2. Academic Validation
  3. β, β-Dimethylacrylshikonin potentiates paclitaxel activity, suppresses immune evasion and triple negative breast cancer progression via STAT3Y705 phosphorylation inhibition based on network pharmacology and transcriptomics analysis

β, β-Dimethylacrylshikonin potentiates paclitaxel activity, suppresses immune evasion and triple negative breast cancer progression via STAT3Y705 phosphorylation inhibition based on network pharmacology and transcriptomics analysis

  • Phytomedicine. 2023 Mar 15;114:154769. doi: 10.1016/j.phymed.2023.154769.
Zhixuan Wu 1,  Haodong Wu 2,  Ziqiong Wang 1,  Hongfeng Li 2,  Hongyi Gu 1,  Erjie Xia 2,  Congzhi Yan 1,  Yinwei Dai 1,  Conghui Liu 1,  Xiaowu Wang 3,  Linxi Lv 2,  Jingxia Bao 1,  Ouchen Wang 4,  Xuanxuan Dai 5
Affiliations

Affiliations

  • 1 Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China; Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China.
  • 2 Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China.
  • 3 Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China.
  • 4 Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China. Electronic address: woc@wmu.edu.cn.
  • 5 Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China; Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China. Electronic address: daoshidaixuanxuan@126.com.
PMID: 36940580 DOI: 10.1016/j.phymed.2023.154769
Abstract

Backgound: Triple negative breast Cancer (TNBC) is an extremely aggressive and rapidly progressing Cancer, wherein existing therapies provide little benefit to patients. β, β-Dimethylacrylshikonin (DMAS), an active naphthoquinone derived from comfrey root, has potent Anticancer activity. However, the antitumor function of DMAS against TNBC remains to be proved.

Purpose: Explore effects of DMAS on TNBC and clarify the mechanism.

Study design: Network pharmacology, transcriptomics and various cell functional experiments were applied to TNBC cells to explore the effects of DMAS on TNBC. The conclusions were further validated in xenograft animal models.

Methods: MTT, EdU, transwell, scratch tests, flow cytometry, immunofluorescence, and immunoblot were utilized to assess the activity of DMAS on three TNBC cell lines. The anti-TNBC mechanism of DMAS was clarified by overexpression and knockdown of STAT3 in BT-549 cells. In vivo efficacy of DMAS was analysed using a xenograft mouse model.

Results: In vitro analysis revealed that DMAS inhibited the G2/M phase transition and suppressed TNBC proliferation. Additionally, DMAS triggered mitochondrial-dependent Apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, DMAS exerted its antitumour effects by inhibiting STAT3Y705 phosphorylation. STAT3 overexpression abolished the inhibitory effect of DMAS. Further studies showed that treatment with DMAS inhibited TNBC growth in a xenograft model. Notably, DMAS potentiated the sensitivity of TNBC to paclitaxel and inhibited immune evasion by downregulating the immune checkpoint PD-L1.

Conclusions: For the first time, our study revealed that DMAS potentiates paclitaxel activity, suppresses immune evasion and TNBC progression by inhibiting STAT3 pathway. It has the potential as a promising agent for TNBC.

Keywords

Immune evasion; Paclitaxel; STAT3; Triple negative breast cancer; β, β-Dimethylacrylshikonin.

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