Atractylenolide-I Sensitizes Human Ovarian Cancer Cells to Paclitaxel by Blocking Activation of TLR4/MyD88-dependent Pathway

• DOI: 10.1038/srep03840
• Publication Date: 2014-01-23T10:06:16Z
• Authors: Jian-Ming Huang; Guo-Nan Zhang; Yu Shi; Xiao Zha; Yi Zhu; Miao-Miao Wang; Qing Lin; Wen Wang; Hai-Yan Lu; Shi-Qi Ma; Jia Cheng; Bi-Fang Deng
• Keywords: Ovarian Neoplasms; 0301 basic medicine; Paclitaxel; Interleukin-6; Blotting, Western; Lymphocyte Antigen 96; NF-kappa B; Apoptosis; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Carcinoma, Ovarian Epithelial; Antineoplastic Agents, Phytogenic; Article; Cholinergic Antagonists; 3. Good health; Molecular Docking Simulation; Lactones; 03 medical and health sciences; Drug Resistance, Neoplasm; Myeloid Differentiation Factor 88; Humans; Female; Neoplasms, Glandular and Epithelial; Cell Proliferation

AbstractPaclitaxel, a known TLR4 ligand, leads to activation of TLR4/MyD88-dependent pathway that mediates chemoresistance and tumor progression in epithelial ovarian carcinoma (EOC). Atractylenolide-I (AO-I), a novel TLR4-antagonizing agent, inhibits TLR4 signaling by interfering with the binding of LPS or paclitaxel to membrane TLR4 of human leukocytes. In this study, AO-I was found to attenuate paclitaxel-induced protein expression of IL-6, VEGF and survivin and to enhance early apoptosis and growth inhibition in MyD88+ EOC cells; AO-I was shown to fit into the hydrophobic pocket of human MD-2 and to partially overlap with the binding site of paclitaxel by docking simulations, suggesting that AO-I may block the MD-2-mediated TLR4/MyD88-dependent paclitaxel signaling in MyD88+ EOC cells. Therefore, AO-I could significantly sensitize the response of MyD88+ EOC cells to paclitaxel by blocking MD-2-mediated TLR4/MyD88 signaling and that AO-I-paclitaxel combination could be a promising strategy for the treatment of EOC with a functional TLR4/MyD88/NF-κB pathway.