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2007 | 54 | 4 | 839-846
Article title

Combined effects of doxorubicin and STI571 on growth, differentiation and apoptosis of CML cell line K562

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EN
Abstracts
EN
STI571 (imatinib mesylate; Gleevec®) is an inhibitor that targets the tyrosine kinase activity of Bcr-Abl present in chronic myelogenous leukemia (CML) cells. Some preclinical studies have demonstrated that the combination of STI571 with chemotherapeutic drugs results in enhanced toxicity in Bcr-Abl-positive leukemias. We investigated the potential benefit of using STI571 to down-regulate Bcr-Abl activity for the enhancement of doxorubicin anti-proliferative action in K562 cell line derived from blast crisis of CML. At low concentrations of both drugs (40 nM doxorubicin combined with STI571 in the range of 100-150 nM), the antiproliferative effects were mainly due to cellular differentiation as assessed by benzidine staining for hemoglobin synthesis level and real-time PCR for γ-globin expression. Higher concentrations of STI571 used in combinations with doxorubicin caused mainly apoptosis as shown by DNA degradation and nuclear fragmentation visualized by fluorescence microscopy after DAPI staining, changes in cell morphology observed after Giemza-May Grünwald staining and cellular membrane organization estimated by flow cytometry after Annexin V staining. As compared with either drug alone, cotreatment with STI571 and DOX induced stronger cellular responses. A low concentration of STI571 in combination with a low concentration of DOX might be tested as an alternative approach to increasing the efficacy of chemotherapy against CML.
Publisher

Year
Volume
54
Issue
4
Pages
839-846
Physical description
Dates
published
2007
received
2007-07-09
revised
2007-09-16
accepted
2007-10-05
(unknown)
2007-10-25
Contributors
  • Department of Molecular Biology of Cancer, Medical University of Lodz, Łódź, Poland
author
  • Department of Molecular and Medical Biophysics, Medical University of Lodz, Łódź, Poland
  • Department of Molecular Biology of Cancer, Medical University of Lodz, Łódź, Poland
  • Department of Molecular Cancerogenesis, Medical University of Lodz, Łódź, Poland
  • Department of Molecular Biology of Cancer, Medical University of Lodz, Łódź, Poland
References
  • Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS, Akhtar AJ, Hilton J, Jones RJ (1995) BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. Blood 86: 1148-1158.
  • Czyz M, Szulawska A, Bednarek AK, Duchler M (2005) Effects of anthracycline derivatives on human leukemia K562 cell growth and differentiation. Biochem Pharmacol 70: 1431-1442.
  • Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2: 561-566.
  • Du Y, Wang K, Fang H, Li J, Xiao D, Zheng P, Chen Y, Fan H, Pan X, Zhao C, Zhang Q, Imbeaud S, Graudens E, Eveno E, Auffray C, Chen S, Chen Z, Zhang J (2006) Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood 107: 1582-1590.
  • Faderl S, Kantarjian H, Talpaz M (1999) Chronic myelogenous leukemia: update on biology and treatment. Oncology 13: 169-180.
  • Fang G, Kim CN, Perkins CL, Ramadevi N, Winton E, Wittmann S, Bhalla KN (2000) CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. Blood 96: 2246-2253.
  • Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57: 727-741.
  • Gong J, Traganos F, Darzynkiewicz Z (1994) A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem 218: 314-319.
  • Gu JJ, Santiago L, Mitchell BS (2005) Synergy between imatinib and mycophenolic acid in inducing apoptosis in cell lines expressing Bcr-Abl. Blood 105: 3270-3277.
  • Kerkelä R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12: 908-916.
  • Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56: 185-229.
  • Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44: 879-894.
  • Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30: e36.
  • Ruchatz H, Puttini M, Cleris L, Pilotti S, Gambacorti-Passerini C, Formelli F (2003) Effect of imatinib on haematopoietic recovery following idarubicin exposure. Leukemia 17: 298-304.
  • Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 289: 1938-1942.
  • Steinherz LJ, Steinherz PG, Tan CTC, Heller G, Murphy L (1991) Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266: 1672-1677.
  • Szulawska A, Arkusinska J, Czyz M (2007) Accumulation of gamma-globin mRNA and induction of irreversible erythroid differentiation after treatment of CML cell line K562 with new doxorubicin derivatives. Biochem Pharmacol 73: 175-184.
  • Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ (2000) Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. Blood 96: 3195-3199.
  • Thomas Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H (2004) Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103: 4396-4407.
  • Towatari M, Yanada M, Usui N, Takeuchi J, Sugiura I, Takeuchi M, Yagasaki F, Kawai Y, Miyawaki S, Ohtake S, Jinnai I, Matsuo K, Naoe T, Ohno R (2004) Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood 104: 3507-3512.
Document Type
Publication order reference
Identifiers
YADDA identifier
bwmeta1.element.bwnjournal-article-abpv54p839kz
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