thiacremonone and Colonic-Neoplasms

Chemotherapeutic strategies commonly use multiple agents to overcome drug resistance and to lower drug toxicity. Activation of nuclear factor-kappaB (NF-kappaB) is implicated in drug resistance in cancer cells. Previously, we reported that thiacremonone, a novel sulfur compound isolated from garlic, inhibited NF-kappaB and cancer cell growth with IC(50) values about 100 microg/mL in colon cancer cells. In the present study, we tested whether thiacremonone could increase susceptibility of cancer cells to chemotherapeutics through inactivation of NF-kappaB. Colon cancer cells were cotreated with thiacremonone (50 microg/mL, half dose of IC(50)) and lower doses of each chemotherapeutic agent (half dose of IC(50)) for 24 hours. NF-kappaB activity was completely abrogated in cells treated with a combination of thiacremonone and docetaxel, whereas thiacremonone on its own did not alter NF-kappaB activity. This combined drug effect was also found with other anticancer drugs in colon cancer and in other cancer cells. In good correlation with inhibition of cell growth and NF-kappaB activity, the combination treatment also regulated NF-kappaB target genes. Oral treatment of mice with thiacremonone (1 mg/kg) by administering it in drinking water for 4 weeks significantly augmented docetaxel (1 mg/kg, i.p., four times)-induced decrease of tumor growth accompanied with regulation of NF-kappaB activity and NF-kappaB target genes. These results warrant carefully designed clinical studies investigating the combination of thiacremonone and commonly used chemotherapeutic agents for the treatment of human cancers.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Docetaxel; Drug Administration Schedule; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Taxoids; Thiophenes; Xenograft Model Antitumor Assays

Compounds such as S-allylmercaptocysteine, diallyl disulfide, and S-trityl-L-cysteine isolated from garlic have been known to be effective in chemoprevention. Nuclear transcription factor-kappaB (NF-kappaB) has been known to be an implicated factor in apoptotic cell death of several cancer cells. In this study, we investigated whether a sulfurcompound (named thiacremonone) isolated from garlic could modulate NF-kappaB activity and thereby induce apoptotic cell death of colon cancer cells. Treatment with different concentrations (30 - 150 microg/ml) of thiacremonone for various periods (0 - 48 h) inhibited colon cancer cell (SW620 and HCT116) growth followed by induction of apoptosis in a dose-dependent manner. We also found that thiacremonone modulated tumor necrosis factor-alpha (TNF-alpha) and tetradeanoyl phorbol acetate (TPA)-induced NF-kappaB transcriptional and DNA binding activity. Moreover, thiacremonone suppressed NF-kappaB target anti-apoptotic genes (Bcl-2, cIAP1/2, and XIAP) and inflammatory genes (iNOS and COX-2), whereas it induced apoptotic genes (Bax, cleaved caspse-3, and cleaved PARP) expression. These results suggest that a novel sulfurocompound from garlic inhibited colon cancer cell growth through induction of apoptotic cell death by modulating of NF-kappaB.

Topics: Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; DNA, Neoplasm; Dose-Response Relationship, Drug; Electrophoretic Mobility Shift Assay; Garlic; Gene Expression Regulation; Humans; NF-kappa B; Tetradecanoylphorbol Acetate; Thiophenes; Transcription, Genetic; Tumor Necrosis Factor-alpha