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Vol. 64 No. 10: Issue 10

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Artesunate and chloroquine induce cytotoxic activity on cholangiocarcinoma cells via different cell death mechanisms

https://doi.org/10.14715/cmb/2018.64.10.18
Diwakar Guragain
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Wunchana Seubwai
Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Daiki Kobayashi
Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Atit Silsinivanit
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Kulthida Vaeteewoottacharn
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Kanlayanee Sawanyawisuth
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Chaisiri Wongkham
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Sopit Wongkham
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Norie Araki
Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Ubon Cha'on
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand

Corresponding Author(s) : Ubon Cha'on

ubocha@kku.ac.th

Cellular and Molecular Biology, Vol. 64 No. 10: Issue 10

Abstract

Chemotherapy for cholangiocarcinoma (CCA) is not quite successful. In this study, we revisited the possibility of artesunate (ART) and chloroquine (CQ), the antimalarial drugs, as therapeutic agents against CCA. The possible mechanisms of these drugs to exert cytotoxicity on CCA cells were also explored. The effects of ART and CQ on proliferation and death patterns of two CCA cell lines, KKU-214 and its highly metastatic subtype KKU-214L5, were examined using water soluble tetrazolium (WST) assay and time-lapse photometry, respectively. To differentiate and verify the death patterns between necrosis and apoptosis, lactate dehydrogenase (LDH) release, and caspase 3 activity were measured. CellROXTM green reagent staining method was used to assess reactive oxygen species (ROS) production in ART- and CQ-treated cells. ART and CQ significantly inhibited proliferation of CCA cells. Both drugs kill malarial parasites via similar mechanism depending on ROS formation, however, ART induced necrotic cell death and CQ induced apoptotic cell death in CCA cells. ART induced LDH release, whereas CQ activated caspase 3, confirming induction of necrotic and apoptotic cell deaths by ART and CQ, respectively. ART treatment induced higher ROS production than CQ. ART and CQ induce CCA cells death via different death pathways. ART should be suitable for necrosis-sensitive CCA, whereas CQ is more suitable for apoptosis-sensitive CCA.

Keywords

Artesunate Chloroquine Cholangiocarcinoma Necrosis Apoptosis.
Guragain, D., Seubwai, W., Kobayashi, D., Silsinivanit, A., Vaeteewoottacharn, K., Sawanyawisuth, K., Wongkham, C., Wongkham, S., Araki, N., & Cha’on, U. (2018). Artesunate and chloroquine induce cytotoxic activity on cholangiocarcinoma cells via different cell death mechanisms. Cellular and Molecular Biology, 64(10), 113–118. https://doi.org/10.14715/cmb/2018.64.10.18
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References
  1. Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastroenterol May 2008; 24(3): 349-356.
  2. Pairojkul C, Shirai T, Hirohashi S et al. Multistage carcinogenesis of liver-fluke-associated cholangiocarcinoma in Thailand. Princess Takamatsu Symp 1991; 22: 77-86.
  3. Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol Jan 2013; 11(1): 13-21 e11; quiz e13-14.
  4. Gatto M, Bragazzi MC, Semeraro R et al. Cholangiocarcinoma: update and future perspectives. Dig Liver Dis Apr 2010; 42(4): 253-260.
  5. Luvira V, Nilprapha K, Bhudhisawasdi V, Pugkhem A, Chamadol N, Kamsa-ard S. Cholangiocarcinoma patient outcome in Northeastern Thailand: single-center prospective study. Asian Pac J Cancer Prev 2016; 17(1): 401-406.
  6. Gupta SC, Sung B, Prasad S, Webb LJ, Aggarwal BB. Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci Sep 2013; 34(9): 508-517.
  7. Manara MC, Garofalo C, Ferrari S, Belfiore A, Scotlandi K. Designing novel therapies against sarcomas in the era of personalized medicine and economic crisis. Curr Pharm Des 2013; 19(30): 5344-5361.
  8. Meshnick SR. Artemisinin antimalarials: mechanisms of action and resistance. Med Trop (Mars) 1998; 58(3 Suppl): 13-17.
  9. Cumming JN, Ploypradith P, Posner GH. Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Adv Pharmacol 1997; 37: 253-297.
  10. Krogstad DJ, Schlesinger PH. The basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH. Am J Trop Med Hyg Mar 1987; 36(2): 213-220.
  11. Schlesinger PH, Krogstad DJ, Herwaldt BL. Antimalarial agents: mechanisms of action. Antimicrob Agents Chemother Jun 1988; 32(6): 793-798.
  12. Ch'ng JH, Liew K, Goh AS, Sidhartha E, Tan KS. Drug-induced permeabilization of parasite's digestive vacuole is a key trigger of programmed cell death in Plasmodium falciparum. Cell Death Dis Oct 13 2011; 2: e216.
  13. Coronado LM, Nadovich CT, Spadafora C. Malarial hemozoin: from target to tool. Biochim Biophys Acta Jun 2014; 1840(6): 2032-2041.
  14. Saentaweesuk W, Araki N, Vaeteewoottacharn K et al. Activation of vimentin is critical to promote a metastatic potential of cholangiocarcinoma cells. Oncol Res Jul 25 2017.
  15. Zong WX, Thompson CB. Necrotic death as a cell fate. Gene Dev Jan 1 2006; 20(1): 1-15.
  16. Saraste A, Pulkki K. Morphologic and biochemical hallmarks of apoptosis. Cardiovasc Res Feb 2000; 45(3): 528-537.
  17. Chan FK, Moriwaki K, De Rosa MJ. Detection of necrosis by release of lactate dehydrogenase activity. Methods Mol Biol 2013; 979: 65-70.
  18. Maes M, Vanhaecke T, Cogliati B et al. Measurement of apoptotic and necrotic cell death in primary hepatocyte cultures. Methods Mol Biol 2015; 1250: 349-361.
  19. Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999; 15: 269-290.
  20. Chaijaroenkul W, Viyanant V, Mahavorasirikul W, Na-Bangchang K. Cytotoxic activity of artemisinin derivatives against cholangiocarcinoma (CL-6) and hepatocarcinoma (Hep-G2) cell lines. Asian Pac J Cancer Prev 2011; 12(1): 55-59.
  21. Xu Q, Li ZX, Peng HQ et al. Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ Sci B Apr 2011; 12(4): 247-255.
  22. Jinawath N, Chamgramol Y, Furukawa Y et al. Comparison of gene expression profiles between Opisthorchis viverrini and non-Opisthorchis viverrini associated human intrahepatic cholangiocarcinoma. Hepatology Oct 2006; 44(4): 1025-1038.
  23. Jusakul A, Cutcutache I, Yong CH et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov Oct 2017; 7(10): 1116-1135.
  24. Jiang PD, Zhao YL, Shi W et al. Cell growth inhibition, G2/M cell cycle arrest, and apoptosis induced by chloroquine in human breast cancer cell line Bcap-37. Cell Physiol Biochem 2008; 22(5-6): 431-440.
  25. Zheng Y, Zhao YL, Deng X et al. Chloroquine inhibits colon cancer cell growth in vitro and tumor growth in vivo via induction of apoptosis. Cancer Invest Mar 2009; 27(3): 286-292.
  26. Rahim R, Strobl JS. Hydroxychloroquine, chloroquine, and all-trans retinoic acid regulate growth, survival, and histone acetylation in breast cancer cells. Anticancer Drugs Sep 2009; 20(8): 736-745.
  27. Fan C, Wang W, Zhao B, Zhang S, Miao J. Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells. Bioorg Med Chem May 1 2006; 14(9): 3218-3222.
  28. Thongchot S, Loilome W, Yongvanit P et al. Chloroquine exerts anti-metastatic activities under hypoxic conditions in cholangiocarcinoma cells. Asian Pac J Cancer Prev 2015; 16(5): 2031-2035.
  29. Button RW, Lin F, Ercolano E et al. Artesunate induces necrotic cell death in schwannoma cells. Cell Death Dis Oct 16 2014; 5: e1466.
  30. Alcantara DD, Ribeiro HF, Cardoso PC et al. In vitro evaluation of the cytotoxic and genotoxic effects of artemether, an antimalarial drug, in a gastric cancer cell line (PG100). J Appl Toxicol Feb 2013; 33(2): 151-156.
  31. Efferth T, Rucker G, Falkenberg M et al. Detection of apoptosis in KG-1a leukemic cells treated with investigational drugs. Arzneimittelforschung Feb 1996; 46(2): 196-200.
  32. Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2015; 2(5): 517-532.
  33. Masud Alam M, Kariya R, Kawaguchi A, Matsuda K, Kudo E, Okada S. Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress. Apoptosis Oct 2016; 21(10): 1191-1201.
  34. Weir GM, Liwski RS, Mansour M. Immune modulation by chemotherapy or immunotherapy to enhance cancer vaccines. Cancers (Basel) Aug 5 2011; 3(3): 3114-3142.
  35. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer Mar 22 2012; 12(4): 237-251.
  36. Zhang J, Lou X, Jin L et al. Necrosis, and then stress induced necrosis-like cell death, but not apoptosis, should be the preferred cell death mode for chemotherapy: clearance of a few misconceptions. Oncoscience 2014; 1(6): 407-422.
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