title: Sensitizing B- and T- cell Lymphoma Cells to Paclitaxel/Abraxane-Induced Death by AS101 via Inhibition of the VLA-4-IL10-Survivin Axis.
abstract: Cancer cell resistance to chemotherapy is a major concern in clinical oncology, resulting in increased tumor growth and decreased patient survival. Manipulation of apoptosis has emerged as a new therapeutic strategy to eliminate cancer cells. The focus of this study resides within a novel approach to target survivin, an integrator of both cell death and mitosis. This protein plays a pivotal role in the resistance of tumors to chemotherapy, especially to paclitaxel. The data herein demonstrate an indirect repression of survivin in both B- and T-cell lymphoma and human NHL by the nontoxic tellurium compound, AS101 [ammonium trichloro(dioxoethylene-o,o')tellurate], via inhibition of tumor autocrine IL10-STAT3-Survivin signaling. As a result of survivin abrogation, sensitization of lymphomas to paclitaxel or to Abraxane, the new albumin-stabilized nanoparticle formulation of paclitaxel, occurs both in vitro and in vivo. Importantly, inhibition of lymphoma cell IL10 secretion is mediated by inactivation of the VLA-4 integrin, recently shown to be an important target of AS101. This activity is followed by inhibition of the PI3K-AKT axis that mediates IL10 suppression. Because a wide variety of lymphomas and other tumor types express VLA-4 and secrete IL10 in an autocrine manner, inhibition of survivin with a small nontoxic agent has vast clinical significance in modulating chemosensitivity in many tumor types.
  
  
  CONCLUSIONS
  Combination therapy with AS101 and paclitaxel has novel therapeutic potential targeting deregulated active pathways in lymphoma, overcoming endogenous resistance to apoptosis.
authors.affiliation: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Danoch
authors.affiliation: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Yona
authors.initials: Y
authors.lastname: Kalechman
authors.affiliation: Chemistry Department, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Albeck
authors.affiliation: Laboratory of Molecular Biology and Immunology, Biomedical Research Center, National Institute of Aging, Baltimore, Maryland.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.affiliation: C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel. srednib@mail.biu.ac.il.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sredni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005030:Ethylenes / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C117749:Birc5 protein, mouse; D005030:Ethylenes; C556062:IL10 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D039041:Integrin alpha4beta1; D012097:Repressor Proteins; D000077022:Survivin; D016753:Interleukin-10; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D017239:Paclitaxel