Skip to main content
SpringerLink
Log in

Antimalarial drug artesunate is effective against chemoresistant anaplastic thyroid carcinoma via targeting mitochondrial metabolism

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid malignancies and resistant to chemotherapy. Novel therapeutic strategy is required for better management of ATC. In this work, we show that artesunate, an antimalarial drug, is active against chemoresistant ATC cells. Artesunate dose-dependently inhibits growth and induces apoptosis in chemo-sensitive (8505C and KAT-4) and -resistant (8505C-r and KAT-4-r) ATC cells, and acts synergistically with doxorubicin. Using multiple xenograft mouse models, artesunate is active against chemo-sensitive and -resistant ATC cells in vivo at doses that do not cause toxicity in mice. Our mechanism analysis reveals that artesunate acts on ATC cells through suppressing mitochondrial functions without affecting glycolysis, leading to oxidative stress and damage, regardless of whether they are sensitive or resistant to chemotherapy. Interestingly, KAT-4-r cells demonstrate decreased glycolysis, increased mitochondrial membrane potential and mitochondrial respiration compared to KAT-4 cells whereas such phenomenon is not observed between 8505C and 8505C-r cells. This suggests that some but not all ATC cells gain enhanced mitochondrial biogenesis after prolonged exposure to chemotherapy drug, which may explain the different sensitivities of 8505C-r and KAT-4-r to artesunate. Our work demonstrates that artesunate is a potential addition to the treatment armamentarium for ATC, particularly those with chemoresistance. Our findings also highlight the therapeutic value of targeting mitochondria in chemoresistant ATC.

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

  • Augustin Y, Krishna S, Kumar D, Pantziarka P (2015) The wisdom of crowds and the repurposing of artesunate as an anticancer drug. Ecancermedicalscience 9:ed50

    Article  Google Scholar 

  • Berte N, Lokan S, Eich M, Kim E, Kaina B (2016) Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibition of homologous recombination and senescence. Oncotarget 7:67235–67250

  • Cabanillas ME, Zafereo M, Gunn GB, Ferrarotto R (2016) Anaplastic thyroid carcinoma: treatment in the age of molecular targeted therapy. J Oncol Pract/Am Soc Clin Oncol 12:511–518

    Article  Google Scholar 

  • Cassano P, Sciancalepore AG, Pesce V, Fluck M, Hoppeler H, Calvani M, Mosconi L, Cantatore P, Gadaleta MN (2006) Acetyl-L-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis. Biochim Biophys Acta 1757:1421–1428

    Article  CAS  Google Scholar 

  • de Padua MC, Delodi G, Vucetic M, Durivault J, Vial V, Bayer P, Noleto GR, Mazure NM, Zdralevic M, Pouyssegur J (2017) Disrupting glucose-6-phosphate isomerase fully suppresses the “Warburg effect” and activates OXPHOS with minimal impact on tumor growth except in hypoxia. Oncotarget 8:87623–87637

    Article  Google Scholar 

  • Dell'Eva R, Pfeffer U, Vene R, Anfosso L, Forlani A, Albini A, Efferth T (2004) Inhibition of angiogenesis in vivo and growth of Kaposi's sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol 68:2359–2366

    Article  CAS  Google Scholar 

  • Dong HY, Wang ZF (2014) Antitumor effects of artesunate on human breast carcinoma MCF-7 cells and IGF-IR expression in nude mice xenografts. Chin J Cancer Res 26:200–207

    PubMed  PubMed Central  CAS  Google Scholar 

  • Du JH, Zhang HD, Ma ZJ, Ji KM (2010) Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother Pharmacol 65:895–902

    Article  CAS  Google Scholar 

  • Efferth T, Li PC, Konkimalla VS, Kaina B (2007a) From traditional Chinese medicine to rational cancer therapy. Trends Mol Med 13:353–361

    Article  CAS  Google Scholar 

  • Efferth T, Giaisi M, Merling A, Krammer PH, Li-Weber M (2007b) Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells. PLoS One 2:e693

    Article  CAS  Google Scholar 

  • Gopalakrishnan AM, Kumar N (2015) Antimalarial action of artesunate involves DNA damage mediated by reactive oxygen species. Antimicrob Agents Chemother 59:317–325

    Article  CAS  Google Scholar 

  • Greenshields AL, Shepherd TG, Hoskin DW (2017) Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate. Mol Carcinog 56:75–93

  • Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, Efferth T, Eils R, Brady NR (2011) Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem 286:6587–6601

    Article  CAS  Google Scholar 

  • Ho WE, Peh HY, Chan TK, Wong WS (2014) Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther 142:126–139

    Article  CAS  Google Scholar 

  • Holien T, Olsen OE, Misund K, Hella H, Waage A, Ro TB, Sundan A (2013) Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Eur J Haematol 91:339–346

    PubMed  CAS  Google Scholar 

  • Keutgen XM, Sadowski SM, Kebebew E (2015) Management of anaplastic thyroid cancer. Gland Surg 4:44–51

    PubMed  PubMed Central  Google Scholar 

  • Kim C, Lee JH, Kim SH, Sethi G, Ahn KS (2015) Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model. Oncotarget 6:4020–4035

    PubMed  PubMed Central  Google Scholar 

  • Klayman DL (1985) Qinghaosu (artemisinin): an antimalarial drug from China. Science 228:1049–1055

    Article  CAS  Google Scholar 

  • Kondo T, Ezzat S, Asa SL (2006) Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6:292–306

    Article  CAS  Google Scholar 

  • Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX (2007) Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer 121:1360–1365

    Article  CAS  Google Scholar 

  • Li S, Xue F, Cheng Z, Yang X, Wang S, Geng F, Pan L (2009) Effect of artesunate on inhibiting proliferation and inducing apoptosis of SP2/0 myeloma cells through affecting NFkappaB p65. Int J Hematol 90:513–521

    Article  CAS  Google Scholar 

  • Li Q, Ni W, Deng Z, Liu M, She L, Xie Q (2017) Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress. Fund Clin Pharmacol 31:301–310

    Article  CAS  Google Scholar 

  • Ma L, Cheng Q (2018) Inhibiting 6-phosphogluconate dehydrogenase reverses doxorubicin resistance in anaplastic thyroid cancer via inhibiting NADPH-dependent metabolic reprogramming. Biochem Biophys Res Commun 498:912–917

    Article  CAS  Google Scholar 

  • Meshnick SR, Taylor TE, Kamchonwongpaisan S (1996) Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev 60:301–315

    Article  CAS  Google Scholar 

  • Morita M, Gravel SP, Chenard V, Sikstrom K, Zheng L, Alain T, Gandin V, Avizonis D, Arguello M, Zakaria C, McLaughlan S, Nouet Y, Pause A, Pollak M, Gottlieb E, Larsson O, St-Pierre J, Topisirovic I, Sonenberg N (2013) mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab 18:698–711

    Article  CAS  Google Scholar 

  • Papanikolaou X, Johnson S, Garg T, Tian E, Tytarenko R, Zhang Q, Stein C, Barlogie B, Epstein J, Heuck C (2014) Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis. Oncotarget 5:4118–4128

    Article  Google Scholar 

  • Perri F, Lorenzo GD, Scarpati GD, Buonerba C (2011) Anaplastic thyroid carcinoma: a comprehensive review of current and future therapeutic options. World J Clin Oncol 2:150–157

    Article  Google Scholar 

  • Ramanathan A, Schreiber SL (2009) Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci U S A 106:22229–22232

    Article  Google Scholar 

  • Saiselet M, Floor S, Tarabichi M, Dom G, Hebrant A, van Staveren WC, Maenhaut C (2012) Thyroid cancer cell lines: an overview. Front Endocrinol 3:133

    Article  CAS  Google Scholar 

  • Subedi A, Futamura Y, Nishi M, Ryo A, Watanabe N, Osada H (2016) High-throughput screening identifies artesunate as selective inhibitor of cancer stemness: involvement of mitochondrial metabolism. Biochem Biophys Res Commun 477:737–742

  • Sun Y, Xu H, Chen X, Li X, Luo B (2019) Inhibition of mitochondrial respiration overcomes hepatocellular carcinoma chemoresistance. Biochem Biophys Res Commun 508:626–632

    Article  CAS  Google Scholar 

  • Tai X, Cai XB, Zhang Z, Wei R (2016) In vitro and in vivo inhibition of tumor cell viability by combined dihydroartemisinin and doxorubicin treatment, and the underlying mechanism. Oncol Lett 12:3701–3706

    Article  CAS  Google Scholar 

  • Thanaketpaisarn O, Waiwut P, Sakurai H, Saiki I (2011) Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-kappaB and PI3K/Akt signaling pathways. Int J Oncol 39:279–285

    PubMed  CAS  Google Scholar 

  • Wu GS, Lu JJ, Guo JJ, Huang MQ, Gan L, Chen XP, Wang YT (2013) Synergistic anti-cancer activity of the combination of dihydroartemisinin and doxorubicin in breast cancer cells. Pharmacological Reports : PR 65:453–459

    Article  CAS  Google Scholar 

  • Zdralevic M, Brand A, Di Ianni L, Dettmer K, Reinders J, Singer K, Peter K, Schnell A, Bruss C, Decking SM, Koehl G, Felipe-Abrio B, Durivault J, Bayer P, Evangelista M, O'Brien T, Oefner PJ, Renner K, Pouyssegur J, Kreutz M (2018) Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism. J Biol Chem 293:15947–15961

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a research grant provided by Hubei Province Health and Family Planning Scientific Research Project (Grant No. WJ2018H206).

Author information

Authors and Affiliations

  1. Department of Endocrinology, First Affiliated Hospital, First Clinical Medical College, Yangtze University, Jingzhou, Hubei, 434000, China

    Ling Ma

  2. Department of Endocrinology, People’s Hospital of Rizhao, No.126, Taian Road, Rizhao, 276826, Shandong, China

    Honghua Fei

Authors
  1. Ling Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Honghua Fei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Honghua Fei.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

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

Ma, L., Fei, H. Antimalarial drug artesunate is effective against chemoresistant anaplastic thyroid carcinoma via targeting mitochondrial metabolism. J Bioenerg Biomembr 52, 123–130 (2020). https://doi.org/10.1007/s10863-020-09824-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-020-09824-w

Keywords

Search

Navigation