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The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro.

The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro.
The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro.
We have studied the in vitro actions of the sesquiterpene lactone parthenolide (PTL) on cells isolated from patients with chronic lymphocytic leukemia (CLL). Dye reduction viability assays showed that the median LD(50) for PTL was 6.2 muM (n=78). Fifteen of these isolates were relatively resistant to the conventional agent chlorambucil but retained sensitivity to PTL. Brief exposures to PTL (1-3 h) were sufficient to induce caspase activation and commitment to cell death. Chronic lymphocytic leukemia cells were more sensitive towards PTL than were normal T lymphocytes or CD34(+) haematopoietic progenitor cells. The mechanism of cell killing was via PTL-induced generation of reactive oxygen species, resulting in turn in a proapoptotic Bax conformational change, release of mitochondrial cytochrome c and caspase activation. Parthenolide also decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B and diminished phosphorylation of its negative regulator IkappaB. Killing of CLL cells by PTL was apparently independent of p53 induction. This is the first report showing the relative selectivity of PTL towards CLL cells. The data here warrant further investigation of this class of natural product as potential therapeutic agents for CLL.
0887-6924
1073-1079
Steele, A.J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Jones, D.T.
e9391aba-4a70-4ce0-99fa-1891ac9ecd21
Ganeshaguru, K.
c56ec2c6-c7a2-4c31-b44f-33c329d88f57
Duke, V.M.
b4886279-dea9-4351-864a-3e8588d13cb8
Yogashangary, B.C.
c96dafa4-86ee-422c-b0cb-1960d241e3a8
North, J.M.
2347bc26-f771-4bc1-a9bb-aa971714568e
Lowdell, M.W.
756be2c1-5f69-44cf-9867-6bf2c9e4a016
Kottaridis, P.D.
f51b4efe-1483-4bcc-9c65-d53db32f2e76
Mehta, A.
d1ffa5c9-13f5-4917-ad89-df743b516d14
Prentice, A.G.
808a94b4-992a-40cc-8ddb-df504675cc1f
Hoffbrand, A.V.
76ead382-b1d5-4528-addb-8e1a04b0cc5b
Wickremasinghe, R.G.
f843f37a-5c69-479f-8dab-bcb783483df3
Steele, A.J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Jones, D.T.
e9391aba-4a70-4ce0-99fa-1891ac9ecd21
Ganeshaguru, K.
c56ec2c6-c7a2-4c31-b44f-33c329d88f57
Duke, V.M.
b4886279-dea9-4351-864a-3e8588d13cb8
Yogashangary, B.C.
c96dafa4-86ee-422c-b0cb-1960d241e3a8
North, J.M.
2347bc26-f771-4bc1-a9bb-aa971714568e
Lowdell, M.W.
756be2c1-5f69-44cf-9867-6bf2c9e4a016
Kottaridis, P.D.
f51b4efe-1483-4bcc-9c65-d53db32f2e76
Mehta, A.
d1ffa5c9-13f5-4917-ad89-df743b516d14
Prentice, A.G.
808a94b4-992a-40cc-8ddb-df504675cc1f
Hoffbrand, A.V.
76ead382-b1d5-4528-addb-8e1a04b0cc5b
Wickremasinghe, R.G.
f843f37a-5c69-479f-8dab-bcb783483df3

Steele, A.J., Jones, D.T., Ganeshaguru, K., Duke, V.M., Yogashangary, B.C., North, J.M., Lowdell, M.W., Kottaridis, P.D., Mehta, A., Prentice, A.G., Hoffbrand, A.V. and Wickremasinghe, R.G. (2006) The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia, 20 (6), 1073-1079. (doi:10.1038/sj.leu.2404230). (PMID:16628188)

Record type: Article

Abstract

We have studied the in vitro actions of the sesquiterpene lactone parthenolide (PTL) on cells isolated from patients with chronic lymphocytic leukemia (CLL). Dye reduction viability assays showed that the median LD(50) for PTL was 6.2 muM (n=78). Fifteen of these isolates were relatively resistant to the conventional agent chlorambucil but retained sensitivity to PTL. Brief exposures to PTL (1-3 h) were sufficient to induce caspase activation and commitment to cell death. Chronic lymphocytic leukemia cells were more sensitive towards PTL than were normal T lymphocytes or CD34(+) haematopoietic progenitor cells. The mechanism of cell killing was via PTL-induced generation of reactive oxygen species, resulting in turn in a proapoptotic Bax conformational change, release of mitochondrial cytochrome c and caspase activation. Parthenolide also decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B and diminished phosphorylation of its negative regulator IkappaB. Killing of CLL cells by PTL was apparently independent of p53 induction. This is the first report showing the relative selectivity of PTL towards CLL cells. The data here warrant further investigation of this class of natural product as potential therapeutic agents for CLL.

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Published date: June 2006

Identifiers

Local EPrints ID: 178127
URI: http://eprints.soton.ac.uk/id/eprint/178127
ISSN: 0887-6924
PURE UUID: e4b03378-e63f-4a88-9a9b-60110823c241
ORCID for A.J. Steele: ORCID iD orcid.org/0000-0003-0667-1596

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Date deposited: 23 Mar 2011 09:59
Last modified: 26 Nov 2019 01:39

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Contributors

Author: A.J. Steele ORCID iD
Author: D.T. Jones
Author: K. Ganeshaguru
Author: V.M. Duke
Author: B.C. Yogashangary
Author: J.M. North
Author: M.W. Lowdell
Author: P.D. Kottaridis
Author: A. Mehta
Author: A.G. Prentice
Author: A.V. Hoffbrand
Author: R.G. Wickremasinghe

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