Download PDF
Drug Res (Stuttg) 2020; 70(11): 512-518
DOI: 10.1055/a-1201-2602
Original Article

The Inhibitory Effect of Curcumin on Hypoxia Inducer Factors (Hifs) as a Regulatory Factor in the Growth of Tumor Cells in Breast Cancer Stem-Like Cells

Mehrnaz Asadi Sarighieh
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Vahideh Montazeri
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Amir Shadboorestan
2   Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
,
Mohammad Hossein Ghahremani
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
,
Seyed Nasser Ostad
1   Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
› Author Affiliations Funding: This project was supported by grant number 93-04-33-27666 from Deputy of Research Tehran University of Medical Sciences.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Hypoxia in the microenvironment is related to chemotherapy resistance, tumor progression, and metastasis. Curcumin, as a phenolic compound extracted from the turmeric, has been used as an anti-cancer agent with low toxicity in recent years. Since curcumin has inhibitory activities against hypoxia-inducible factors (HIFs) in several cancers, this study was conducted to examine the effect of curcumin on MCF-7 cells and cancer stem-like cells (CS-LCs) under hypoxic and normoxic conditions. CS-LCs were isolated from MCF-7 cells using the magnet activated cell sorting (MACS) method based on CD44 +/ CD24 - surface markers. The effects of curcumin on the viability of MCF-7 cells and CS-LCs were examined in hypoxic and normoxic conditions using the MTT test. The effects of curcumin on apoptosis and cell cycle of CS-LCs and MCF-7 cells were analyzed using flow cytometry. Moreover, the inhibitory effects of curcumin on the levels of HIF-1 and HIF-2α protein in CS-LCs were investigated using the western blot method. Early apoptosis occurred in CSC-LCs more than MCF-7 cells under hypoxic conditions. Flow cytometry assay showed that curcumin caused cell cycle arrest of CSC-LCs and MCF-7 at the G2/M phase under hypoxic conditions while under normoxic conditions, arrest occurred at the G0/G1 phase in MCF-7 cells and at S and G2/M phases in CS-LCs. Based on the results, the curcumin inhibited the expression of HIF-1 by degrading ARNT in CS-LCs.

In conclusion, curcumin has inhibitory effects on MCF- 7 cells and CS- LCs and thus may be used as an antitumor agent.

Key words

anticancer drugs - apoptosis - toxicology


Publication History

Received: 27 April 2020

Accepted: 15 June 2020

Article published online:
22 September 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Parks R, Derks M, Bastiaannet E. et al. Breast cancer epidemiology. Breast Cancer Management for Surgeons. Springer; 2018: 19-29
    Google Scholar
  • 2 DeSantis C, Howlader N, Cronin KA. et al. Breast cancer incidence rates in US women are no longer declining. Cancer Epidem Biomar 2011; 20: 733-739
    CrossrefPubMedGoogle Scholar
  • 3 Wahba HA, El-Hadaad HA. Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med 2015; 12: 106
    PubMedGoogle Scholar
  • 4 García-Aranda M, Redondo M. Immunotherapy: A Challenge of Breast Cancer Treatment. Cancers 2019; 11: 1822
    CrossrefPubMedGoogle Scholar
  • 5 Boo L, Ho WY, Ali NM. et al. MiRNA transcriptome profiling of spheroid-enriched cells with cancer stem cell properties in human breast MCF-7 cell line. Int J Biol Sci 2016; 12: 427
    CrossrefPubMedGoogle Scholar
  • 6 Turdo A, Veschi V, Gaggianesi M. et al. Meeting the challenge of targeting cancer stem cells. Front Cell Dev Biol 2019; 7: 16
    CrossrefPubMedGoogle Scholar
  • 7 Smith AG, Macleod KF. Autophagy, cancer stem cells and drug resistance. J Pathol 2019; 247: 708-718
    CrossrefPubMedGoogle Scholar
  • 8 Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013; 501: 328-337
    CrossrefPubMedGoogle Scholar
  • 9 Sankpal UT, Nagaraju GP, Gottipolu SR. et al. Combination of tolfenamic acid and curcumin induces colon cancer cell growth inhibition through modulating specific transcription factors and reactive oxygen species. Oncotarget 2016; 7: 3186
    CrossrefPubMedGoogle Scholar
  • 10 Li W, Ma H, Zhang J. et al. Unraveling the roles of CD44/CD24 and ALDH1 as cancer stem cell markers in tumorigenesis and metastasis. Sci Rep 2017; 7: 13856
    CrossrefPubMedGoogle Scholar
  • 11 Choi H, Chun Y-S, Kim T-Y. et al. HIF-2α enhances β-catenin/TCF-driven transcription by interacting with β-catenin. Cancer Res 2010; 70: 10101-10111
    CrossrefPubMedGoogle Scholar
  • 12 Yu T, Tang B, Sun X. Development of inhibitors targeting hypoxia-inducible factor 1 and 2 for cancer therapy. Yonsei Med J 2017; 58: 489-496
    CrossrefPubMedGoogle Scholar
  • 13 Kocaadam B, Şanlier N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr 2017; 57: 2889-2895
    CrossrefPubMedGoogle Scholar
  • 14 Shadboorestan A, Tarfiei GA, Montazeri H. et al. Invasion and migration of MDA-MB-231 cells are inhibited by block of AhR and NFAT: role of AhR/NFAT1/β4 integrin signaling. J Appl Toxicol 2019; 39: 375-384
    CrossrefPubMedGoogle Scholar
  • 15 Phi LTH, Sari IN, Yang Y-G, et al. Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int 2018; 2018: 5416923
  • 16 Ki J, Shim Y, Song JM. High-content cell death imaging using quantum dot-based TIRF microscopy for the determination of anticancer activity against breast cancer stem cell. J Biophotonics 2017; 10: 118-127
    CrossrefPubMedGoogle Scholar
  • 17 Sajadian S, Vatankhah M, Majdzadeh M. et al. Cell cycle arrest and apoptogenic properties of opium alkaloids noscapine and papaverine on breast cancer stem cells. Toxicol Mech Method 2015; 25: 388-395
    CrossrefPubMedGoogle Scholar
  • 18 Cui J, Hollmén M, Li L. et al. New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate. Oncotarget 2017; 8: 1007
    CrossrefPubMedGoogle Scholar
  • 19 Wang L, He Y, Wu L. et al. Isolation and characterization of human breast tumor stem cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2012; 28: 1261-1264
    PubMedGoogle Scholar
  • 20 Hatcher H, Planalp R, Cho J. et al. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 2008; 65: 1631-1652
    CrossrefPubMedGoogle Scholar
  • 21 Dhillon N, Wolff R, Abbruzzese J. et al. Phase II clinical trial of curcumin in patients with advanced pancreatic cancer. J Clin Oncol 2006; 24: 14151-14151
    CrossrefPubMedGoogle Scholar
  • 22 Liu L-d, Pang Y-x, Zhao X-r. et al. Curcumin induces apoptotic cell death and protective autophagy by inhibiting AKT/mTOR/p70S6K pathway in human ovarian cancer cells. Arch Gynecol Obstet 2019; 299: 1627-1639
    CrossrefPubMedGoogle Scholar
  • 23 Anitha A, Deepa N, Chennazhi K. et al. Combinatorial anticancer effects of curcumin and 5-fluorouracil loaded thiolated chitosan nanoparticles towards colon cancer treatment. Biochim Biophys Acta 2014; 1840: 2730-2743
    CrossrefPubMedGoogle Scholar
  • 24 Zhu Y, Bu S Curcumin induces autophagy, apoptosis, and cell cycle arrest in human pancreatic cancer cells. Evid Based Complement Alternat Med 2017; 2017: 5787218
  • 25 Shankar S, Srivastava RK. Involvement of Bcl-2 family members, phosphatidylinositol 3′-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer. Int J Oncol 2007; 30: 905-918
    PubMedGoogle Scholar
  • 26 Zhao G, Han X, Zheng S. et al. Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells. Oncol Rep 2016; 35: 1065-1074
    CrossrefPubMedGoogle Scholar
  • 27 Harris AL. Hypoxia−a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38
    CrossrefPubMedGoogle Scholar
  • 28 Anderson TMR, Peacock DL, Daniel AR. et al. Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression. Cancer Res 2013; 73: 5810-5820
    CrossrefPubMedGoogle Scholar
  • 29 Xing Y, Mi C, Wang Z. et al. Fraxinellone has anticancer activity in vivo by inhibiting programmed cell death-ligand 1 expression by reducing hypoxia-inducible factor-1α and STAT3. Pharmacol Res 2018; 135: 166-180
    CrossrefPubMedGoogle Scholar
  • 30 Ströfer M, Jelkmann W, Depping R. Curcumin decreases survival of Hep3B liver and MCF-7 breast cancer cells. Strahlenther Onkol 2011; 187: 393-400
    CrossrefPubMedGoogle Scholar