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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 proliferation, and induces cell cycle arrest and apoptosis(A) Basal expression of HDAC1, HDAC2 and EGFR in ATC cell lines. (B) Cell proliferation assay. Error bars are mean ± SD. (C) Cell cycle analysis after 24 hours of treatment. (D) The Caspase-Glo 3/7 assay after 48 hours of treatment with CUDC-101. *p < 0.05, **p < 0.01, ***p < 0.001. NS, no significant difference.
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Figure 3: CUDC-101 inhibits ATC cell proliferation, and induces cell cycle arrest and apoptosis(A) Basal expression of HDAC1, HDAC2 and EGFR in ATC cell lines. (B) Cell proliferation assay. Error bars are mean ± SD. (C) Cell cycle analysis after 24 hours of treatment. (D) The Caspase-Glo 3/7 assay after 48 hours of treatment with CUDC-101. *p < 0.05, **p < 0.01, ***p < 0.001. NS, no significant difference.

Mentions: As previously reported, HDAC1, HDAC2, and EGFR are over-expressed in ATC [15–19]. Therefore, we validated the antiproliferative activity of CUDC-101 using seven different ATC cell lines: 8505c, C-643, SW-1736, THJ-11T (KRAS mutation), THJ-16T (TP53, RB, PI3KCA mutations), THJ-21T (TP53, RB, BRAF mutations), and THJ-29T (RB mutation) [20]. We first determined the baseline expression of EGFR, HDAC1 and HDAC2 in these cell lines. As shown in Figure 3A, all the ATC cell lines expressed EGFR, HDAC1 and HDAC2, the targets of CUDC-101, under regular culture conditions. We then validated the activity of CUDC-101 on cell proliferation, and found dose- and time-dependent inhibition of cellular growth with cell death at higher concentrations of CUDC-101 in all seven ATC cell lines (Figure 3B).


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 proliferation, and induces cell cycle arrest and apoptosis(A) Basal expression of HDAC1, HDAC2 and EGFR in ATC cell lines. (B) Cell proliferation assay. Error bars are mean ± SD. (C) Cell cycle analysis after 24 hours of treatment. (D) The Caspase-Glo 3/7 assay after 48 hours of treatment with CUDC-101. *p < 0.05, **p < 0.01, ***p < 0.001. NS, no significant difference.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: CUDC-101 inhibits ATC cell proliferation, and induces cell cycle arrest and apoptosis(A) Basal expression of HDAC1, HDAC2 and EGFR in ATC cell lines. (B) Cell proliferation assay. Error bars are mean ± SD. (C) Cell cycle analysis after 24 hours of treatment. (D) The Caspase-Glo 3/7 assay after 48 hours of treatment with CUDC-101. *p < 0.05, **p < 0.01, ***p < 0.001. NS, no significant difference.
Mentions: As previously reported, HDAC1, HDAC2, and EGFR are over-expressed in ATC [15–19]. Therefore, we validated the antiproliferative activity of CUDC-101 using seven different ATC cell lines: 8505c, C-643, SW-1736, THJ-11T (KRAS mutation), THJ-16T (TP53, RB, PI3KCA mutations), THJ-21T (TP53, RB, BRAF mutations), and THJ-29T (RB mutation) [20]. We first determined the baseline expression of EGFR, HDAC1 and HDAC2 in these cell lines. As shown in Figure 3A, all the ATC cell lines expressed EGFR, HDAC1 and HDAC2, the targets of CUDC-101, under regular culture conditions. We then validated the activity of CUDC-101 on cell proliferation, and found dose- and time-dependent inhibition of cellular growth with cell death at higher concentrations of CUDC-101 in all seven ATC cell lines (Figure 3B).

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