Skip to main content

Advertisement

SpringerLink
Log in

Curcumin analog EF24 induces apoptosis via ROS-dependent mitochondrial dysfunction in human colorectal cancer cells

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Colorectal cancer is the most commonly diagnosed malignancy with high mortality rates worldwide. Improved therapeutic strategies with minimal adverse side effects are urgently needed. In this study, the anti-tumor effects of EF24, a novel analog of the natural compound curcumin, were evaluated in colorectal cancer cells.

Methods

The anti-tumor activity of EF24 on human colon cancer lines (HCT-116, SW-620, and HT-29) was determined by measures of cell cycle arrest, apoptosis, and mitochondrial function. The contribution of ROS in the EF24-induced anti-tumor activity was evaluated by measures of H2O2 and pretreatment with an ROS scavenger, NAC.

Results

The findings indicated that EF24 treatment dose-dependently inhibited cell viability and caused cell cycle arrest at G2/M phase in all the tested colon cancer cell lines. Furthermore, we demonstrated that EF24 treatment induced apoptosis effectively via enhancing intracellular accumulation of ROS in both HCT-116 and SW-620 cells, but with moderate effects in HT-29 cells. We found that EF24 treatment decreased the mitochondrial membrane potential in the colon cancer cells, leading to the release of mitochondrial cytochrome c. Also, EF24 induced activation of caspases 9 and 3, causing decreased Bcl-2 protein expression and Bcl-2/Bax ratio. Pretreatment with NAC, a ROS scavenger, abrogated the EF24-induced cell death, apoptosis, cell cycle arrest, and mitochondrial dysfunction, suggesting an upstream ROS generation which was responsible for the anticancer effects of EF24.

Conclusions

Our findings support an anticancer mechanism by which EF24 enhanced ROS accumulation in colon cancer cells, thereby resulting in mitochondrial membrane collapse and activated intrinsic apoptotic signaling. Thus, EF24 could be a potential candidate for therapeutic application of colon 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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108. doi:10.3322/caac.21262

    Article  PubMed  Google Scholar 

  2. Ciombor KK, Wu C, Goldberg RM (2015) Recent therapeutic advances in the treatment of colorectal cancer. Annu Rev Med 66:83–95. doi:10.1146/annurev-med-051513-102539

    Article  CAS  PubMed  Google Scholar 

  3. Wilken R, Veena MS, Wang MB, Srivatsan ES (2011) Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer 10:12. doi:10.1186/1476-4598-10-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Geng C, Li J, Ding F, Wu G, Yang Q, Sun Y, Zhang Z, Dong T, Tian X (2016) Curcumin suppresses 4-hydroxytamoxifen resistance in breast cancer cells by targeting SLUG/Hexokinase 2 pathway. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2016.03.067

    Google Scholar 

  5. Ye M, Zhang J, Miao Q, Yao L (2015) Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer. Cancer Lett 357(1):196–205. doi:10.1016/j.canlet.2014.11.028

    Article  CAS  PubMed  Google Scholar 

  6. Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, Marczylo TH, Morgan B, Hemingway D, Plummer SM, Pirmohamed M, Gescher AJ, Steward WP (2004) Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 10(20):6847–6854. doi:10.1158/1078-0432.CCR-04-0744

    Article  CAS  PubMed  Google Scholar 

  7. Zhang P, Bai H, Liu G, Wang H, Chen F, Zhang B, Zeng P, Wu C, Peng C, Huang C, Song Y, Song E (2015) MicroRNA-33b, upregulated by EF24, a curcumin analog, suppresses the epithelial-to-mesenchymal transition (EMT) and migratory potential of melanoma cells by targeting HMGA2. Toxicol Lett 234(3):151–161. doi:10.1016/j.toxlet.2015.02.018

    Article  CAS  PubMed  Google Scholar 

  8. Zhang D, Wang Y, Dong L, Huang Y, Yuan J, Ben W, Yang Y, Ning N, Lu M, Guan Y (2013) Therapeutic role of EF24 targeting glucose transporter 1-mediated metabolism and metastasis in ovarian cancer cells. Cancer Sci 104(12):1690–1696. doi:10.1111/cas.12293

    Article  CAS  PubMed  Google Scholar 

  9. Xiang T, Du L, Pham P, Zhu B, Jiang S (2015) Nelfinavir, an HIV protease inhibitor, induces apoptosis and cell cycle arrest in human cervical cancer cells via the ROS-dependent mitochondrial pathway. Cancer Lett 364(1):79–88. doi:10.1016/j.canlet.2015.04.027

    Article  CAS  PubMed  Google Scholar 

  10. Zou P, Xia Y, Ji J, Chen W, Zhang J, Chen X, Rajamanickam V, Chen G, Wang Z, Chen L, Wang Y, Yang S, Liang G (2016) Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer. Cancer Lett 375(1):114–126. doi:10.1016/j.canlet.2016.02.058

    Article  CAS  PubMed  Google Scholar 

  11. Ling YH, Liebes L, Zou Y, Perez-Soler R (2003) Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. J Biol Chem 278(36):33714–33723. doi:10.1074/jbc.M302559200

    Article  CAS  PubMed  Google Scholar 

  12. Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79(3):629–661. doi:10.1021/acs.jnatprod.5b01055

    Article  CAS  PubMed  Google Scholar 

  13. Yuan X, Zhang B, Gan L, Wang ZH, Yu BC, Liu LL, Zheng QS, Wang ZP (2013) Involvement of the mitochondrion-dependent and the endoplasmic reticulum stress-signaling pathways in isoliquiritigenin-induced apoptosis of HeLa cell. Biomed Environ Sci 26(4):268–276. doi:10.3967/0895-3988.2013.04.005

    CAS  PubMed  Google Scholar 

  14. Acharya A, Das I, Chandhok D, Saha T (2010) Redox regulation in cancer: a double-edged sword with therapeutic potential. Oxid Med Cell Longev 3(1):23–34. doi:10.4161/oxim.3.1.10095

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95. doi:10.1038/nrc2981

    Article  CAS  PubMed  Google Scholar 

  16. Fiskus W, Saba N, Shen M, Ghias M, Liu J, Gupta SD, Chauhan L, Rao R, Gunewardena S, Schorno K, Austin CP, Maddocks K, Byrd J, Melnick A, Huang P, Wiestner A, Bhalla KN (2014) Auranofin induces lethal oxidative and endoplasmic reticulum stress and exerts potent preclinical activity against chronic lymphocytic leukemia. Cancer Res 74(9):2520–2532. doi:10.1158/0008-5472.CAN-13-2033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12(12):931–947. doi:10.1038/nrd4002

    Article  CAS  PubMed  Google Scholar 

  18. Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW (2011) Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475(7355):231–234. doi:10.1038/nature10167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zou P, Chen M, Ji J, Chen W, Chen X, Ying S, Zhang J, Zhang Z, Liu Z, Yang S, Liang G (2015) Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer. Oncotarget 6(34):36505–36521. doi:10.18632/oncotarget.5364

    PubMed  PubMed Central  Google Scholar 

  20. Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL, Xu B, Cassidy J, Darling JL, Wang W (2011) Disulfiram modulated ROS-MAPK and NFkappaB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer 104(10):1564–1574. doi:10.1038/bjc.2011.126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jutooru I, Guthrie AS, Chadalapaka G, Pathi S, Kim K, Burghardt R, Jin UH, Safe S (2014) Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents. Mol Cell Biol 34(13):2382–2395. doi:10.1128/MCB.01602-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gandhy SU, Kim K, Larsen L, Rosengren RJ, Safe S (2012) Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs. BMC Cancer 12:564. doi:10.1186/1471-2407-12-564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chintharlapalli S, Papineni S, Lei P, Pathi S, Safe S (2011) Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer 11:371. doi:10.1186/1471-2407-11-371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jutooru I, Chadalapaka G, Sreevalsan S, Lei P, Barhoumi R, Burghardt R, Safe S (2010) Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth. Exp Cell Res 316(13):2174–2188. doi:10.1016/j.yexcr.2010.04.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chadalapaka G, Jutooru I, Safe S (2012) Celastrol decreases specificity proteins (Sp) and fibroblast growth factor receptor-3 (FGFR3) in bladder cancer cells. Carcinogenesis 33(4):886–894. doi:10.1093/carcin/bgs102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pathi SS, Jutooru I, Chadalapaka G, Sreevalsan S, Anand S, Thatcher GR, Safe S (2011) GT-094, a NO-NSAID, inhibits colon cancer cell growth by activation of a reactive oxygen species-microRNA-27a: ZBTB10-specificity protein pathway. Mol Cancer Res 9(2):195–202. doi:10.1158/1541-7786.MCR-10-0363

    Article  CAS  PubMed  Google Scholar 

  27. Jutooru I, Chadalapaka G, Abdelrahim M, Basha MR, Samudio I, Konopleva M, Andreeff M, Safe S (2010) Methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a. Mol Pharmacol 78(2):226–236. doi:10.1124/mol.110.064451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Harris MH, Thompson CB (2000) The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ 7(12):1182–1191. doi:10.1038/sj.cdd.4400781

    Article  CAS  PubMed  Google Scholar 

  29. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2(9):647–656. doi:10.1038/nrc883

    Article  CAS  PubMed  Google Scholar 

  30. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275(5303):1132–1136

    Article  CAS  PubMed  Google Scholar 

  31. Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30(11):630–641. doi:10.1016/j.tibs.2005.09.005

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Z, Wang H, Li M, Agrawal S, Chen X, Zhang R (2004) MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem 279(16):16000–16006. doi:10.1074/jbc.M312264200

    Article  CAS  PubMed  Google Scholar 

  33. Ando T, Kawabe T, Ohara H, Ducommun B, Itoh M, Okamoto T (2001) Involvement of the interaction between p21 and proliferating cell nuclear antigen for the maintenance of G2/M arrest after DNA damage. J Biol Chem 276(46):42971–42977. doi:10.1074/jbc.M106460200

    Article  CAS  PubMed  Google Scholar 

  34. Hill DS, Martin S, Armstrong JL, Flockhart R, Tonison JJ, Simpson DG, Birch-Machin MA, Redfern CP, Lovat PE (2009) Combining the endoplasmic reticulum stress-inducing agents bortezomib and fenretinide as a novel therapeutic strategy for metastatic melanoma. Clin Cancer Res 15(4):1192–1198. doi:10.1158/1078-0432.CCR-08-2150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang CC, Chiang YM, Sung SC, Hsu YL, Chang JK, Kuo PL (2008) Plumbagin induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human melanoma A375.S2 cells. Cancer Lett 259(1):82–98. doi:10.1016/j.canlet.2007.10.005

    Article  CAS  PubMed  Google Scholar 

  36. Verfaillie T, Garg AD, Agostinis P (2013) Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett 332(2):249–264. doi:10.1016/j.canlet.2010.07.016

    Article  CAS  PubMed  Google Scholar 

  37. Zou P, Zhang J, Xia Y, Kanchana K, Guo G, Chen W, Huang Y, Wang Z, Yang S, Liang G (2015) ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer. Oncotarget 6(8):5860–5876. doi:10.18632/oncotarget.3333

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Professor Hazel Lum from Rush University (Chicago, Illinois) for language editing of the manuscript. The work was supported by National Natural Science Foundation of China (81572448 to H.Z., 81472307 to Y.W., 81560500 to Y.X., and 81160289 to Y.X.).

Author information

Author notes

    Authors and Affiliations

    1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

      Guodong He, Chen Feng, Rajamanickam Vinothkumar, Weiqian Chen, Xuanxuan Dai, Xi Chen, Qingqing Ye, Chenyu Qiu, Yi Wang, Guang Liang & Wei Wu

    2. Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

      Guodong He

    3. Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China

      Guodong He & Yubo Xie

    4. Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

      Huiping Zhou & Wei Wu

    Authors
    1. Guodong He
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Chen Feng
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Rajamanickam Vinothkumar
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Weiqian Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xuanxuan Dai
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Xi Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Qingqing Ye
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Chenyu Qiu
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Huiping Zhou
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Yi Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Guang Liang
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Yubo Xie
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Wei Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Yubo Xie or Wei Wu.

    Ethics declarations

    Conflict of interest

    The authors disclose no potential conflict of interest.

    Additional information

    Guodong He and Chen Feng have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (PDF 767 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    He, G., Feng, C., Vinothkumar, R. et al. Curcumin analog EF24 induces apoptosis via ROS-dependent mitochondrial dysfunction in human colorectal cancer cells. Cancer Chemother Pharmacol 78, 1151–1161 (2016). https://doi.org/10.1007/s00280-016-3172-x

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00280-016-3172-x

    Keywords

    Search

    Navigation