Doxorubicin and a butyric acid derivative effectively reduce levels of BCL-2 protein in the cells of chronic lymphocytic leukemia patient.
B-chronic lymphocytic leukemia (B-CLL) is a disease caused primarily by defects in the apoptosis mechanism. AN-9, a butyric acid (BA) derivative, is a potent differentiating and an anti-cancer drug that induces apoptosis in HL-60 cells. Herein we show the affect of AN-9, alone and in combination with doxorubicin, on cell cultures from B-CLL patients. Cells from 17 patients were cultured and tested for viability, apoptosis, bcl-2 and bax protein expression. Exposure of B-CLL cell cultures to AN-9 was accompanied by apoptosis and a marked viability loss (up to 46%, p=0.0017). AN-9 reduced up to 51% (p=0.0017) the levels of bcl-2 in 57% of the cultures that express bcl-2. The combination of low concentrations of AN-9 and doxorubicin more than additively enhanced apoptosis and reduced bcl-2 levels in B-CLL cultures which were resistant to AN-9. AN-9 enhanced bax expression up to 58%(p=0.008) in cultures from 53% of the patients, but had no effect on bax levels when combined with doxorubicin. In conclusion, AN-9 alone reduced bcl-2 and enhanced bax expression in cultures from B-CLL patients, and the reduction of bcl-2 levels in combination with doxorubicin was greater than additive. These results may be beneficial in possible future combination therapy with AN-9 in B-CLL.
Rabizadeh
E
E
Institute of Hematology and Felsenstein Medical Research Center, Rabin Medical Center, Belinson Campus, Petach Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Bairey
O
O
Aviram
A
A
Ben-Dror
I
I
Shaklai
M
M
Zimra
Y
Y
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D002087:Butyrates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C070441:pivalyloxymethyl butyrate; D004317:Doxorubicin