title: Bone marrow stroma-induced resistance of chronic lymphocytic leukemia cells to arsenic trioxide involves Mcl-1 upregulation and is overcome by inhibiting the PI3Kδ or PKCβ signaling pathways.
abstract: CLL remains an incurable disease in spite of the many new compounds being studied. Arsenic trioxide (ATO) induces apoptosis in all CLL cell types and could constitute an efficient therapy. To further explore this, we have studied the influence of stromal cells, key components of the CLL microenvironment, on the response of CLL cells to ATO. Bone marrow stromal cells induced CLL cell resistance to 2 μM ATO and led to activation of Lyn, ERK, PI3K and PKC, as well as NF-κB and STAT3. Mcl-1, Bcl-xL, and Bfl-1 were also upregulated after the co-culture. Inhibition experiments indicated that PI3K and PKC were involved in the resistance to ATO induced by stroma. Moreover, idelalisib and sotrastaurin, specific inhibitors for PI3Kδ and PKCβ, respectively, inhibited Akt phosphorylation, NF-κB/STAT3 activation and Mcl-1 upregulation, and rendered cells sensitive to ATO. Mcl-1 was central to the mechanism of resistance to ATO, since: 1) Mcl-1 levels correlated with the CLL cell response to ATO, and 2) blocking Mcl-1 expression or function with specific siRNAs or inhibitors overcame the protecting effect of stroma. We have therefore identified the mechanism involved in the CLL cell resistance to ATO induced by bone marrow stroma and show that idelalisib or sotrastaurin block this mechanism and restore sensibility to ATO. Combination of ATO with these inhibitors may thus constitute an efficient treatment for CLL.
authors.affiliation: Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Amigo-Jiménez
authors.affiliation: Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Bailón
authors.affiliation: Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Aguilera-Montilla
authors.affiliation: Hematology Department, Hospital Clínico Universitario, Valencia, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Terol
authors.affiliation: Molecular Cytogenetics Unit, Hematology Department, Instituto de Investigación Sanitaria Puerta de Hierro-Majadahonda, Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: García-Marco
authors.affiliation: Cellular and Molecular Medicine Department, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: García-Pardo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D010087:Oxides; D047428:Protein Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D051057:Proto-Oncogene Proteins c-akt; C579054:PRKCB protein, human; D064546:Protein Kinase C beta; D019311:Staurosporine; D000077237:Arsenic Trioxide; C552946:idelalisib
keywords: CLL; Mcl-1; arsenic trioxide; idelalisib; stromal cells