Sensitizing B- and T- cell Lymphoma Cells to Paclitaxel/Abraxane–Induced Death by AS101 via Inhibition of the VLA-4–IL10–Survivin Axis

Hila Danoch, Yona Kalechman, Michael Albeck, Dan L. Longo, Benjamin Sredni
2014 Molecular Cancer Research  
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
more » ... 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 0 )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. Implications: Combination therapy with AS101 and paclitaxel has novel therapeutic potential targeting deregulated active pathways in lymphoma, overcoming endogenous resistance to apoptosis.
doi:10.1158/1541-7786.mcr-14-0459 pmid:25351768 fatcat:5vizdur5kbcu5jl53tffdm2wmu