Hematotoxicity of the Chinese Herbal Medicine Tripterygium wilfordii Hook f in CD34-Positive Human Bone Marrow Cells
- 1Molecular Toxicology and Environmental Health Sciences (D.W.P., Y.Y., A.L., W.S., R.D.I.),2 School of Pharmacy (B.M.); 3Department of Pathology, School of Medicine (R.D.I.); and 4Cancer Center (R.D.I.), University of Colorado Health Sciences Center, Denver, Colorado
Abstract
T2, a chloroform/methanol extract of the herbTripterygium wilfordii Hook f, has been used in China for the treatment of autoimmune and inflammatory diseases for many years. Recent experimental evidence has confirmed that T2 has potent anti-inflammatory and immunosuppressive activity, and a United States Food and Drug Administration-approved clinical trial is currently exploring the efficacy of T2 in the treatment of rheumatoid arthritis. Despite the potential therapeutic benefits of T2, there is ample documentation that T2 is toxic, targeting, among other things, the hematopoietic system, and its use has resulted in cases of leukopenia, thrombocytopenia, and aplastic anemia. This investigation was undertaken to characterize the in vitro effects of T2 on primary human CD34-positive (CD34+) bone marrow cells. Our results demonstrate that T2 has a potent inhibitory effect on the clonogenic response of human bone marrow cells to exogenously added hematopoietic growth factors. The inhibition of colony formation by T2 is not the result of direct cytotoxicity or increased apoptosis and indicates a functional suppression of hematopoiesis. Additional experiments demonstrate that T2 also alters transcriptional regulation in bone marrow cells by inhibiting nuclear factor-κB. This transcription factor is found in CD34+ bone marrow cells and has been recently shown to be a requirement for colony formation. These results demonstrate that therapeutic concentrations of T2 exert a significant hematotoxic effect by inhibiting growth factor response in CD34+ bone marrow cells and suggest that inhibition of nuclear factor-κB may play a role in the blood dyscrasias encountered with the use of this drug.
Footnotes
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Send reprint requests to: Richard Irons, Ph.D., D.A.B.T., University of Colorado Health Sciences Center, 4200 E. 9th Ave., Box C238, Denver, CO. E-mail: richard.irons{at}uchsc.edu
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This publication was made possible by Grant ES06258 from the National Institute of Environmental Health Sciences.
- Abbreviations:
- TWH
- Tripterygium wilfordii Hook f
- RA
- rheumatoid arthritis
- IL
- interleukin
- TNF
- tumor necrosis factor
- CFU
- colony forming unit
- GM-CSF
- granulocyte-macrophage-colony stimulating factor
- SCF
- stem cell factor
- EPO
- erythropoietin
- EMSA
- electrophoretic mobility shift assay
- NF-κB
- nuclear factor-κB
- NFAT
- nuclear factor of activated T cells
- CsA
- cyclosporine A
- HPC
- hematopoietic progenitor cells
- GEMM
- granulocyte, erythroid, macrophage, megakaryocytic
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- Received August 30, 1999.
- Accepted November 22, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
