the survival of mice implanted with high-risk neuroblastoma cells. Conclusion: Taken together, this study shows the efficacy of using curcumin in combination with doxorubicin to improve the survival rate and has the potential to enhance the quality of life of neuroblastoma patients.

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“…It has been found that a variety of extracellular signals can activate STAT3, then forming a two dimers and come into the nucleus, to recognize and bind to specific DNA promoter, in order to regulate the transcriptional of the target gene [32,33]. STAT3 signal transduction pathway is activated in a variety of primary tumors and tumor derived cell lines [34], which plays an important role in the regulation of tumor cell growth, proliferation and apoptosis process, this is may be related to the activation of a series of target gene followed STAT3 activation [35,36]. In the recent years, there are many researches on the relationship between STAT3 and cancers, and these research suggest that the activation of STAT3 is closely associated with colorectal cancer [37].…”

Section: Discussionmentioning

confidence: 99%

The mechanism and tumor inhibitory study of Lagopsis supine ethanol extract on colorectal cancer in nude mice

Wei

Wang

Xia

et al. 2019

BMC Complement Altern Med

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Background: This study was aimed to determination the tumor inhibitory effect and explore the potential mechanisms of Lagopsis supine ethanol extract (Ls) on colorectal cancer. Methods: The cell growth inhibition experiment of Ls in colorectal cancer cell lines was determined by MTT method in the time course of 24, 48 and 72 h in four gradient drug concentrations. The protein expression levels of pSTAT3, pJAK2, STAT3, JAK2, Bcl-2 and caspase 3 were measured by Western blot method. The mRNA levels of the downstream genes of STAT3 were detected through semi-quantitative RT PCR. Sixty Balb/c-nude mice were xenograft with HCT116 colorectal cancer cells through subcutaneously. The xenografts were divided into five groups: model group, positive group (capecitabine 300 mg/kg) and three dosages of Ls treated groups (75, 150 and 300 mg/kg). Tumor size and tumor weight were calculated for evaluation the anti-tumor effects. H & E staining and immunohistochemical analysis were used to determine the histopathological changes and the levels of pSTAT3 and pJAK2 in the tumor tissues. Results: Ls exhibited a significant anti-proliferation effect in HCT116 and SW480 cells in vitro. The protein levels of pSTAT3, pJAK2 and Bcl-2, and the mRNA levels of Bcl-2 and Bak notably reduced with a dose-dependent manner. While the protein levels of caspase 3, and mRNA levels of Bax and caspase-3 remarkably increased in the gradient dosage of Ls in HCT116 cells. HCT116 in vivo xenografts experiment showed that the growth of the tumors significantly inhibited by Ls administration, which with no any significant body weight changes in each experiment group. The histopathology analysis displayed that Ls significantly reduced the inflammatory cells in tumor tissue. Furthermore, Ls also significantly down-regulate the protein levels of pSTAT3 and pJAK2 in the tumor tissues, compared with the model group. Conclusions: This work shows that Ls inhibited the cell proliferation of colorectal cancer in vitro and significantly reduced the tumor growth in HCT116 xenografts in vivo, which is probably related with the JAK/STAT signal pathway.

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Targeting STAT3 with silibinin to improve cancer therapeutics

Cited by 92 publications

References 108 publications

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

Silibinin Induces G2/M Cell Cycle Arrest by Activating Drp1-Dependent Mitochondrial Fission in Cervical Cancer

Combinatorial treatment of curcumin or silibinin with doxorubicin sensitises high-risk neuroblastoma

The mechanism and tumor inhibitory study of Lagopsis supine ethanol extract on colorectal cancer in nude mice

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