2. Academic Validation
  3. Atractylenolide-I sensitizes human ovarian cancer cells to paclitaxel by blocking activation of TLR4/MyD88-dependent pathway

Atractylenolide-I sensitizes human ovarian cancer cells to paclitaxel by blocking activation of TLR4/MyD88-dependent pathway

  • Sci Rep. 2014 Jan 23;4:3840. doi: 10.1038/srep03840.
Jian-Ming Huang 1,  Guo-Nan Zhang 2,  Yu Shi 3,  Xiao Zha 1,  Yi Zhu 4,  Miao-Miao Wang 3,  Qing Lin 3,  Wen Wang 3,  Hai-Yan Lu 3,  Shi-Qi Ma 5,  Jia Cheng 5,  Bi-Fang Deng 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Gynaecologic Oncology, Sichuan Cancer Hospital, No. 55, Section 4, South People's Road, Chengdu 610041, Sichuan, P. R. China.
  • 4 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.
  • 5 Department of Biochemistry & Molecular Biology, Sichuan Cancer Institute, Chengdu 610041, Sichuan, P. R. China.
PMID: 24452475 DOI: 10.1038/srep03840
Abstract

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.

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