Arsenic Trioxide Selectively Induces Apoptosis within the Leukemic Cells of APL Patients with t(15;17) Translocation Possibly through the Fas Pathway
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Abstract
Background: Acute Promyelocytic Leukemia is a sub-type of acute myelogenous leukemia that occurs in about 10-15% of patients with AML. Approximately 20%-30% of these patients, who are treated with the current standard All Trans Retinoic Acid (ATRA) and Anthracyclin-based chemotherapy regimen, suffer relapse in less than a year. Arsenic trioxide (ATO) as a single agent can induce complete remission even in refractory and relapsed patients with few adverse effects. The investiga¬tors efforts regarding elucidation of the mechanisms of action underlying these clinical responses has shown that Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations in cellular function, among which the most prominent ones are the induction of differentiation & apoptosis with low & high doses of arsenic, respectively.
Purposes: In vivo apoptosis on these patients has not been evaluated yet and despite previous In vitro studies, which mostly reveal Fas/Apo1 is not expressed during ATO treatment, its in vivo expression has not been evaluated yet. Materials & methodes: In order to study the apoptotic pattern in leukemic cells of APL patients, we conducted a single-laser, triple-color flowcytometric experiment, to detect leukemic apoptotic cells in a heterogeneous population of bone mar¬row samples with the Annexin V & 7AAD technique. The Fas expression was also evaluated in promyelocyte population cells in a dual color panel.
Results & Conclusion: A substantial Apoptosis was selectively detected in Promyelocytic cells during the early and middle stages of treatment and the concurrent Fas expression indicates its involvent in Apoptosis induced by Arsenic Trioxide.
- Warrell RP Jr, The H, Wang Z-Y, et al. Acute promye- locytic leukemia. N Engl J Med. 1993;329:177-189
- Grignani F, Ferrucci PF, Testa U, et al. The Acute promyelocytic leukemia-specific PML-RARα fusion pro- tein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993;74:423
- Fenaux P, Chevert S, Gueric A et al. Long term fol- lowup confirms the benefit of all-trans retinoic acid in Acute promyelocytic leukemia. Leukemia 2000;14:1371- 1377
- Antman KH. The history of arsenic cancer therapy. Oncologist. 2001;6:1-2
- Kitamura K, Yoshida H, Ohno R, Naoe T. Toxic ef- fects of arsenic (As3+) and other metal ions on acute promyelocytic leukemia cells. Int J Hematol.1997;65(2): 179-185
- Guo-Qiang Chen, Xue-Geng Shi, Wei Tang, et al. Use of Arsenic Trioxide (As2O3) in the Treatment of Acute Promyelocytic Leukemia (APL): I. As2O3 Exerts Dose- Dependent Dual Effects on APL Cells. Blood 1997;89:3345-3353
- Chen GQ, Zhu J, Shi XG, et al. In vitro studies on cel- lular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leuke- mia: As2O3 induces NB4 cell apoptosis with downregu- lation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood 1996;88(3):1052-1061
- Zhen-Yi Wang and Zhu Chen, Differentiation and Apoptosis induction therapy in acute promyelocytic leu- kemia. The lancet oncology 2000;1:101-106
- Miller WH Jr. Molecular targets of arsenic trioxide in malignant cells. Oncologist 2002;7,1:1-13
- Miller WH, Schipper HM, Lee JS, et al. Mechanisms of action of arsenic trioxide. Cancer Res 2002;62(14):3893-3903
- X Cai, Y-L Shen, Q Zhu, et al. Arsenic trioxide- induced apoptosis and differentiation are associated re- spectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia. Leukemia 2000;14:262-270
- S-H Woo, I-C Park, M-J Park, et al.Arsenic trioxide induces apoptosis through a reactive oxygen species- dependent pathway and loss of mitochondrial membrane potential in Hela cells. Int J Oncol 2002;21:57-63
- Li H, Zhu H, Xu Cl, et al. Cleavage of Bid by cas- pase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94:491-501
- Luo X, Budihardjo I, Zou H, et al. Bid, a Bcl2 inter- acting protein, mediates cytochrom C release from mito- chondria in response to activation of cell surface death receptors. Cell 1998;94:481-490
- Kitamura K, Minami Y, Yamamoto K, et al. In- volvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis. Leukemia 2000;14(10):1743-1750
- Zhu J,Okumura H, Ohtake S, et al. Arsenic trioxide induces apoptosis in leukemia/lymphoma cell lines via the CD95/CD95L system. Oncol Rep 2003;10(3):705- 709
- Herault O, Colombat P, Domenech J, et al. A rapid single-laser flow cytometric method for discrimination of early apoptotic cells in a heterogenous cell population. Br J Haematol 1999;104(3):530-507
- Zhu J, Lallemand-Breitenbach V, de The H. Path- ways of retinoic acid or arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degrada- tion in disease remission. Oncogene 2001;20(49):7257- 7265
- Van Engeland M, Nieland LJ, Ramaekers FC, et al Annexin V-affinity assay: a review on an apoptosis de- tection system based on phosphatidylserine exposure. Cytometry 1998;31(1):1-9.
- Blankenberg F.G, Katsikis P, Tait J.F, et al. In vivo detection and imaging of phsphatidylserine expression during programmed cell death. Proc. Nact. Acad. Sci. USA.1998;95:6349-6354
- Yongkui Jing, Jie Dai, Ruth M.E. Chalmers-Redman, Willam G.et al. Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell Apoptosis Via a Hydrogen Peroxide-Dependent Pathway. Blood;199994:2102-2111
- Halicka HD, Smolewski P, Darzynkiewicz Z, et al. Arsenic trioxide arrests cells early in mitosis leading to apoptosis. Cell Cycle. 2002;1(3):201-209
- .Ashkenazi A, Dixit VM. Death receptor: Signaling nd modulation. Sciences 1998;281:1305-1308
- Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLIC, a novel FADD-homologous ICE-CED-3-like protease, is recruited to the CD95 (Fas/Apo1) death-inducing signal- ing complex. Cell 1996;85:817-827
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| Issue | Vol 1, No 2 (2004) | |
| Section | Articles | |
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| Acute Promyelocytic Leukemia Arsenic trioxide Apoptosi Fas/Apo1 Flowcytometry | ||
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