PC-SPES decreases proliferation and induces differentiation and apoptosis of human acute myeloid leukemia cells.
PC-SPES is an eight herbal mixture which has been shown to be active against prostate cancer cells in vitro as well as in patients. In this study, we discovered that it has anti-leukemia activity. HL-60, NB4, U937 and THP-1 human acute myeloid leukemia cells were cultured in the presence of various concentrations of PC-SPES (0.06-0.5 micro l/ml) for 4 days, and cell numbers were counted by Trypan blue exclusion. PC-SPES inhibited proliferation of these cells with an ED50 of 0.17, 0.09, 0.18, 0.32 micro l/ml, respectively. In clonogenic assay, PC-SPES inhibited growth of HL-60 cells (ED50, 0.043 micro l/ml). On the other hand, PC-SPES (0.1 micro l/ml) stimulated growth of normal myeloid committed stem cells (CFU-GM) by 1.4-fold of control (p=0.03). Anti-leukemia effects also occurred against freshly isolated leukemia cells from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Interestingly, when PC-SPES was combined with ATRA, the antiproliferative effect was markedly enhanced. For example, PC-SPES (0.125 micro l/ml) or ATRA (10(-8) mol/l) inhibited growth of HL-60 cells after 4 days of culture, by approximately 40 and 30%, respectively; simultaneous treatment with both, suppressed growth by 80%. In addition, PC-SPES induced differentiation of HL-60 and NB4 cells, as measured by expression of CD11b and reduction of NBT. ATRA synergistically enhanced this activity. For example, either PC-SPES (0.5 micro l/ml) or ATRA (10(-8) mol/l) induced 23 and 18% of HL-60 cells, respectively to express CD11b on day 2 of culture; and when both were combined, 60% of HL-60 cells were stimulated to express CD11b antigen. Furthermore, PC-SPES (0.5 micro l/ml) produced apoptosis of HL-60 and NB4 cells, as measured by TUNEL assay, with 17% of HL-60 cells and 52% of NB4 cells becoming apoptotic on their third day of culture. Importantly, PC-SPES stimulated expression of the novel myeloid specific transcription factor C/EBPepsilon in HL-60 and NB4 cells. Taken together, PC-SPES inhibits growth and induces differentiation and apoptosis of myeloid leukemia cells, and enhances the antiproliferative and prodifferentiative effects of ATRA on these cells. PC-SPES might be useful with ATRA for treatment of patients with acute promyelocytic leukemia (APL), and it could have a role in other types of cancers including MDS.
Ikezoe
Takayuki
T
Department of Medicine, Kochi Medical School, Nankoku, Kochi 783-8505, Japan. ikezoet@med.kochi-ms.ac.jp
Chen
Sophie
S
Saito
Tsuyako
T
Asou
Hiroya
H
Kyo
Taiichi
T
Tanosaki
Sakae
S
Heber
David
D
Taguchi
Hirokuni
H
Koeffler
H Phillip
HP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D039481:CD11b Antigen / Q000096:biosynthesis; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D013997:Time Factors; D020298:U937 Cells
D000972:Antineoplastic Agents, Phytogenic; D039481:CD11b Antigen; D004365:Drugs, Chinese Herbal; C114209:herbal preparation PC-SPES