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Synergistic effects of tanshinone IIA and andrographolide on the apoptosis of cancer cells via crosstalk between p53 and reactive oxygen species pathways

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Abstract

Background

Tanshinone IIA (Tan IIA) and andrographolide (Andro) are natural compounds that are reported to exhibit anticancer activities against various types of cancers. The aim of this study is to evaluate the synergistic anticancer effects of the combination of Tan IIA and Andro, and to investigate the mechanisms of pharmacological effect and their potential applications as an anticancer therapy in clinics.

Methods

The anticancer effects of the combination of Tan IIA and Andro on MCF7, SMMC7721, and BGC823 cells were explored. The apoptosis of the cancer cells was determined by MTT and AV-PI dual stain assays. The intracellular GSH level was measured by DTNB assay, and the intracellular levels of reactive oxygen species (ROS) were examined by flow cytometry. The expression of the proteins in the apoptosis pathway was determined by immunobloting.

Results

The combination of Tan IIA and Andro exhibited significant synergistic anticancer effects against cancer cells, especially at low concentrations. Andro reacted with the thiol group of intracellular GSH, thus disrupting the GSH redox cycle and eventually increasing the level of intracellular ROS. Tan IIA triggered p53 responses and apoptosis by binding to the DNA of cancer cells. The crosstalk between ROS and p53 exhibited a synergistic effect on the apoptosis of cancer cells.

Conclusion

The combination of Tan IIA and Andro showed significant synergistic effects on cancer cell apoptosis by promoting crosstalk between ROS and p53, providing a novel and effective combination that has the potential to be applied in clinical anticancer therapy.

Graphic abstract

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Abbreviations

Andro:

Andrographolide

AV-PI:

Annexin V-fluorescein isothiocyanate-propidium iodide

BSO:

Buthionine sulfoximine

CI:

Combination index

DETC:

Diethylthiocarbamate

DCF:

Dichlorofluorescein

DHE:

Dihydroethidium

DMSO:

Dimethyl sulfoxide

DTNB:

5,5′-dithiobis(2-nitrobenzoic acid)

GSH:

Glutathione

HPLC:

High performance liquid chromatography

MTT:

3-(4,5-dimethylthiazol-2 -yl)-2,5-diphenyl tetrazolium bromide

NAC:

N-acetyl-l-cysteine

PFT-α:

1-(4-methylphenyl)-2-(4,5,6,7-tetrahydro-2-imino-3(2H)-benzothiazolyl) ethanone hydrobromide

PVDF:

Polyvinylidene fluoride

ROS:

Reactive oxygen species

Tan IIA:

Tanshinone IIA

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Acknowledgements

The authors are grateful for the financial support of the National Natural Science Foundation of China (Grant No. 21376039), and Panjin Campus for Food Science and Technology Research Initiative, Dalian University of Technology.

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Correspondence to Yachen Li or Yongming Bao.

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Li, Y., Jiang, B., Wang, R. et al. Synergistic effects of tanshinone IIA and andrographolide on the apoptosis of cancer cells via crosstalk between p53 and reactive oxygen species pathways. Pharmacol. Rep (2020). https://doi.org/10.1007/s43440-019-00006-z

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Keywords

  • Tanshinone IIA
  • Andrographolide
  • Reactive oxygen species
  • Apoptosis
  • p53