Abstract
Histone deacetylases are promising targets for cancer treatment. Here we studied the in vitro effects of a potent histone deacetylase inhibitor, FK228 (formerly FR901228), on human leukemia/lymphoma cells and cell lines compared with normal hematopoietic cells. In a lymphoma cell line, Raji, a nanomolar concentration of FK228 induced G1 arrest and/or apoptotic cell death, depending on the concentration and exposure time. Growth of lymphoid cell lines including Raji (N=13) was inhibited by 50% (IC50) after 2-day treatment at concentrations of 0.83 to 1.87 ng/ml. Viability of clinical samples from patients with acute lymphoblastic leukemia was decreased by 50% at 0.78±0.46 ng/ml, whereas the IC50 values for normal mononuclear cells from peripheral blood and bone marrow were 2.3±0.96 and 7.8±1.0 ng/ml, respectively. The IC50 values for normal progenitor cells were 3.1, 4.4 and 7.8 ng/ml for BFU-E, CFU-GM and CFU-Mix, respectively. Expression levels of HDAC-1 and HDAC-3 proteins, which varied among cell lines, but were stable during the treatment with FK228, did not correlate with the sensitivity to FK288. This novel agent might be useful in the treatment of lymphoid malignancies, because the above concentrations are clinically achievable in vivo according to a recent clinical study.
| Original language | English |
|---|---|
| Pages (from-to) | 1154-1160 |
| Number of pages | 7 |
| Journal | Japanese Journal of Cancer Research |
| Volume | 91 |
| Issue number | 11 |
| Publication status | Published - 2000 |
| Externally published | Yes |
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Keywords
- Apoptosis
- FK228
- Histone deacetylase inhibitor
- Leukemia
- Lymphoma
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228, on malignant lymphoid cells. / Murata, M.; Towatari, M.; Kosugi, H.; Tanimoto, M.; Ueda, R.; Saito, H.; Naoe, T.
In: Japanese Journal of Cancer Research, Vol. 91, No. 11, 2000, p. 1154-1160.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228, on malignant lymphoid cells
AU - Murata, M.
AU - Towatari, M.
AU - Kosugi, H.
AU - Tanimoto, M.
AU - Ueda, R.
AU - Saito, H.
AU - Naoe, T.
PY - 2000
Y1 - 2000
N2 - Histone deacetylases are promising targets for cancer treatment. Here we studied the in vitro effects of a potent histone deacetylase inhibitor, FK228 (formerly FR901228), on human leukemia/lymphoma cells and cell lines compared with normal hematopoietic cells. In a lymphoma cell line, Raji, a nanomolar concentration of FK228 induced G1 arrest and/or apoptotic cell death, depending on the concentration and exposure time. Growth of lymphoid cell lines including Raji (N=13) was inhibited by 50% (IC50) after 2-day treatment at concentrations of 0.83 to 1.87 ng/ml. Viability of clinical samples from patients with acute lymphoblastic leukemia was decreased by 50% at 0.78±0.46 ng/ml, whereas the IC50 values for normal mononuclear cells from peripheral blood and bone marrow were 2.3±0.96 and 7.8±1.0 ng/ml, respectively. The IC50 values for normal progenitor cells were 3.1, 4.4 and 7.8 ng/ml for BFU-E, CFU-GM and CFU-Mix, respectively. Expression levels of HDAC-1 and HDAC-3 proteins, which varied among cell lines, but were stable during the treatment with FK228, did not correlate with the sensitivity to FK288. This novel agent might be useful in the treatment of lymphoid malignancies, because the above concentrations are clinically achievable in vivo according to a recent clinical study.
AB - Histone deacetylases are promising targets for cancer treatment. Here we studied the in vitro effects of a potent histone deacetylase inhibitor, FK228 (formerly FR901228), on human leukemia/lymphoma cells and cell lines compared with normal hematopoietic cells. In a lymphoma cell line, Raji, a nanomolar concentration of FK228 induced G1 arrest and/or apoptotic cell death, depending on the concentration and exposure time. Growth of lymphoid cell lines including Raji (N=13) was inhibited by 50% (IC50) after 2-day treatment at concentrations of 0.83 to 1.87 ng/ml. Viability of clinical samples from patients with acute lymphoblastic leukemia was decreased by 50% at 0.78±0.46 ng/ml, whereas the IC50 values for normal mononuclear cells from peripheral blood and bone marrow were 2.3±0.96 and 7.8±1.0 ng/ml, respectively. The IC50 values for normal progenitor cells were 3.1, 4.4 and 7.8 ng/ml for BFU-E, CFU-GM and CFU-Mix, respectively. Expression levels of HDAC-1 and HDAC-3 proteins, which varied among cell lines, but were stable during the treatment with FK228, did not correlate with the sensitivity to FK288. This novel agent might be useful in the treatment of lymphoid malignancies, because the above concentrations are clinically achievable in vivo according to a recent clinical study.
KW - Apoptosis
KW - FK228
KW - Histone deacetylase inhibitor
KW - Leukemia
KW - Lymphoma
UR - http://www.scopus.com/inward/record.url?scp=0033639025&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033639025&partnerID=8YFLogxK
M3 - Article
VL - 91
SP - 1154
EP - 1160
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 11
ER -