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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4138-4139. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Holyoake, T. L. Articles by Copland, M. Search for Related Content PubMed Articles by Holyoake, T. L. Articles by Copland, M. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Guzman et al, page 4427,and Guzman et al, page 4436 LSC defenses breached by chemical arsenal Tessa L. Holyoake, and Mhairi Copland SECTION OF EXPERIMENTAL HAEMATOLOGY, UNIVERSITY OF GLASGOW In this issue of Blood, Guzman and colleagues describe 2 significant advances in the selective targeting of leukemic progenitor cells. First, they identify a novel agent, TDZD-8, that induces apoptosis of leukemic stem cells (LSCs) with extremely rapid kinetics. Second, they describe the development of an orally bioavailable parthenolide (PTL) analog, DMAPT, that is now heading to phase 1 clinical trial following the preclinical work described in this issue. LSCs share many of the inherent properties of normal hematopoietic stem cells (HSCs), making the selective targeting of LSCs a significant challenge for investigators. Guzman et al addressed this challenge using a variety of approaches that have already been productive, and they collectively demonstrate that it may indeed be possible to target the LSC population without necessarily causing damage to normal HSCs.1–3 In a search for inhibitors of pathways implicated in early hematopoiesis, the authors investigated a large number of GSK-3β inhibitors and found that TDZD-8 was potently cytotoxic to multiple primary leukemic cells, including AML, ALL, CLL, and blast-crisis CML. The drug also killed phenotypically and functionally defined LSCs, with little bystander effect on normal HSCs. Although not fully understood, the mechanism of action involved very rapid loss of membrane integrity and irreversible cell damage within 15 to 30 minutes (see figure). As shown in their previous work,2,3 the authors found that TDZD-8 exposure also led to inhibition of NF-B and induction of oxidative stress, both of which the authors argue are critical components of LSC-selective killing. View larger version (51K): [in this window] [in a new window]   Rapid effect of TDZD-8 compared with PTL on CD34+38– AML cell viability (top panel). Loss of membrane integrity as measured by MBBr with both TDZD-8 and DMAPT (bottom left; shaded histograms) and YoPro-1 (bottom right; TDZD-8). See the complete figures in the articles beginning on pages 4427 and 4436.   This new work is exciting because it suggests that there are potent agents that can reach into the LSC compartment. Potential limitations of the work include the high concentration of TDZD-8 that was required to induce LSC apoptosis and the fact that its cytotoxic effect was mediated not through inhibition of GSK-3β, but by an "off-target" effect. While this is scientifically intriguing, it creates a major challenge for developing an analog that can be used clinically, since the true mechanism of action of TDZD-8 remains elusive. It is also difficult to understand, from the work presented to date, how this cytotoxic agent achieves its apparent level of selectivity for LSCs versus HSCs. In the companion paper, the authors confirm that DMAPT has equal potency to PTL in inducing selective death of LSCs from both myeloid and lymphoid leukemias. Although PTL and DMAPT inhibit NF-B, induce oxidative stress responses, and activate p53, the kinetics of response are much slower that those of TDZD-8 (see figure). Preliminary evidence for in vivo bioactivity was demonstrated through murine xenograft models and against a few cases of spontaneous canine leukemia. Although tantalizing, these preclinical canine data should be interpreted with caution, since few animals were included and all received potentially confounding drugs. We eagerly await the phase 1 clinical trial data. Overall, Guzman and colleagues are to be congratulated for their perse-verance, which has now delivered new and important weapons against the Achilles heel of hematological malignancy, the LSC. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Hassane DC, Guzman ML, Li X, Corbett C, Jordan CT. Molecular signature for parthenolide-induced apoptosis in AML CD34+ cells reveals targets for improving induction of leukemia-specific cell death [abstract]. Blood 2006; 108:732a. Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005; 105:4163–4169.[Abstract/Free Full Text] Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A 2002; 99:16220–16225.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8) Monica L. Guzman, Xiaojie Li, Cheryl A. Corbett, Randall M. Rossi, Timothy Bushnell, Jane L. Liesveld, Josée Hébert, Fay Young, and Craig T. Jordan Blood 2007 110: 4436-4444. [Abstract] [Full Text] [PDF] An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells Monica L. Guzman, Randall M. Rossi, Sundar Neelakantan, Xiaojie Li, Cheryl A. Corbett, Duane C. Hassane, Michael W. Becker, John M. Bennett, Edmund Sullivan, Joshua L. Lachowicz, Andrew Vaughan, Christopher J. Sweeney, William Matthews, Martin Carroll, Jane L. Liesveld, Peter A. Crooks, and Craig T. Jordan Blood 2007 110: 4427-4435. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Holyoake, T. L. Articles by Copland, M. Search for Related Content PubMed Articles by Holyoake, T. L. Articles by Copland, M. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?

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