Editor's Note: Cotreatment with STI-571 Enhances Tumor Necrosis Factor α-related Apoptosis-inducing Ligand (TRAIL or Apo-2L)–induced Apoptosis of Bcr-Abl–positive Human Acute Leukemia Cells

Bcr-Abl tyrosine kinase inhibitor STI-571 induces differentiation and apoptosis of HL-60/Bcr-Abl (with ectopic expression of p190 Bcr-Abl) and K562 (with endogenous expression of p210 Bcr-Abl) cells (Blood, 96: 2246–2253, 2000). Cotreatment with STI-571 partially overcomes the resistance to antileukemic drug-induced apoptosis of HL-60/Bcr-Abl and K562 cells. Tumor necrosis factor (TNF) αrelated apoptosis-inducing ligand (Apo-2L/TRAIL), after binding with its signaling death receptors (DR4 and DR5), triggers the intrinsic “mitochondrial” pathway of apoptosis more efficiently in the cancer than do normal cells. In the present studies, we compared the apoptotic effects of Apo-2L/TRAIL, with or without cotreatment with STI-571, in HL-60/neo, HL-60/Bcr-Abl, and K562 cells. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells are relatively resistant to Apo-2L/TRAIL-induced apoptosis. In HL-60/Bcr-Abl and K562 versus HL-60/neo cells, Apo-2L/TRAIL caused less cytosolic accumulation of cytochrome c and the processing of caspase-9 and -3. This was also associated with decreased processing of caspase-8, c-FLIP L and Bid. Reduced effects of Apo-2L/TRAIL in Bcr-Abl-positive leukemic cells were not attributable to diminished expression of DR4 and DR5, or higher expressions of the decoy receptors DcR1 and -2 or c-FLIP L . Cotreatment with STI-571 significantly enhanced Apo-2L/TRAIL-induced apoptosis ( P < 0.01) as well as increased the processing of caspase-9 and -3 and XIAP, without affecting the levels of DR4, DR5, decoy receptors, or c-FLIP L . Cotreatment with STI-571 did not enhance Apo-2L/TRAIL-induced apoptosis of HL-60/neo cells. These studies suggest that a combined treatment with STI-571 may be an effective strategy to selectively sensitize Bcr-Abl-positive leukemic blasts to Apo-2L/TRAIL-induced apoptosis.

[1]  C. L. Perkins,et al.  CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. , 2000, Blood.

[2]  S. Srinivasula,et al.  Negative regulation of cytochrome c‐mediated oligomerization of Apaf‐1 and activation of procaspase‐9 by heat shock protein 90 , 2000, The EMBO journal.

[3]  S. Asano,et al.  Oncogene inactivation in a mouse model , 2000, Nature.

[4]  J. Melo,et al.  Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. , 2000, Blood.

[5]  Xiaodong Wang,et al.  Smac, a Mitochondrial Protein that Promotes Cytochrome c–Dependent Caspase Activation by Eliminating IAP Inhibition , 2000, Cell.

[6]  S. Strom,et al.  Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand , 2000, Nature Medicine.

[7]  J. Tschopp,et al.  TRAIL receptor-2 signals apoptosis through FADD and caspase-8 , 2000, Nature Cell Biology.

[8]  K. Bhalla,et al.  The role of Apaf-1, caspase-9, and bid proteins in etoposide- or paclitaxel-induced mitochondrial events during apoptosis. , 2000, Cancer research.

[9]  M. Varella‐Garcia,et al.  Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. , 2000, Blood.

[10]  I. Sánchez-García,et al.  In vivo inhibition by a site-specific catalytic RNA subunit of RNase P designed against the BCR-ABL oncogenic products: a novel approach for cancer treatment. , 2000, Blood.

[11]  K. Bhalla,et al.  Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L). , 2000, Blood.

[12]  E. Bröcker,et al.  Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes. , 2000, Cancer research.

[13]  S. Anderson,et al.  Increased Expression of Death Receptors 4 and 5 Synergizes the Apoptosis Response to Combined Treatment with Etoposide and TRAIL , 2000, Molecular and Cellular Biology.

[14]  G. Salvesen,et al.  Caspase activation: the induced-proximity model. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Z. Estrov,et al.  Chronic Myelogenous Leukemia: Biology and Therapy , 1999, Annals of Internal Medicine.

[16]  D. Green,et al.  Suicidal Tendencies: Apoptotic Cell Death by Caspase Family Proteinases* , 1999, The Journal of Biological Chemistry.

[17]  P. Hersey,et al.  Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. , 1999, Cancer research.

[18]  X. Liu,et al.  An APAF-1·Cytochrome c Multimeric Complex Is a Functional Apoptosome That Activates Procaspase-9* , 1999, The Journal of Biological Chemistry.

[19]  Y. Lazebnik,et al.  Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis. , 1999, Cancer research.

[20]  M. Nau,et al.  Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. , 1999, Cancer research.

[21]  C. Rauch,et al.  Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo , 1999, Nature Medicine.

[22]  E. Buchdunger,et al.  In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. , 1999, Journal of the National Cancer Institute.

[23]  S. Korsmeyer,et al.  Caspase Cleaved BID Targets Mitochondria and Is Required for Cytochrome c Release, while BCL-XL Prevents This Release but Not Tumor Necrosis Factor-R1/Fas Death* , 1999, The Journal of Biological Chemistry.

[24]  J C Reed,et al.  IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. , 1998, Cancer research.

[25]  M. Jäättelä,et al.  Hsp70 exerts its anti‐apoptotic function downstream of caspase‐3‐like proteases , 1998, The EMBO journal.

[26]  D. Green.  Apoptotic Pathways The Roads to Ruin , 1998, Cell.

[27]  C. Y. Wang,et al.  NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. , 1998, Science.

[28]  V. Dixit,et al.  Death receptors: signaling and modulation. , 1998, Science.

[29]  Junying Yuan,et al.  Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis , 1998, Cell.

[30]  Xiaodong Wang,et al.  Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors , 1998, Cell.

[31]  José Luis de la Pompa,et al.  Differential Requirement for Caspase 9 in Apoptotic Pathways In Vivo , 1998, Cell.

[32]  J C Reed,et al.  IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases , 1998, The EMBO journal.

[33]  D. Cortez,et al.  A requirement for NF-κB activation in Bcr–Abl-mediated transformation , 1998 .

[34]  D. Goeddel,et al.  FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. , 1998, Science.

[35]  D. Green,et al.  Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome C and activation of caspase-3. , 1998, Blood.

[36]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[37]  G. Salvesen,et al.  Caspases: Intracellular Signaling by Proteolysis , 1997, Cell.

[38]  J. D'halluin,et al.  Activation of p65 NF-κB protein by p210BCR – ABL in a myeloid cell line (P210BCR – ABL activates p65 NF-κB) , 1997, Oncogene.

[39]  J. Melo,et al.  The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. , 1997, Blood.

[40]  B. Calabretta,et al.  Transformation of hematopoietic cells by BCR/ABL requires activation of a PI‐3k/Akt‐dependent pathway , 1997, The EMBO journal.

[41]  K. Bhalla,et al.  Overexpression of Bcl-X(L) inhibits Ara-C-induced mitochondrial loss of cytochrome c and other perturbations that activate the molecular cascade of apoptosis. , 1997, Cancer research.

[42]  S. Srinivasula,et al.  FLAME-1, a Novel FADD-like Anti-apoptotic Molecule That Regulates Fas/TNFR1-induced Apoptosis* , 1997, The Journal of Biological Chemistry.

[43]  Guy S. Salvesen,et al.  X-linked IAP is a direct inhibitor of cell-death proteases , 1997, Nature.

[44]  B. Calabretta,et al.  Treatment of Philadelphia leukemia in severe combined immunodeficient mice by combination of cyclophosphamide and bcr/abl antisense oligodeoxynucleotides. , 1997, Journal of the National Cancer Institute.

[45]  K. Bhalla,et al.  Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[46]  J. Melo,et al.  The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. , 1996, Blood.

[47]  K. Bhalla,et al.  Bcl-xL overexpression inhibits taxol-induced Yama protease activity and apoptosis. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[48]  W. El-Deiry,et al.  BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. , 1995, Blood.

[49]  K. Bhalla,et al.  1-β-d-arabinofuranosylcytosine-, mitoxantrone-, and paclitaxel-induced apoptosis in HL-60 cells: improved method for detection of internucleosomal DNA fragmentation , 1994, Cancer Chemotherapy and Pharmacology.

[50]  C. Reutelingsperger,et al.  Expression on B Cells Undergoing Apoptosis Annexin V for Flow Cytometric Detection of Phosphatidylserine , 2022 .

[51]  D. Green,et al.  BCR-ABL Maintains Resistance of Chronic Myelogenous Leukemia Cells to Apoptotic Cell Death , 1994 .

[52]  D. Kazanas.  Observations beyond the limit , 1989, Nature.

[53]  K. Bhalla,et al.  Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells , 2001, Leukemia.

[54]  K. Bhalla,et al.  Cotreatment with STI-571 enhances tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL or apo-2L)-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[55]  J. Griffin,et al.  Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. , 2000, Blood.

[56]  E. Sausville,et al.  Effects of the bcr/abl kinase inhibitors AG957 and NSC 680410 on chronic myelogenous leukemia cells in vitro. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[57]  B. Druker,et al.  Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. , 2000, The Journal of clinical investigation.

[58]  I. Krantz,et al.  KILLER/DR5 is a DNA damage–inducible p53–regulated death receptor gene , 1997, Nature Genetics.