Immunosuppression of CTL activation and effector functions by immuno suppressive cells is a major challenge in cancer immunotherapy. read this However, recent studies revealed that the immuno suppressive Treg cells only selectively suppress the perforin pathway without inhibiting CTL activation and proliferation Inhibitors,Modulators,Libraries in vivo, suggesting that Treg cells may not suppress the Fas/FasL effector mechanism of CTL in vivo. Indeed, our recent study showed that tumor infiltrating CTLs in tumor bearing mice and CTLs from human colon and breast cancer patients are FasL. Therefore, the Fas/FasL effector mechanism might be functional in the immuno suppressive tumor microenvir onment. However, metastatic human colon and breast cancer cells are often resistant to Fas mediated apoptosis.

Therefore, a therapeutic agent that can sensitize tumor cell Fas resistance may represent an effective enhancer of CTL based cancer immunotherapy Inhibitors,Modulators,Libraries against metastatic colon and breast cancers. Our data suggest that LCL85 is potentially such an agent. Although LCL85 does not effectively sensitize Colon 26 cells to FasL induced apoptosis, LCL85 is effective in suppress ing Colon 26 cell metastatic potential in vivo, suggesting that other host factors, such as IFN and TNF se creted by T cells, might also act to sensitize the tumor cells to apoptosis in vivo, which requires further study. Conclusions We envision that a sublethal dose of LCL85 can be used as a sensitizer in cancer immunotherapy for metastatic colon and breast cancers. This idea is analogous to a one two punch concept.

First, cancer patients are treated with a non cytotoxic dose of LCL85 to sensitize cancer cells to apoptosis. Once sensitized, Inhibitors,Modulators,Libraries patients are then treated with FasL CTLs based immunotherapy to suppress cancer metastasis. Our in vivo tumor suppression Inhibitors,Modulators,Libraries studies showed that low doses of LCL85 exhib ited potent tumor suppression activity in immune competent mice in vivo. A previous study showed that lack of ceramide accumulation in target cells is a significant cause of resistance to cyto toxic T lymphocyte induced apoptosis. In this study, we observed that a large portion of the tumor infiltrating CTLs are FasL, and low doses of LCL85 effectively suppresses colon and breast tumor growth and metastasis in immune competent mice. Our observations thus indicate that LCL85 might sensitize tumor cells to CTL induced apoptosis through inducing ceramide accumulation in the tumor cells in vivo.

Background Arsenic trioxide has been reported to be Inhibitors,Modulators,Libraries an ef fective therapeutic agent in both newly diagnosed and relapsed patients with acute promyelocytic Wortmannin DNA-PK leukemia. This success has prompted an interest in understanding the molecular mechanisms of action underlying the clinical effectiveness of ATO. ATO is re ported to induce apoptosis in leukemic promyelocytes. ATO induced apoptosis appears to be dependent on the intracellular redox homeostasis.