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. Combination therapy with AS101 and paclitaxel has novel therapeutic potential targeting deregulated active pathways in lymphoma, overcoming endogenous resistance to apoptosis.
Highlights
From the increasing evidence that dysregulation of apoptosis contributes to in vivo drug resistance of tumor cells comes confidence that new therapeutic approaches aimed at correcting the dysfunctional apoptotic program could improve the treatment outcome of patients with chemotherapy-refractory tumors
We have recently shown that AS101 inactivates the VLA-4 integrin by redox modulation of vicinal thiols within the exofacial membranal side [34]
Because we showed that inhibition of lymphoma cells IL10 by AS101 accounts for both its inhibition of pStat3 and its sensitizing effects to paclitaxel, we assumed that AS101 sensitizes lymphoma cells to paclitaxel via inhibition of the IL10–pStat3 axis
Summary
From the increasing evidence that dysregulation of apoptosis contributes to in vivo drug resistance of tumor cells comes confidence that new therapeutic approaches aimed at correcting the dysfunctional apoptotic program could improve the treatment outcome of patients with chemotherapy-refractory tumors. The possibility of modulating the chemosensitivity of various cancer cell types by targeting survivin has been actively pursued in the last few years. This protein is a structurally unique member of the inhibitor of apoptosis (IAP) family, which acts as a cell survival factor because it is involved in the control of mitotic progression and inhibition of apoptosis [1] and is selectively expressed in most common human tumors [2]. 1C.A.I.R. Institute, The Safdie AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
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