nitrophenols and cafestol

Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Biphenyl Compounds; Carcinoma, Renal Cell; Cell Line, Tumor; Diterpenes; Drug Synergism; Drug Therapy, Combination; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; Male; Membrane Proteins; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Primary Cell Culture; Proto-Oncogene Proteins; RNA, Small Interfering; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays