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Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Zhang L, Zhang Y, Mehta A, Boufraqech M, Davis S, Wang J, Tian Z, Yu Z, Boxer MB, Kiefer JA, Copland JA, Smallridge RC, Li Z, Shen M, Kebebew E - Oncotarget (2015)

Bottom Line: The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin.In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival.Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression.

View Article: PubMed Central - PubMed

Affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.

No MeSH data available.


Related in: MedlinePlus

CUDC-101 inhibits ATC cell migration and regulates EMT marker expression(A) ATC cell migration with and without CUDC-101 treatment. The numbers of migrated cells were counted and calculated with the vehicle-treated cells as 100%. Data was for an average of three fields. Error bars are mean ± SD. *p < 0.05, **p < 0.01. (B) EMT marker expression. ATC cells were treated with CUDC-101 for 24 hours, and the blots were probed with the indicated antibodies to measure protein expression. Each corresponding anti-β-actin blot was used as loading control.
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Figure 4: CUDC-101 inhibits ATC cell migration and regulates EMT marker expression(A) ATC cell migration with and without CUDC-101 treatment. The numbers of migrated cells were counted and calculated with the vehicle-treated cells as 100%. Data was for an average of three fields. Error bars are mean ± SD. *p < 0.05, **p < 0.01. (B) EMT marker expression. ATC cells were treated with CUDC-101 for 24 hours, and the blots were probed with the indicated antibodies to measure protein expression. Each corresponding anti-β-actin blot was used as loading control.

Mentions: We next investigated whether CUDC-101 had any effect on cellular migration because ATC is a highly invasive cancer and the EGFR/RAS/BRAF/MEK/ERK pathway has been shown to regulate cellular migration and epithelial-mesenchymal transition (EMT) [21–23]. Compared to control, CUDC-101 significantly inhibited cellular migration in the ATC cell lines (Figure 4A). Given this effect on cellular migration, we evaluated whether CUDC-101 had any effect on EMT marker expression. ATC cells had basal expression of mesenchymal markers vimentin and N-cadherin (Figure 4B). In contrast, E-cadherin, a known tumorigenicity and tumor dissemination suppressor, was almost undetectable under the regular culture condition. CUDC-101 decreased N-cadherin level in 8505c and SW-1736 cells, but had minimal effect in the C-643 cell line (Figure 4B). For vimentin, CUDC-101 slightly reduced its level in 8505c and C-643 cells, but had no effect on its expression in SW-1736 cells. Interestingly, in SW-1736 cells, which had high basal expression of N-cadherin, treatment with CUDC-101 induced a significant increase in E-cadherin expression (Figure 4B), suggesting that this drug is effective even in cancer cells with high-levels of pro-EMT proteins.


Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Zhang L, Zhang Y, Mehta A, Boufraqech M, Davis S, Wang J, Tian Z, Yu Z, Boxer MB, Kiefer JA, Copland JA, Smallridge RC, Li Z, Shen M, Kebebew E - Oncotarget (2015)

CUDC-101 inhibits ATC cell migration and regulates EMT marker expression(A) ATC cell migration with and without CUDC-101 treatment. The numbers of migrated cells were counted and calculated with the vehicle-treated cells as 100%. Data was for an average of three fields. Error bars are mean ± SD. *p < 0.05, **p < 0.01. (B) EMT marker expression. ATC cells were treated with CUDC-101 for 24 hours, and the blots were probed with the indicated antibodies to measure protein expression. Each corresponding anti-β-actin blot was used as loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496203&req=5

Figure 4: CUDC-101 inhibits ATC cell migration and regulates EMT marker expression(A) ATC cell migration with and without CUDC-101 treatment. The numbers of migrated cells were counted and calculated with the vehicle-treated cells as 100%. Data was for an average of three fields. Error bars are mean ± SD. *p < 0.05, **p < 0.01. (B) EMT marker expression. ATC cells were treated with CUDC-101 for 24 hours, and the blots were probed with the indicated antibodies to measure protein expression. Each corresponding anti-β-actin blot was used as loading control.
Mentions: We next investigated whether CUDC-101 had any effect on cellular migration because ATC is a highly invasive cancer and the EGFR/RAS/BRAF/MEK/ERK pathway has been shown to regulate cellular migration and epithelial-mesenchymal transition (EMT) [21–23]. Compared to control, CUDC-101 significantly inhibited cellular migration in the ATC cell lines (Figure 4A). Given this effect on cellular migration, we evaluated whether CUDC-101 had any effect on EMT marker expression. ATC cells had basal expression of mesenchymal markers vimentin and N-cadherin (Figure 4B). In contrast, E-cadherin, a known tumorigenicity and tumor dissemination suppressor, was almost undetectable under the regular culture condition. CUDC-101 decreased N-cadherin level in 8505c and SW-1736 cells, but had minimal effect in the C-643 cell line (Figure 4B). For vimentin, CUDC-101 slightly reduced its level in 8505c and C-643 cells, but had no effect on its expression in SW-1736 cells. Interestingly, in SW-1736 cells, which had high basal expression of N-cadherin, treatment with CUDC-101 induced a significant increase in E-cadherin expression (Figure 4B), suggesting that this drug is effective even in cancer cells with high-levels of pro-EMT proteins.

Bottom Line: The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin.In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival.Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression.

View Article: PubMed Central - PubMed

Affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

ABSTRACT
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.

No MeSH data available.


Related in: MedlinePlus