Skip to main content
SpringerLink
Log in

Paeonol triggers apoptosis in HeLa cervical cancer cells: the role of mitochondria-related caspase pathway

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Paeonol is a biologically active component purified from the root bark of Cortex Moutan that exerts pharmacological effects on the cervical cancer. In this study, we aim to evaluate the anti-cervical cancer capacity of paeonol and to investigate the mechanism driving its anti-cervical cancer effect. Paeonol administration markedly restrained the proliferation and caused apoptosis in HeLa cells. Furthermore, paeonol treatment resulted in a mitochondrial dysfunction in HeLa cells, including the inducing of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, and the release of cytochrome c. Moreover, the Bcl-2/Bax proportion was obviously downregulated and cleaved caspase-3 expression was evaluated through paeonol treatment. Additionally, the expression of p-PI3K and p-Akt was noticeably reduced in response to paeonol treatment in HeLa cells. Our findings indicated that paeonol exerts an anticancer potential in HeLa cells, at least in a manner, via triggering the mitochondrial pathway of cellular apoptosis by inhibiting PI3K/Akt signaling. Thus, paeonol has great potential as a promising therapeutic compound to resist human cervical cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Bernardi P, Azzone GF (1981) Cytochrome c as an electron shuttle between the outer and inner mitochondrial membranes. J Biol Chem 256(14):7187–7192

    Article  CAS  Google Scholar 

  • Bray F, Balcaen T, Baro E, Gandon A, Ficheur G, Chazard E (2019) Increased incidence of cholecystectomy related to gallbladder disease in France: analysis of 807,307 cholecystectomy procedures over a period of seven years. J Visc Surg 156:209–215

    Article  CAS  Google Scholar 

  • Burris HA 3rd. (2013) Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol 71(4):829–842

    Article  CAS  Google Scholar 

  • Choi H, Lee DG (2015) Lycopene induces apoptosis in Candida albicans through reactive oxygen species production and mitochondrial dysfunction. Biochimie 115:108–115

    Article  CAS  Google Scholar 

  • Choy KW, Lau YS, Murugan D, Vanhoutte PM, Mustafa MR (2018) Paeonol attenuates LPS-induced endothelial dysfunction and apoptosis by inhibiting BMP4 and TLR4 signaling simultaneously but independently. J Pharmacol Exp Ther 364(3):420–432

    Article  CAS  Google Scholar 

  • Dhanasekaran A, Gruenloh SK, Buonaccorsi JN, Zhang R, Gross GJ, Falck JR, Patel PK, Jacobs ER, Medhora M (2008) Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia. Am J Physiol Heart Circ Physiol 294(2):H724–H735

    Article  CAS  Google Scholar 

  • Du J, Yang D, Luo ZW, Lee SY (2018) Metabolic engineering of Escherichia coli for the production of indirubin from glucose. J Biotechnol 267:19–28

    Article  CAS  Google Scholar 

  • Du J, Li L, Zhou S (2019) Microbial production of cyanophycin: from enzymes to biopolymers. Biotechnol Adv 37:107400

    Article  CAS  Google Scholar 

  • Hail N Jr, Lotan R (2009) Cancer chemoprevention and mitochondria: targeting apoptosis in transformed cells via the disruption of mitochondrial bioenergetics/redox state. Mol Nutr Food Res 53(1):49–67

    Article  CAS  Google Scholar 

  • Ishaq M, Kumar S, Varinli H, Han ZJ, Rider AE, Evans MD et al (2014) Atmospheric gas plasma-induced ROS production activates TNF-ASK1 pathway for the induction of melanoma cancer cell apoptosis. Mol Biol Cell 25(9):1523–1531

    Article  Google Scholar 

  • Korsmeyer SJ (1992) Bcl-2: an antidote to programmed cell death. Cancer Surv 15:105–118

    CAS  PubMed  Google Scholar 

  • Lei, Y, Li, HX, Jin, WS, Peng, WR, Zhang, CJ, Bu, LJ, du YY, Ma T, Sun GP 2013. The radiosensitizing effect of Paeonol on lung adenocarcinoma by augmentation of radiation-induced apoptosis and inhibition of the PI3K/Akt pathway. Int J Radiat Biol 89(12): 1079-1086.

  • Lei H, Wen Q, Li H, Du S, Wu JJ, Chen J et al (2016) Paeonol inhibits lipopolysaccharide-induced HMGB1 translocation from the nucleus to the cytoplasm in RAW264.7 cells. Inflammation 39(3):1177–1187

    CAS  PubMed  Google Scholar 

  • Li Y, Chan PH (1998) Identification of the pro-oncogene stathmin/op18 mRNA in the brain of mitochondrial Mn-superoxide dismutase-deficient mice by a modified differential display PCR. Brain research. Mol Brain Res 55(2):277–284

    Article  CAS  Google Scholar 

  • Li M, Tan SY, Zhang J, You HX (2013) Effects of paeonol on intracellular calcium concentration and expression of RUNX3 in LoVo human colon cancer cells. Mol Med Rep 7(5):1425–1430

    Article  CAS  Google Scholar 

  • Liu J, Wang S, Feng L, Ma D, Fu Q, Song Y, Jia X, Ma S (2013) Hypoglycemic and antioxidant activities of paeonol and its beneficial effect on diabetic encephalopathy in streptozotocin-induced diabetic rats. J Med Food 16(7):577–586

    Article  CAS  Google Scholar 

  • Lyu ZK, Li CL, Jin Y, Liu YZ, Zhang X, Zhang F, Ning LN, Liang ES, Ma M, Gao W, Zhang MX, Liu DS (2017) Paeonol exerts potential activities to inhibit the growth, migration and invasion of human gastric cancer BGC823 cells via downregulating MMP2 and MMP9. Mol Med Rep 16(5):7513–7519

    Article  CAS  Google Scholar 

  • Ou Y, Li Q, Wang J, Li K, Zhou S (2014) Antitumor and apoptosis induction effects of paeonol on mice bearing EMT6 breast carcinoma. Biomol Ther 22(4):341–346

    Article  CAS  Google Scholar 

  • Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I et al (2001) The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol 117(2):333–340

    Article  CAS  Google Scholar 

  • Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399(6735):483–487

    Article  CAS  Google Scholar 

  • Song X, Wang Z, Liang H, Zhang W, Ye Y, Li H, Hu Y, Zhang Y, Weng H, Lu J, Wang X, Li M, Liu Y, Gu J (2017) Dioscin induces gallbladder cancer apoptosis by inhibiting ROS-mediated PI3K/AKT signalling. Int J Biol Sci 13(6):782–793

    Article  CAS  Google Scholar 

  • Wang IK, Lin-Shiau SY, Lin JK (1999) Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur J Cancer 35(10):1517–1525

    Article  CAS  Google Scholar 

  • Wang H, Khor, TO, Shu L, Su ZY, Fuentes F, Lee JH et al (2012) Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability. Anti Cancer Agents Med Chem 12(10):1281–1305

    Article  CAS  Google Scholar 

  • Wang J, Yuan L, Xiao H, Xiao C, Wang Y, Liu X (2013) Momordin Ic induces HepG2 cell apoptosis through MAPK and PI3K/Akt-mediated mitochondrial pathways. Apoptosis 18(6):751–765

    Article  CAS  Google Scholar 

  • Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87

    Article  CAS  Google Scholar 

  • Xu X, Zhang Y, Qu D, Jiang T, Li S (2011) Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway. J Exp Clin Cancer Res 30:33

    Article  Google Scholar 

  • Xu Y, Zhu JY, Lei ZM, Wan LJ, Zhu XW, Ye F, Tong YY (2017) Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3. J Physiol Biochem 73(2):157–165

    Article  CAS  Google Scholar 

  • Yin J, Wu N, Zeng F, Cheng C, Kang K, Yang H (2013) Paeonol induces apoptosis in human ovarian cancer cells. Acta Histochem 115(8):835–839

    Article  CAS  Google Scholar 

  • Zhang L, Tao L, Shi T, Zhang F, Sheng X, Cao Y, Zheng S, Wang A, Qian W, Jiang L, Lu Y (2015) Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-kappaB and STAT3 pathways. IUBMB Life 67(10):778–788

    Article  CAS  Google Scholar 

  • Zhang L, Chen Z, Gong W, Zou Y, Xu F, Chen L, Huang H (2018) Paeonol ameliorates diabetic renal fibrosis through promoting the activation of the Nrf2/ARE pathway via up-regulating Sirt1. Front Pharmacol 9:512

    Article  Google Scholar 

  • Zhou HM, Sun QX, Cheng Y (2017) Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor. Exp Ther Med 14(4):3213–3220

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the Guangdong Natural Science Foundation (No. 2018A030313084), Administration of Traditional Chinese Medicine of Guangdong Province of China (20191187), the Public Service Platform Open Project Fund of South China Sea for R&D Marine Biomedicine Resources (2HC18010), and Project of Educational Commission of Guangdong Province (4SG20124G & 4SG20126G) and Fund of Guangdong Medical University (GDMUZ2020005).

Author information

Author notes

  1. Jikun Du, Daibo Song, Jinwen Li and Yuanhua Li contributed equally to this work.

Authors and Affiliations

  1. Dongguan Scientific Research Center, Department of Pharmacology, Guangdong Medical University, Dongguan, China

    Daibo Song, Jinwen Li, Yuanhua Li, Baohong Li & Li Li

  2. Central Research Laboratory, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, The Second People’s Hospital of Bao’an Shenzhen (Group), Shajing People’s Hospital of Bao’an Shenzhen, Shenzhen, China

    Jikun Du

Authors
  1. Jikun Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daibo Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinwen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuanhua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Baohong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Li Li and Baohong Li generated the idea. Li Li and Jikun Du designed the project. Daibo Song, Jinwen Li, and Li Li performed the experiments. Li Li and Yuanhua Li analyzed the data. Jikun Du and Li Li wrote the manuscript.

Corresponding author

Correspondence to Li Li.

Ethics declarations

Ethical Statement

This work does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare no conflict of interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, J., Song, D., Li, J. et al. Paeonol triggers apoptosis in HeLa cervical cancer cells: the role of mitochondria-related caspase pathway. Psychopharmacology 239, 2083–2092 (2022). https://doi.org/10.1007/s00213-021-05811-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-021-05811-0

Keywords

Search

Navigation