Chemosenstizing Effects of a Novel Anti-inflammatory Small Molecule, UTL-5g, and Its Analogs.

Our previous studies showed that UTL-5g, a novel anti-inflammatory TNF-a inhibitor, enhanced the chemotherapeutic efficacy of cisplatin against HCT-15 human colon cancer cells in an animal tumor model. To extend the study, we set out to investigate 3 newly synthesized analogs of UTL-5g (UTLOH-4a, -4b, and -4c) on whether they are associated with similar biological effects. Chemosensitizing effects of UTL-5g and its 3 analogs were investigated using HCT-15 cells in vitro with increasing doses of cisplatin, carboplatin, or oxaliplatin. IC50 of each drug was determined from the dose-response surviving curves. The antiinflammatory effects were examined by their ability to inhibit PGE2 production in mouse RAW cells stimulated with LPS. Myelotoxicity induced by cisplatin was examined with human CFU-GM clonogenic assay. All 4 compounds significantly potentiated the cytotoxic effect of cisplatin against HCT-15 cancer cells by lowering the IC50 values. Among them, UTL-5g appeared to be the most promising sensitizer of cisplatin and UTLOH-4b was the most potent sensitizer of carboplatin. Anti-inflammatory study showed that UTL-5g, UTLOH-4a, and -4c inhibited PGE2 production in LPS-stimulated RAW cells. In addition, UTL-5g and UTLOH-4a enhanced the survival of CFU-GM colony counts in cultures containing cisplatin, carboplatin and oxaliplatin respectively. [ABSTRACT FROM AUTHOR]