Skip to main content

Advertisement

SpringerLink
Log in

Inhibiting reactive oxygen species-dependent autophagy enhanced baicalein-induced apoptosis in oral squamous cell carcinoma

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

A Correction to this article was published on 06 October 2020

This article has been updated

Abstract

Autophagy modulation has been considered a potential therapeutic strategy for oral squamous cell carcinoma (OSCC). A previous study confirmed that baicalein might possess significant anti-carcinogenic activity. However, whether baicalein induces autophagy and its role in cell death in OSCC are still unclear. The aim of this study was to investigate the anticancer activity and molecular targets of baicalein in OSCC in vitro. In this study, we found that baicalein induced significant apoptosis in OSCC cells Cal27. In addition to showing apoptosis induction, we also demonstrated baicalein-induced autophagic response in Cal27 cells. Moreover, pharmacologically or genetically blocking autophagy enhanced baicalein-induced apoptosis, indicating the cytoprotective role of autophagy in baicalein-treated Cal27 cells. Importantly, we found that baicalein triggered reactive oxygen species (ROS) generation in Cal27 cells. Furthermore, N-acetyl-cysteine, a ROS scavenger, abrogated the effects of baicalein on ROS-dependent autophagy. Therefore, we found that baicalein increased autophagy through the promotion of ROS signaling pathways in OSCC. These data also suggest that a strategy of blocking ROS-dependent autophagy to enhance the activity of baicalein warrants further attention for the treatment of OSCC.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Change history

  • 06 October 2020

    In the original publication of the article, an incorrect immunofluorescence of GFP-LC3 puncta was included in the Fig. 3a. The correct version of Fig. 3a is provided below.

References

  1. Chi AC, Day TA, Neville BW (2015) Oral cavity and oropharyngeal squamous cell carcinoma—an update. CA Cancer J Clin 65:401–421

    Article  PubMed  Google Scholar 

  2. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C (2015) Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol 33:3235–3242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Han S, Xu W, Wang Z, Qi X, Wang Y, Ni Y, Shen H, Hu Q, Han W (2016) Crosstalk between the HIF-1 and Toll-like receptor/nuclear factor-kappaB pathways in the oral squamous cell carcinoma microenvironment. Oncotarget 7:37773–37789

    PubMed  PubMed Central  Google Scholar 

  4. Singh S, Singh PP, Roberts LR, Sanchez W (2014) Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 11:45–54

    Article  CAS  PubMed  Google Scholar 

  5. Li M, Chen Q, Yu X (2017) Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer. Cancer Res 77:448–458

    Article  CAS  PubMed  Google Scholar 

  6. Liu JC, Hao WR, Hsu YP, Sung LC, Kao PF, Lin CF, Wu AT, Yuan KS, Wu SY (2016) Statins dose-dependently exert a significant chemopreventive effect on colon cancer in patients with chronic obstructive pulmonary disease: a population-based cohort study. Oncotarget 7:65270–65283

    PubMed  Google Scholar 

  7. BoseDasgupta S, Das BB, Sengupta S, Ganguly A, Roy A, Dey S, Tripathi G, Dinda B, Majumder HK (2008) The caspase-independent algorithm of programmed cell death in Leishmania induced by baicalein: the role of LdEndoG, LdFEN-1 and LdTatD as a DNA ‘degradesome’. Cell Death Differ 15:1629–1640

    Article  CAS  PubMed  Google Scholar 

  8. Liu H, Dong Y, Gao Y, Du Z, Wang Y, Cheng P, Chen A, Huang H (2016) The fascinating effects of baicalein on cancer: a review. Int J Mol Sci 17(10):1681

    Article  PubMed Central  Google Scholar 

  9. Cathcart MC, Useckaite Z, Drakeford C, Semik V, Lysaght J, Gately K, O’Byrne KJ, Pidgeon GP (2016) Anti-cancer effects of baicalein in non-small cell lung cancer in vitro and in-vivo. BMC Cancer 16:707

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lovey J, Nie D, Tovari J, Kenessey I, Timar J, Kandouz M, Honn KV (2013) Radiosensitivity of human prostate cancer cells can be modulated by inhibition of 12-lipoxygenase. Cancer Lett 335:495–501

    Article  CAS  PubMed  Google Scholar 

  11. Markaverich BM, Crowley J, Rodriquez M, Shoulars K, Thompson T (2007) Tetrahydrofurandiol stimulation of phospholipase A2, lipoxygenase, and cyclooxygenase gene expression and MCF-7 human breast cancer cell proliferation. Environ Health Perspect 115:1727–1731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chao JI, Su WC, Liu HF (2007) Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT. Mol Cancer Ther 6:3039–3048

    Article  CAS  PubMed  Google Scholar 

  13. Ding L, He S, Sun X (2014) HSP70 desensitizes osteosarcoma cells to baicalein and protects cells from undergoing apoptosis. Apoptosis 19:1269–1280

    Article  CAS  PubMed  Google Scholar 

  14. Staff PO (2015) Correction: baicalein selectively induces apoptosis in activated lymphocytes and ameliorates concanavalin a-induced hepatitis in mice. PLoS One 10:e0117635

    Article  Google Scholar 

  15. Liu B, Jian Z, Li Q, Li K, Wang Z, Liu L, Tang L, Yi X, Wang H, Li C, Gao T (2012) Baicalein protects human melanocytes from H(2)O(2)-induced apoptosis via inhibiting mitochondria-dependent caspase activation and the p38 MAPK pathway. Free Radic Biol Med 53:183–193

    Article  CAS  PubMed  Google Scholar 

  16. Yang ZJ, Chee CE, Huang S, Sinicrope FA (2011) The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 10:1533–1541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sheng R, Qin ZH (2015) The divergent roles of autophagy in ischemia and preconditioning. Acta Pharmacol Sin 36:411–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7:961–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pi H, Xu S, Zhang L, Guo P, Li Y, Xie J, Tian L, He M, Lu Y, Li M, Zhang Y, Zhong M, Xiang Y, Deng L, Zhou Z, Yu Z (2013) Dynamin 1-like-dependent mitochondrial fission initiates overactive mitophagy in the hepatotoxicity of cadmium. Autophagy 9:1780–1800

    Article  CAS  PubMed  Google Scholar 

  20. Pi H, Xu S, Reiter RJ, Guo P, Zhang L, Li Y, Li M, Cao Z, Tian L, Xie J, Zhang R, He M, Lu Y, Liu C, Duan W, Yu Z, Zhou Z (2015) SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy 11:1037–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li M, Pi H, Yang Z, Reiter RJ, Xu S, Chen X, Chen C, Zhang L, Yang M, Li Y, Guo P, Li G, Tu M, Tian L, Xie J, He M, Lu Y, Zhong M, Zhang Y, Yu Z, Zhou Z (2016) Melatonin antagonizes cadmium-induced neurotoxicity by activating the transcription factor EB-dependent autophagy-lysosome machinery in mouse neuroblastoma cells. J Pineal Res 61:353–369

    Article  CAS  PubMed  Google Scholar 

  22. Delaney JR, Patel C, McCabe KE, Lu D, Davis MA, Tancioni I, von Schalscha T, Bartakova A, Haft C, Schlaepfer DD, Stupack DG (2015) A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer. Oncotarget 6:31104–31118

    PubMed  PubMed Central  Google Scholar 

  23. He Z, Agostini M, Liu H, Melino G, Simon HU (2015) p73 regulates basal and starvation-induced liver metabolism in vivo. Oncotarget 6:33178–33190

    PubMed  PubMed Central  Google Scholar 

  24. Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, van de Vosse E, Wijmenga C, van Crevel R, Oosterwijk E, Grotenhuis AJ, Vermeulen SH, Kiemeney LA, van de Veerdonk FL, Chamilos G, Xavier RJ, van der Meer JW, Netea MG, Joosten LA (2014) Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog 10:e1004485

    Article  PubMed  PubMed Central  Google Scholar 

  25. Albini A, DeCensi A, Cavalli F, Costa A (2016) Cancer prevention and interception: a new era for chemopreventive approaches. Clin Cancer Res 22:4322–4327

    Article  CAS  PubMed  Google Scholar 

  26. White E, DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 15:5308–5316

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang D, Wang W, Sun X, Xu D, Wang C, Zhang Q, Wang H, Luo W, Chen Y, Chen H, Liu Z (2016) AMPK regulates autophagy by phosphorylating BECN1 at Threonine 388. Autophagy 12:1447–1459

    Article  CAS  PubMed  Google Scholar 

  28. Takahashi Y, Meyerkord CL, Wang HG (2009) Bif-1/endophilin B1: a candidate for crescent driving force in autophagy. Cell Death Differ 16:947–955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qin W, Li C, Zheng W, Guo Q, Zhang Y, Kang M, Zhang B, Yang B, Li B, Yang H, Wu Y (2015) Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells. Oncotarget 6:39839–39854

    PubMed  PubMed Central  Google Scholar 

  30. Kaminskyy VO, Zhivotovsky B (2014) Free radicals in cross talk between autophagy and apoptosis. Antioxid Redox Signal 21:86–102

    Article  CAS  PubMed  Google Scholar 

  31. Radogna F, Cerella C, Gaigneaux A, Christov C, Dicato M, Diederich M (2016) Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma. Oncogene 35:3839–3853

    Article  CAS  PubMed  Google Scholar 

  32. Wang Z, Jiang C, Chen W, Zhang G, Luo D, Cao Y, Wu J, Ding Y, Liu B (2014) Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. Biomed Res Int 2014:732516

    PubMed  PubMed Central  Google Scholar 

  33. Hung KC, Huang HJ, Wang YT, Lin AM (2016) Baicalein attenuates alpha-synuclein aggregation, inflammasome activation and autophagy in the MPP+-treated nigrostriatal dopaminergic system in vivo. J Ethnopharmacol 194:522–529

    Article  CAS  PubMed  Google Scholar 

  34. Choi EO, Park C, Hwang HJ, Hong SH, Kim GY, Cho EJ, Kim WJ, Choi YH (2016) Baicalein induces apoptosis via ROS-dependent activation of caspases in human bladder cancer 5637 cells. Int J Oncol 49:1009–1018

    PubMed  Google Scholar 

  35. Chang HT, Chou CT, Kuo DH, Shieh P, Jan CR, Liang WZ (2015) The mechanism of Ca(2+) movement in the involvement of baicalein-induced cytotoxicity in ZR-75-1 human breast cancer cells. J Nat Prod 78:1624–1634

    Article  CAS  PubMed  Google Scholar 

  36. Sato D, Kondo S, Yazawa K, Mukudai Y, Li C, Kamatani T, Katsuta H, Yoshihama Y, Shirota T, Shintani S (2013) The potential anticancer activity of extracts derived from the roots of Scutellaria baicalensis on human oral squamous cell carcinoma cells. Mol Clin Oncol 1:105–111

    PubMed  Google Scholar 

  37. Shao BZ, Han BZ, Zeng YX, Su DF, Liu C (2016) The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol Sin 37:150–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Copetti T, Bertoli C, Dalla E, Demarchi F, Schneider C (2009) p65/RelA modulates BECN1 transcription and autophagy. Mol Cell Biol 29:2594–2608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fan TF, Bu LL, Wang WM, Ma SR, Liu JF, Deng WW, Mao L, Yu GT, Huang CF, Liu B, Zhang WF, Sun ZJ (2015) Tumor growth suppression by inhibiting both autophagy and STAT3 signaling in HNSCC. Oncotarget 6:43581–43593

    PubMed  PubMed Central  Google Scholar 

  40. Liu A, Huang L, Guo E, Li R, Yang J, Li A, Yang Y, Liu S, Hu J, Jiang X, Dirsch O, Dahmen U, Sun J (2016) Baicalein pretreatment reduces liver ischemia/reperfusion injury via induction of autophagy in rats. Sci Rep 6:25042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fan TF, Wu TF, Bu LL, Ma SR, Li YC, Mao L, Sun ZJ, Zhang WF (2016) Dihydromyricetin promotes autophagy and apoptosis through ROS-STAT3 signaling in head and neck squamous cell carcinoma. Oncotarget 7:59691–59703

    PubMed  Google Scholar 

  42. Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36:30–38

    Article  CAS  PubMed  Google Scholar 

  43. Lightfoot AP, McArdle A, Jackson MJ, Cooper RG (2015) In the idiopathic inflammatory myopathies (IIM), do reactive oxygen species (ROS) contribute to muscle weakness? Ann Rheum Dis 74:1340–1346

    Article  CAS  PubMed  Google Scholar 

  44. Ren G, Sha T, Guo J, Li W, Lu J, Chen X (2015) Cucurbitacin B induces DNA damage and autophagy mediated by reactive oxygen species (ROS) in MCF-7 breast cancer cells. J Nat Med 69:522–530

    Article  CAS  PubMed  Google Scholar 

  45. Qi Z, Yin F, Lu L, Shen L, Qi S, Lan L, Luo L, Yin Z (2013) Baicalein reduces lipopolysaccharide-induced inflammation via suppressing JAK/STATs activation and ROS production. Inflamm Res 62:845–855

    Article  CAS  PubMed  Google Scholar 

  46. Naveenkumar C, Raghunandhakumar S, Asokkumar S, Devaki T (2013) Baicalein abrogates reactive oxygen species (ROS)-mediated mitochondrial dysfunction during experimental pulmonary carcinogenesis in vivo. Basic Clin Pharmacol Toxicol 112:270–281

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, People’s Republic of China

    Bo Li, Mei Lu, Xin-Xiang Jiang, Meng-Xiong Pan, Jun-Wu Mao & Mei Chen

Authors
  1. Bo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin-Xiang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meng-Xiong Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun-Wu Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mei Chen.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, B., Lu, M., Jiang, XX. et al. Inhibiting reactive oxygen species-dependent autophagy enhanced baicalein-induced apoptosis in oral squamous cell carcinoma. J Nat Med 71, 433–441 (2017). https://doi.org/10.1007/s11418-017-1076-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-017-1076-7

Keywords

Search

Navigation