Abstract
Radiation therapy is an important treatment choice for unresectable advanced human lung cancers, and a critical adjuvant treatment for surgery. However, radiation as a lung cancer treatment remains far from satisfactory due to problems associated with radiation resistance in cancer cells and severe cytotoxicity to non-cancer cells, which arise at doses typically administered to patients. We have recently identified a promising novel inhibitor of β-catenin/Tcf4 interaction, named BC-23 (C21H14ClN3O4S), which acts as a potent cell death enhancer when used in combination with radiation. Sequential exposure of human p53-null non-small cell lung cancer (NSCLC) H1299 cells to low doses of x-ray radiation, followed 1 hour later by administration of minimally cytotoxic concentrations of BC-23, resulted in a highly synergistic induction of clonogenic cell death (combination index <1.0). Co-treatment with BC-23 at low concentrations effectively inhibits Wnt/β-catenin signaling and down-regulates c-Myc and cyclin D1 expression. S phase arrest and ROS generation are also involved in the enhancement of radiation effectiveness mediated by BC-23. BC-23 therefore represents a promising new class of radiation enhancer.
Highlights
Despite recent advances in the delivery of radiotherapy and chemotherapy for locally advanced lung cancer, most patients relapse and succumb to their disease [1,2,3]
We determined the direct inhibitory effects of selected compounds on the interaction between β-catenin and Tcf4 using our recently-developed cell-free competitive binding assay based on fluorescence polarization (FP)
We examined the expression of other genes (e.g., β-actin) that were not related to regulation by βcatenin/Tcf4 interaction and their expression was not affected by BC-23
Summary
Despite recent advances in the delivery of radiotherapy and chemotherapy for locally advanced lung cancer, most patients relapse and succumb to their disease [1,2,3]. This may be due, in large part, to the presence of lung cancer stem cells: a population of cells that is capable of selfrenewal, proliferation, and metastasis and that shows appreciable radioresistance [4,5,6]. Investigations are ongoing on several new classes of small molecule radiosensitizers and their radiation enhancing effects on NSCLCs and other human cancers [9,10,11,12]. A critical need remains for the discovery and development of novel radiation enhancers that show high efficiency and low toxicity
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