Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells

Mateen, Samiha; Raina, Komal; Jain, Anil K.; Agarwal, Chapla; Chan, Daniel C.; Agarwal, Rajesh

doi:10.4161/epi.22070

Cited by 52 publications

(41 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mateenet al observed that the treatment of small and nonsmall lung cancer cells with silibinininhibitedtheHDACi (histone deacetylase inhibitors) in NSCLC lung cancer cell line and increased in general the acetylation of histones H3 and H4. They further treated the cells with silibinin and HDACi and observed the expression of P21 (Mateen et al, 2012). Roy et al observed that silibinin increased the expression of P53, and activated the P21 as well.…”

Section: Discussionmentioning

confidence: 99%

Silibilin-Induces Apoptosis in Breast Cancer Cells by Modulating p53, p21, Bak and Bcl-xl Pathways

Pirouzpanah¹,

Sabzichi²,

Pirouzpanah³

et al. 2015

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Nowadays herbal-derived medicines are attracting attention as new sources of drugs with few side effects. Silibinin is a flavonoid compound with chemotheraputic effects on different cancers such as examples in the prostate, lung, colon and breast. In the present study, the cytotoxic effects of silibinin on MCF7 breast cancer cells were investigated. Apoptosis was determined by flow cytometry and the impact of silibinin on the expression of pivotal genes including Bak, P53, P21, BRCA1, BCL-X1 and ATM was analyzed. Treatment for 24h had a significant dose-dependent inhibitory effect on cell growth (p<0.05) with dose-and time-dependent induction of apoptosis (p<0.05). In addition, there were significant increases in BRCA1, ATM, Bak and Bcl-XL gene expression at the mRNA level with different concentrations of silibinin for 24 or 48 h (p<0.05). Taken together, the results suggest that silibinin inhibits the proliferation and induces apoptosis of MCF-7 cells by down-regulating Bak, P53, P21, BRCA1, BCL-Xl and thus may be considered as an effective adjuvant drug to produce a better chemopreventive response for the cancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Silibilin-Induces Apoptosis in Breast Cancer Cells by Modulating p53, p21, Bak and Bcl-xl Pathways

Pirouzpanah¹,

Sabzichi²,

Pirouzpanah³

et al. 2015

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

show abstract

“…Our data indicate that entinostat additionally induces growth inhibition itself through induction of cell cycle arrest genes (p21 Waf , GADD45), thereby blocking cell cycle progression, represented by the observed G1 arrest (BT474) or G2 arrest (SUM190). Previous studies have shown that enhanced p21 Waf levels induced by an HDAC inhibitor promoted proteasomal degradation of cyclin B1 and resulted in G2/M arrest [40] and that GADD45 promotes G2/M arrest via nuclear export and kinase activity of Cdc2 [41]. We observed that single treatment with entinostat appeared more effective in inhibiting growth than single treatment with lapatinib in soft agar culture.…”

Section: Discussionmentioning

confidence: 60%

A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression

Lee

Bartholomeusz

Mansour

et al. 2014

Breast Cancer Res Treat

View full text Add to dashboard Cite

Purpose Although there are effective HER2-targeted agents, novel combination strategies in HER2-overexpressing breast cancers are needed for patients whose tumors develop drug resistance. To develop new therapeutic strategy, we investigated the combinational effect of entinostat, an oral isoform-selective histone deacetylase type I inhibitor, and lapatinib, a HER2/EGFR dual tyrosine kinase inhibitor, in HER2+ breast cancer cells. Methods We assessed the combinational synergistic effect and its mechanism by CellTiter Blue assay, flow cytometry, anchorage-independent growth, quantitative real-time PCR, small interfering RNA, Western blotting, and mammary fat pad xenograft mouse models. Results We found that compared with entinostat or lapatinib alone, the two drugs in combination synergistically inhibited proliferation (P < 0.001) and reduced in vitro colony formation (P < 0.05) and resulted in significant in vivo tumor shrinkage or growth inhibition in two xenograft mouse models (BT474 and SUM190, P < 0.001). The synergistic anti-tumor activity of the entinostat/lapatinib combination was due to downregulation of phosphorylated Akt, which activated transcriptional activity of FOXO3, resulting in induction of Bim1 (a BH3 domain-containing pro-apoptotic protein). Furthermore, entinostat sensitized trastuzumab/lapatinib-resistance-HER2-overexpressing cells to the trastuzumab/lapatinib combination and enhanced the anti-proliferation effect compare with single or double combination treatment. Conclusions This study provides evidence that entinostat has enhanced anti-tumor effect in combination with HER2-targeted reagent, lapatinib, and resulting induction of apoptosis by FOXO3-mediated Bim1 expression. Our finding justifies for conducting a clinical trial of combinational treatment with entinostat, lapatinib and trastuzumab in patients with HER2-overexpressing breast cancer resistant to trastuzumab-based treatment.

show abstract

“…The final concentration of DMSO in medium during different treatments did not exceed 0.1% (v/v). Compared with previous studies in which we assessed the cell growth inhibitory activity of silibinin (up to 75 mM concentration) in lung cancer cells (Mateen et al, 2010(Mateen et al, , 2012, here we chose relatively lower doses of silibinin (3.75-12.5 mM) so that silibinin alone or in combination with other drugs does not affect growth and death of NSCLC cells and thus could be used for future invasion and migration studies.…”

Section: Methodsmentioning

confidence: 99%

“…In this regard, silibinin, a nontoxic chemopreventive agent, has shown strong anticancer efficacy against NSCLC cells in culture and nude mice (Mateen et al, 2010), together with the potential to alter enzymatic activity and protein levels of HDACs in NSCLC cells (Mateen et al, 2012). Specifically, silibinin was found to inhibit HDAC activity and decrease HDAC 1-3 levels in NSCLC cells, leading to an overall increase in global histone acetylation states of H3 and H4 (Mateen et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, silibinin was found to inhibit HDAC activity and decrease HDAC 1-3 levels in NSCLC cells, leading to an overall increase in global histone acetylation states of H3 and H4 (Mateen et al, 2012). Accordingly, here we examined the effect of silibinin, either alone or in combination with epigenetic therapies (HDAC or DNMT inhibitor), on regulating the mechanisms that are responsible for silencing E-cadherin in NSCLC cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Silibinin Synergizes with Histone Deacetylase and DNA Methyltransferase Inhibitors in Upregulating E-cadherin Expression Together with Inhibition of Migration and Invasion of Human Non-small Cell Lung Cancer Cells

Mateen

Raina

Agarwal

et al. 2013

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Aggressive cancers in the epithelial-to-mesenchymal transition (EMT) phase are characterized by loss of cell adhesion, repression of E-cadherin, and increased cell mobility. Non-small cell lung cancer (NSCLC) differs in basal level of E-cadherin; predominantly exhibiting silenced expression due to epigeneticrelated modifications. Accordingly, effective treatments are needed to modulate these epigenetic events that in turn can positively regulate E-cadherin levels. Herein, we investigated silibinin, a natural flavonolignan with anticancer efficacy against lung cancer, either alone or in combination with epigenetic therapies to modulate E-cadherin expression in a panel of NSCLC cell lines. Silibinin combined with HDAC inhibitor Trichostatin A [TSA; 7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide] or DNMT inhibitor 59-Aza-deoxycytidine (Aza) significantly restored E-cadherin levels in NSCLC cells harboring epigenetically silenced E-cadherin expression. These combination treatments also strongly decreased the invasion/migration of these cells, which further emphasized the biologic significance of E-cadherin restoration. Treatment of NSCLC cells, with basal E-cadherin levels, by silibinin further increased the E-cadherin expression and inhibited their migratory and invasive potential. Additional studies showed that silibinin alone as well as in combination with TSA or Aza downmodulate the expression of Zeb1, which is a major transcriptional repressor of E-cadherin. Overall these findings demonstrate the potential of combinatorial treatments of silibinin with HDAC or DNMT inhibitor to modulate EMT events in NSCLC cell lines, leading to a significant inhibition in their migratory and invasive potentials. These results are highly significant, since loss of E-cadherin and metastatic spread of the disease via EMT is associated with poor prognosis and high mortalities in NSCLC.

show abstract

Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells

Abstract: (2012) Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells,

Cited by 52 publications

References 41 publications

Silibilin-Induces Apoptosis in Breast Cancer Cells by Modulating p53, p21, Bak and Bcl-xl Pathways

Silibilin-Induces Apoptosis in Breast Cancer Cells by Modulating p53, p21, Bak and Bcl-xl Pathways

A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through FOXO3-mediated Bim1 expression

Silibinin Synergizes with Histone Deacetylase and DNA Methyltransferase Inhibitors in Upregulating E-cadherin Expression Together with Inhibition of Migration and Invasion of Human Non-small Cell Lung Cancer Cells

Contact Info

Product

Resources

About