Sorafenib Sensitizes Solid Tumors to Apo2L-TRAIL and Apo2L-TRAIL Receptor Agonist Antibodies by the Jak2-Stat3-Mcl1 AxisReportar como inadecuado




Sorafenib Sensitizes Solid Tumors to Apo2L-TRAIL and Apo2L-TRAIL Receptor Agonist Antibodies by the Jak2-Stat3-Mcl1 Axis - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Background

Approximately half of tumor cell lines are resistant to the tumor-selective apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand Apo22L-TRAIL. Previously, we showed that combining Apo2L-TRAIL with sorafenib, a multikinase inhibitor, results in dramatic efficacy in Apo2L-TRAIL-resistant tumor xenografts via inhibition of Mcl-1. Soluble Apo2L-TRAIL is capable of binding to several surface receptors, including the pro-apoptotic death receptors, DR4 and DR5, and decoy receptors, DcR1 and DcR2. Monoclonal antibodies targeting either of these death receptors are being investigated as antitumor agents in clinical trials. We hypothesized that sorafenib and Apo2L-TRAIL or Apo2L-TRAIL death receptor agonist TRA antibodies against DR4 mapatumumab and DR5 lexatumumab will overcome resistance to Apo2L-TRAIL-mediated apoptosis and as increase antitumor efficacy in Apo2L-TRAIL-sensitive solid tumors.

Methodology-Principal Findings

We found that Apo2L-TRAIL or TRA antibodies combined with sorafenib synergistically reduce cell growth and increase cell death across a panel of solid tumor cell lines in vitro. This panel included human breast, prostate, colon, liver and thyroid cancers. The cooperativity of these combinations was also observed in vivo, as measured by tumor volume and TUNEL staining as a measure of apoptosis. We found that sorafenib inhibits Jak-Stat3 signaling and downregulates their target genes, including cyclin D1, cyclin D2 and Mcl-1, in a dose-dependent manner.

Conclusions-Significance

The combination of sorafenib with Apo2L-TRAIL or Apo2L-TRAIL receptor agonist antibodies sensitizes Apo2L-TRAIL-resistant cells and increases the sensitivity of Apo2L-TRAIL-sensitive cells. Our findings demonstrate the involvement of the Jak2-Stat3-Mcl1 axis in response to sorafenib treatment, which may play a key role in sorafenib-mediated sensitization to Apo2L-TRAIL.



Autor: Junaid Abdulghani, Joshua E. Allen, David T. Dicker, Yingqiu Yvette Liu, David Goldenberg, Charles D. Smith, Robin Humphreys, Waf

Fuente: http://plos.srce.hr/



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