J Breast Cancer.  2009 Dec;12(4):241-248. 10.4048/jbc.2009.12.4.241.

Comparison between Therapeutic Efficacies of Histone Deacetylase Inhibitors and Established Drug Regimens Against Breast Cancer Cells using the Histoculture Drug Response Assay

Affiliations
  • 1Department of Surgery, University of Ulsan College of Medicin, Seoul, Korea. jckim@amc.seoul.kr
  • 2Institute of Innovative Cancer Research, Asan Institute for Life Sciences and Asan Medical Center, Seoul, Korea.
  • 3Division of Medical Genetics, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea.
  • 4Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea.

Abstract

PURPOSE
Histone deacetylase inhibitors (HDACIs) induce accumulation of acetylated histones in nucleosomes, which lead to reactivate gene expression and inhibit the growth and survival of tumor cells. This study evaluated the efficacy of HDACIs in breast cancer cells in comparison with other established drug regimens. METHODS: Drug responses of tumor samples from mastectomy specimens of 78 breast cancer patients were evaluated using the histoculture drug response assay (HDRA). Tumor inhibition rates (IRs) of established drug regimens such as doxorubicin, cyclophosphamide, doxorubicin with cyclophosphamide (AC), paclitaxel, docetaxel and doxorubicin with docetaxel (AT), as well as those of three HDACIs (SAHA, PXD101, and a novel compound CG-2) were evaluate. RESULTS: The percentages of chemosensitive tumors (chemoresponsiveness) were 26.9-60.3% with established regimens and 61.5-73.1% with HDACIs when the cutoff value for inhibition rate was set at 30%. Breast cancer cells appeared to be more chemoresponsive to HDACIs than to established drug regimens. Chemoresponsiveness to AT was the highest among the established drug regimens. A combination regimen offered higher activity than did a single drug (doxorubicin vs AT; p<0.001). HER2/Neu-overexpressing breast cancers were chemosensitive to SAHA and AT (p=0.031 and 0.04, respectively). CONCLUSION: Our findings show that breast cancer cells were sensitive to HDACIs, with therapeutic efficacies comparable to those of established drug regimens. Specific biological markers such as HER2/Neu could be assessed for effectiveness as HDACIs chemosensitivity markers in further clinical trials.

Keyword

Breast neoplasms, Chemosensitivity, Histone deacetylase inhibitor; Histoculture drug response assay

MeSH Terms

Biomarkers
Breast
Breast Neoplasms
Cyclophosphamide
Doxorubicin
Gene Expression
Histone Deacetylase Inhibitors
Histone Deacetylases
Histones
Humans
Hydroxamic Acids
Mastectomy
Nucleosomes
Paclitaxel
Sulfonamides
Taxoids
Cyclophosphamide
Doxorubicin
Histone Deacetylase Inhibitors
Histone Deacetylases
Histones
Hydroxamic Acids
Nucleosomes
Paclitaxel
Sulfonamides
Taxoids

Figure

  • Figure 1 Inhibition rate (IR) of tumor growth (A) and percentage of chemosensitive tumors (chemosensitivity) (B) to established drugs and their combinations. ADR=doxorubicin; CYC=cyclophosphamide; AC=combination of doxorubicin and cyclophosphamide; AT=combination of doxorubicin and docetaxel. p-values in parentheses. (A) AC vs docetaxel (p=0.047) and AT (0.014), docetacel vs paclitaxel (p=0.042), (B) doxorubicin vs paclitaxel (p<0.001) and docetaxel (p<0.001) and AT (p<0.001) at IR30.

  • Figure 2 Inhibition rate (IR) of tumor growth (A) and percentage of chemosensitive tumors (chemosensitivity) (B) to HDAC inhibitors. p-values in parentheses. A; PXD101 vs CG-2 (0.032).


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