stilbenes and Sarcoma--Ewing

SIRT1-activating compounds (STACs) may have potential in the management of cancer. However, the best-studied STAC, the naturally occurring compound resveratrol, is reported to have contradictory effects in combination chemotherapy regimens: It has been shown both to increase and to decrease the action of anticancer agents. To shed more light on this issue, we comparatively investigated the impact of resveratrol and the synthetic STAC SRT1720 on the responsiveness of Ewing's sarcoma (ES) cells to the chemotherapeutic drugs etoposide and vincristine.. Because the effects of STACs can depend on the functionality of the tumor suppressor protein p53, we used three ES cell lines differing in their p53 status, i.e., wild-type p53 WE-68 cells, mutant p53 SK-ES-1 cells and p53 null SK-N-MC cells. Single agent and combination therapy effects were assessed by flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization, by measuring caspase 3/7 activity and by gene expression profiling.. When applied as single agents, both STACs were effective in ES cells irrespective of their p53 status. Strikingly, however, when applied in conjunction with cytostatic agents, the STACs displayed reverse effects: SRT1720 largely enhanced etoposide- and vincristine-induced cell death, while resveratrol inhibited it. Combination index analyses validated the antipodal impact of the STACs on the effectiveness of the chemotherapeutics.. These findings suggest that the synthetic STAC SRT1720 may be useful to enhance the efficacy of anticancer therapy in ES. But they also suggest that the dietary intake of the natural STAC resveratrol may be detrimental during chemotherapy of ES.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Neoplasms; Caspases; Cell Proliferation; Etoposide; Flow Cytometry; Heterocyclic Compounds, 4 or More Rings; Humans; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sarcoma, Ewing; Sirtuin 1; Stilbenes; Tumor Cells, Cultured; Vincristine

The effects of the tubulin-binding vascular-disrupting agents (VDAs), combretastatin A4 phosphate (CA4P), OXi4503/CA1P and OXi8007, in subcutaneous mouse models of the Ewing's sarcoma family of tumours (ESFTs) have been investigated alone and in combination with doxorubicin. Delay in subcutaneous tumour growth was observed following treatment of mice with multiple doses of OXi4503/CA1P but not with CA4P or OXi8007. A single dose of OXi4503/CA1P caused complete shutdown of vasculature by 24h and extensive haemorrhagic necrosis by 48h. However, a viable rim of proliferating cells remained, which repopulated the tumour within 10 days following the withdrawal of treatment. Combined treatment with doxorubicin 1h prior to administration of OXi4503/CA1P enhanced the effects of OXi4503/CA1P causing a synergistic delay in tumour growth (p<0.001). This study demonstrates that OXi4503/CA1P is a potent VDA in ESFT and in combination with conventional cytotoxic agents represents a promising treatment strategy for this tumour group.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bibenzyls; Bone Neoplasms; Cell Proliferation; Diphosphates; Disease Models, Animal; Doxorubicin; Drug Evaluation, Preclinical; Mice; Mice, Nude; Necrosis; Neoplasm Transplantation; Neovascularization, Pathologic; Sarcoma, Ewing; Stilbenes