Vielanin K enhances doxorubicin-induced apoptosis via activation of IRE1α- TRAF2 - JNK pathway and increases mitochondrial Ca2 + influx in MCF-7 and MCF-7/MDR cells

  • Phytomedicine. 2020 Nov;78:153329. doi: 10.1016/j.phymed.2020.153329.
Li-Na Zhang  1 ,  Yuan-Zheng Xia  1 ,  Chao Zhang  1 ,  Hao Zhang  1 ,  Jian-Guang Luo  1 ,  Lei Yang  2 ,  Ling-Yi Kong  3
Affiliations
  • 1. Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China.
  • 2. Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China. Electronic address: [email protected].
  • 3. Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nan Jing 210009, China. Electronic address: [email protected].
PMID: 32896708 DOI: 10.1016/j.phymed.2020.153329
Abstract

Background: Therapeutic failure and drug resistance are common and have important implications in the poor prognosis of advanced breast Cancer. It is necessary to acquire a natural product to overcome the resistance of Cancer and increase the sensitivity of drug-resistant cells to Anticancer agents.

Purpose: To demonstrate whether the compound Vielanin K (VK) has the potential to increase the sensitivity of MCF-7 and MCF-7/MDR cells to Anticancer agents.

Methods: Cell viability and proliferative capacity were determined by MTT, colony formation and EdU assays. Apoptosis and CA2+ accumulation were evaluated by flow cytometry. Then, proteins were detected by immunoblotting, and gene expression levels were explored by qRT-PCR.

Results: In MCF-7 and corresponding MDR cells, VK increased the fluorescence intensity of Rho123, but not CFDA. VK treatment did not affect the protein expression of P-gp, MRP1 or BCRP. VK treatment enhanced the DOX-induced apoptotic cascade, while VK combined with DOX increased JNK phosphorylation by activating the IRE1α-TRAF2 signaling pathway. In addition, CA2+ was released from the endoplasmic reticulum following combination treatment, thereby giving rise to mitochondrial Apoptosis. Silencing IRE1α and JNK with small interfering RNA (siRNA) efficiently attenuated combination treatment-induced Apoptosis. These effects caused mitochondrial depolarization and reduced viability in MCF-7 and corresponding MCF-7/MDR cells.

Conclusion: VK combined with DOX increases the Apoptosis of MCF-7 and corresponding MCF-7/MDR cells by activating ER stress and mitochondrial Apoptosis via IRE1α-TRAF2-JNK signaling.

Keywords
Ca(2+); ER stress; Mitochondria; Vielanin K; dimeric guaianes compound.
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