Atractylenolide-I sensitizes human ovarian cancer cells to paclitaxel by blocking activation of TLR4/MyD88-dependent pathway.
Paclitaxel, 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.
1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China [2] Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.
Jian-Ming
JM
Huang
1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China [2] Graduate School, Guangxi Medical University, Nanning 530021, Guangxi, P. R. China.
Guo-Nan
GN
Zhang
Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China.
Yu
Y
Shi
1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China [2] Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.
Xiao
X
Zha
1] Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China [2] Department of Ultrasound, Sichuan Cancer Hospital, Chengdu 610041, Sichuan, P. R. China.
Yi
Y
Zhu
Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China.
Miao-Miao
MM
Wang
Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China.
Qing
Q
Lin
Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China.
Wen
W
Wang
Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China.
Hai-Yan
HY
Lu
Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.
Shi-Qi
SQ
Ma
Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.
Jia
J
Cheng
Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.
Bi-Fang
BF
Deng
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D049109:Cell Proliferation / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D018680:Cholinergic Antagonists; D015850:Interleukin-6; C495377:LY96 protein, human; D007783:Lactones; D051218:Lymphocyte Antigen 96; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D012717:Sesquiterpenes; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C424804:atractylenolide I; D017239:Paclitaxel