Baicalein sensitizes triple negative breast cancer MDA-MB-231 cells to doxorubicin via autophagy-mediated down-regulation of CDK1

Mol Cell Biochem. 2023 Jul;478(7):1519-1531. doi: 10.1007/s11010-022-04597-9. Epub 2022 Nov 21.

Abstract

Triple negative breast cancer (TNBC) is a kind of refractory cancer with poor response to conventional chemotherapy. Recently, the combination of baicalein and doxorubicin was reported to exert a synergistic antitumor effect on breast cancer. However, the underlying mechanism how baicalein sensitizes breast cancer cells to doxorubicin remains to be elucidated. Here, it was found that 20 μM baicalein increased the autophagy markers including the ratio of LC3B II/I, GFP-LC3 punctate aggregates and down-regulation of p62 expression, and up-regulated mitophagy marker PINK1 and Parkin in TNBC MDA-MB-231 cells as well. In contrast, doxorubicin decreased the levels of autophagy markers, and significantly up-regulated CDK1 in MDA-MB-231 cells. Pretreatment with baicalein markedly inhibited the doxorubicin-induced decrease in autophagy markers and up-regulation of CDK1, which was reversed by the autophagy inhibitor 3-Methyladenine. Moreover, baicalein alleviated the doxorubicin-induced expression and phosphorylation (at Ser616) of mitochondrial fission protein Drp1. Intriguingly, the autophagy inhibitor 3-Methyladenine also significantly weakened the effect of baicalein on doxorubicin-induced viability decrease and apoptosis in MDA-MB-231 cells. Taken together, our data indicate that baicalein improves the chemosensitivity of TNBC cells to doxorubicin through promoting the autophagy-mediated down-regulation of CDK1, also suggest a novel strategy for prevention of TNBC in the future.

Keywords: Autophagy; Baicalein; Cyclin-dependent kinase 1; Doxorubicin; Triple negative breast cancer.

MeSH terms

  • Apoptosis
  • Autophagy
  • CDC2 Protein Kinase / metabolism
  • CDC2 Protein Kinase / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Humans
  • MDA-MB-231 Cells
  • Triple Negative Breast Neoplasms* / metabolism

Substances

  • baicalein
  • Doxorubicin
  • CDK1 protein, human
  • CDC2 Protein Kinase