Review Article

Is Artesunate the Best Partner of Gemcitabine in Pancreatic Cancer?

Tomas Koltai
Hospital del Centro Gallego de Buenos Aires, Argentina
* Corresponding author
DOI icon 10.24018/clinicmed.2022.3.3.202

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Submitted 2022-04-19
Published 2022-05-20

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Article Main Content

Pancreatic adenocarcinoma (PDAC) is still one of the most malignant and difficult to treat cancers. The therapeutic protocols in use, such as gemcitabine, gemcitabine associated with nab-paclitaxel and/or cisplatin or the FOLFIRINOX scheme have added very little to PDAC outcome. It is clear by now, that none of them can do the job alone. The more than 3,300 trials registered in clinicaltrials.gov is the best proof that research has not yet found an adequate response to tackle this disease. Thus, an innovative search is badly needed. As part of this investigation we came across a phytotherapeutic product that has been very successful for the treatment of falciparum- and vivax- caused malaria: artemisinin derivatives. These derivatives showed very low toxicity for humans and have been tested in millions of patients with paludism.

Interestingly, they have also shown important anti-cancer properties. Regarding PDAC in particular there is strong evidence supporting not only an additive effect to gemcitabine without a concomitant increase in human toxicity, but also decreased resistance. This mini-review will discuss the evidence showing that artemisinin derivatives can be the best possible association with gemcitabine for PDAC chemotherapeutic treatment.

Keywords: Artemisisnin, artesunate,dihydroartemisin, pancreatic cancer, ferroptosis, PDAC

References

  1. Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World Journal of Oncology. 2019; 10(1): 10.
     Google Scholar
  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018; 68(6): 394-424.
     Google Scholar
  3. Klein AP. Pancreatic cancer: a growing burden. The Lancet Gastroenterology & Hepatology. 2019; 4(12): 895-6.
     Google Scholar
  4. Burris H, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology. 1997: 15(6): 2403-2413.
     Google Scholar
  5. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New England Journal of Medicine. 2011; 364(19): 1817-25.
     Google Scholar
  6. Cindy H. Lasker Award Rekindles Debate Over Artemisinin's Discovery. Science. 2011.
     Google Scholar
  7. Miller LH, Su, X. Artemisinin: Discovery from the Chinese herbal garden. Cell. 2011; 146(6): 855–858.
     Google Scholar
  8. Jianfang Z. A detailed chronological record of project 523 and the discovery and development of qinghaosu (artemisinin). Strategic Book Publishing; 2013.
     Google Scholar
  9. Shang A, Huwiler K, Nartey L, Jüni P, Egger M. Placebo-controlled trials of Chinese herbal medicine and conventional medicine comparative study. Int J Epidemiol. 2007; 36(5): 1086-92.
     Google Scholar
  10. Tu, Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med 2011; 17: 1217–1220.
     Google Scholar
  11. Meshnick SR, Taylor TE, Kamchonwongpaisan S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiological Reviews. 1996; 60(2): 301-15.
     Google Scholar
  12. WHO guidelines for the treatment of malaria. World Health Organization. Third Edition. [Internet] 2015. Available from: https://apps.who.int/iris/handle/10665/162441
     Google Scholar
  13. WHO Guidelines for malaria. [Internet] 2022. Available from: https://www.who.int/publications/i/item/guidelines-for-malaria accessed April 4 2022.
     Google Scholar
  14. van Agtmael M, Eggelte TA, van Boxtel CJ. Artemisinin drugs in the treatment of malaria: From medicinal herb to registered medication. Trends Pharmacol Sci. 1999; 20(5): 199–205.
     Google Scholar
  15. Nair MS, Basile DV. Bioconversion of arteannuin B to artemisinin. Journal of Natural Products. 1993; 56(9): 1559-66.
     Google Scholar
  16. Chaturvedi D, Goswami A, Saikia PP, Barua NC, Rao PG. Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents. Chemical Society Reviews. 2010; 39(2): 435-54.
     Google Scholar
  17. Ellis DS, Li ZL, Gu HM, Peters W, Robinson BL, Tovey G, et al. The chemotherapy of rodent malaria, XXXIX: Ultrastructural changes following treatment with artemisinine of Plasmodium berghei infection in mice, with observations of the localization of [3H]-dihydroartemisinine in P. falciparum in vitro. Annals of Tropical Medicine & Parasitology. 1985; 79(4): 367-74.
     Google Scholar
  18. Maeno Y, Toyoshima T, Fujioka H, Ito Y, Meshnick SR, Benakis A, et al. Morphologic effects of artemisinin in Plasmodium falciparum. The American Journal of Tropical Medicine and Hygiene. 1993; 49(4): 485-91.
     Google Scholar
  19. Mercer AE, Maggs JL, Sun XM, Cohen GM, Chadwick J, O’Neill PM, et al. Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds. Journal of Biological Chemistry. 2007; 282(13): 9372-82.
     Google Scholar
  20. Pandey AV, Tekwani BL, Singh RL, Chauhan VS. Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite. J Biol Chem. 1999; 274: 19383.
     Google Scholar
  21. Posner GH, O’Neill PM. Knowledge of the proposed chemical mechanism of action and cytochrome p450 metabolism of antimalarial trioxanes like artemisinin allows rational design of new antimalarial peroxides. Acc. Chem. Res. 2004; 37: 397.
     Google Scholar
  22. Tanaka Y, Kamei K, Otoguro K, Omura S. Heme-dependent radical generation: possible involvement in antimalarial action of non-peroxide microbial metabolites, nanaomycin A and radicicol. J. Antibiot. 1999; 52: 880 –888.
     Google Scholar
  23. Lisewski AM, Quiros JP, Ng CL, Adikesavan AK, Miura K, Putluri N, et al. Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014; 158(4): 916-28.
     Google Scholar
  24. Eckstein-Ludwig U, Webb RJ, Van Goethem IDA, East JM, Lee AG, Kimura M, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003; 424(6951): 957-61.
     Google Scholar
  25. Arnou B, Montigny C, Morth JP, Nissen P, Jaxel C, Moller JV, et al. The Plasmodium falciparum Ca2+-ATPase PfATP6: insensitive to artemisinin, but a potential drug target. Biochem Soc Trans. 2011; 39(3): 823-31.
     Google Scholar
  26. Woerdenbag HJ, Moskal TA, Pras N, Malingré TM, El-Feraly FS, Kampinga HH, et al. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. Journal of Natural Products. 1993; 56(6): 849-56.
     Google Scholar
  27. Krishna S, Bustamante L, Haynes RK, Staines HM. Artemisinins: their growing importance in medicine. Trends in Pharmacological Sciences. 2008; 29(10): 520-7.
     Google Scholar
  28. O’neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin—the debate continues. Molecules. 2010; 15(3): 1705-21.
     Google Scholar
  29. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5): 1060-72.
     Google Scholar
  30. Dixon SJ. Ferroptosis: bug or feature?. Immunological Reviews. 2017; 277(1): 150-7.
     Google Scholar
  31. Lei P, Bai T, Sun Y. Mechanisms of ferroptosis and relations with regulated cell death: a review. Frontiers inPhysiology. 2019; 10: 139.
     Google Scholar
  32. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan V, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014; 156(1-2): 317-31.
     Google Scholar
  33. Kong Z, Liu R, Cheng Y. Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomedicine & Pharmacotherapy. 2019;109: 2043-53.
     Google Scholar
  34. Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. International Journal for Parasitology. 2002; 32(13): 1655-60.
     Google Scholar
  35. Manz DH, Blanchette NL, Paul BT, Torti FM, Torti SV. Iron and cancer: recent insights. Annals of the New York Academy of Sciences. 2016; 1368(1): 149-61.
     Google Scholar
  36. Torti SV, Manz DH, Paul BT, Blanchette-Farra N, Torti FM. Iron and cancer. Annual Review of Nutrition. 2018; 38: 97-125.
     Google Scholar
  37. Lai H, Sasaki T, Singh NP, Messay A. Effects of artemisinin-tagged holotransferrin on cancer cells. Life Sci. 2005; 76(11): 2277-80.
     Google Scholar
  38. Toshiyama R, Konno M, Eguchi H, Asai A, Noda T, Koseki J, et al. Association of iron metabolic enzyme hepcidin expression levels with the prognosis of patients with pancreatic cancer. Oncology Letters. 2018; 15(5): 8125-33.
     Google Scholar
  39. Bhutia YD, Ogura J, Grippo PJ, Torres C, Sato T, Wachtel M, et al. Chronic exposure to excess iron promotes EMT and cancer via p53 loss in pancreatic cancer. Asian Journal of Pharmaceutical Sciences. 2020; 15(2): 237-51.
     Google Scholar
  40. Cheng R, Li C, Li C, Li W, Li L, Zhang Y, et al. The artemisinin derivative artesunate inhibits corneal neovascularization by inducing ROS-dependent apoptosis in vascular endothelial cells. Investigative Ophthalmology & Visual Science. 2013; 54(5): 3400-9.
     Google Scholar
  41. Vandewynckel YP, Laukens D, Geerts A, Vanhoe C, Descamps B, Colle I, et al. Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent. Eur J Gastroenterol Hepatol. 2014; 26(8): 861-70.
     Google Scholar
  42. Saeed ME, Kadioglu O, Seo EJ, Greten HJ, Brenk R, Efferth T. Quantitative structure-activity relationship and molecular docking of artemisinin derivatives to vascular endothelial growth factor receptor 1. Anticancer Res. 2015; 35(4): 1929-34.
     Google Scholar
  43. Da Eun Jeong HJ, Lim S, Lee SJ, Lim JE, Nam D-H, Joo KM, et al. Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis. Oncotarget. 2015; 6(32): 33046.
     Google Scholar
  44. Chen H, Shi L, Yang X, Li S, Guo X, Pan L. Artesunate inhibiting angiogenesis induced by human myeloma RPMI8226 cells. Int J Hematol. 2010; 92(4): 587-97.
     Google Scholar
  45. Zhou HJ, Wang WQ, Wu GD, Lee J, Li A. Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. Vascul Pharmacol. 2007; 47(2-3): 131-8.
     Google Scholar
  46. Chen HH, Zhou HJ, Wu GD, Lou XE. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology. 2004; 71(1): 1-9.
     Google Scholar
  47. Wang J, Zhang B, Guo Y, Li G, Xie Q, Zhu B, et al. Artemisinin Inhibits Tumor Lymphangiogenesis by Suppression of Vascular Endothelial Growth Factor C. Pharmacology. 2008; 82: 148-155.
     Google Scholar
  48. Willoughby Sr JA, Sundar SN, Cheung M, Tin AS, Modiano J, Firestone GL. Artemisinin blocks prostate cancer growth and cell cycle progression by disrupting Sp1 interactions with the cyclin-dependent kinase-4 (CDK4) promoter and inhibiting CDK4 gene expression. Journal of Biological Chemistry. 2009; 284(4): 2203–13.
     Google Scholar
  49. Tin AS, Sundar SN, Tran KQ, Park AH, Poindexter KM, Firestone GL. Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes. Anticancer Drugs. 2012; 23(4): 370-9.
     Google Scholar
  50. Yang YZ, Little B, Meshnick SR. Alkylation of proteins by artemisinin. Effects of heme, pH and drug structure. Biochem Pharmacol. 1994; 48(3): 569-73.
     Google Scholar
  51. Wang Y, Huang ZQ, Wang CQ,Wang L-S, Meng S, Zhang Y-C, et al. Artemisinin inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 expression via a protein kinase Co/p38/extracellular signal regulated kinase pathway in phorbol myristate acetate-induced THP-1 macrophages. Clin Exp Phrmacol Physiol. 2011; 38(1): 11-18.
     Google Scholar
  52. Kolligs FT, Bommer G, Göke B. Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion. 2002; 66(3): 131-44.
     Google Scholar
  53. Heiser PW, Cano DA, Landsman L, Kim GE, Kench JG, Klimstra DS, et al. Stabilization of β-catenin induces pancreas tumor formation. Gastroenterology. 2008; 135(4): 1288-300.
     Google Scholar
  54. Cui J, Jiang W, Wang S, Wang L, Xie K. Role of Wnt/β-catenin signaling in drug resistance of pancreatic cancer. Current Pharmaceutical Design. 2012; 18(17): 2464-71.
     Google Scholar
  55. Hua YQ, Zhang K, Sheng J, Ning Z-Y, Li Y, Shi W-D, et al. Fam83D promotes tumorigenesis and gemcitabine resistance of pancreatic adenocarcinoma through the Wnt/β-catenin pathway. Life Sciences. 2021; 287: 119205.
     Google Scholar
  56. Li LN, Zhang HD, Yuan SJ, Tian Z-Y, Wang Li, Sun Z-X. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/b-catenin pathway. Int. J. Cancer. 2007; 121: 1360–1365.
     Google Scholar
  57. Cui C, Feng H, Shi X, Wang Y, Feng Z, Liu J, et al. Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor β1 and interleukin-10. International Immunopharmacology. 2015; 27(1): 110-21.
     Google Scholar
  58. Odaka Y, Xu B, Luo Y, Shen T, Shang C, Wu Y, et al. Dihydroartemisinin inhibits the mammalian target of rapamycin-mediated signaling pathways in tumor cells. Carcinogenesis. 2014; 35(1): 192-200
     Google Scholar
  59. Li Q, Ni W, Deng Z, Liu M, She L, Xie Q. Targeting nasopharyngeal carcinoma by artesunate through inhibiting Akt/mTOR and inducing oxidative stress. Fundamental & Clinical Pharmacology. 2017; 31(3): 301-10.
     Google Scholar
  60. Li PC, Lam E, Roos WP, Zdzienicka MZ, Kaina B, Efferth T. Artesunate derived from traditional Chinese medicine induces DNA damage and repair. Cancer Research. 2008; 68(11): 4347-51.
     Google Scholar
  61. Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B. Artesunate induces oxidative DNA damage, sustained double-strand breaks, and the ATM/ATR damage response in cancer cells. Mol Cancer Ther. 2011; 10: 2224-2233.
     Google Scholar
  62. Reungpatthanaphong P, Mankhetkorn S. Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines. Biological and Pharmaceutical Bulletin. 2002; 25(12): 1555-61.
     Google Scholar
  63. Efferth T, Sauerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, et al. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol. 2003; 64(2): 382-94.
     Google Scholar
  64. Cheng C, Ho WE, Goh FY, Guan SP, Kong LR, Lai W-Q, et al. Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PLoS One. 2011; 6(6): e20932.
     Google Scholar
  65. Xu H, He Y, Yang X, Liang L, Zhan Z, Ye Y, et al. Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology (Oxford). 2007; 46(6): 920-6.
     Google Scholar
  66. Thanaketpaisarn O, Waiwut P, Sakurai H, Saiki I. Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-κB and PI3K/Akt signaling pathways. International Journal of Oncology. 2011; 39(1): 279-85.
     Google Scholar
  67. Xiao Q, Yang L, Hu H, Ke Y. Artesunate targets oral tongue squamous cell carcinoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/ mTOR inhibition. Journal of Bioenergetics and Biomembranes. 2020; 52(2): 113-21.
     Google Scholar
  68. Chen X, Wong YK, Lim TK, Lim WH, Lin Q, Wang J, et al. Artesunate activates the intrinsic apoptosis of HCT116 cells through the suppression of fatty acid synthesis and the NF-κB pathway. Molecules. 2017; 22(8): 1272.
     Google Scholar
  69. Spiridonov NA, Konovalov DA, Arkhipov VV. Cytotoxicity of some Russian ethnomedicinal plants and plant compounds. Phytother. Res., 2005; 19: 428–432.
     Google Scholar
  70. Woerdenbag HJ, Moskal TA, Pras N, Malingré TM, el-Feraly FS, Kampinga HH, et al. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J Nat Prod. 1993; 56(6): 849-56.
     Google Scholar
  71. Sun WC, Han JX, Yang WY, Deng DA, Yue XF. Antitumor activities of 4 derivatives of artemisic acid and artemisinin B in vitro. Zhongguo Yao Li Xue Bao. 1992; 13(6): 541-3.
     Google Scholar
  72. Zheng GQ. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med. 1994; 60(1): 54-57.
     Google Scholar
  73. Zyad A, Tilaoui M, Jaafari A, Oukerrou MA, Mouse HA. More insights into the pharmacological effects of artemisinin. Phytotherapy Research. 2018; 32(2): 216-29.
     Google Scholar
  74. Nam W, Tak J, Ryu JK, Jung M, Yook J-I, Kim H-J, et al. Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells. Head & Neck. 2007; 29(4): 335-40.
     Google Scholar
  75. Singh NP, Verma KB. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Archive of Oncology. 2002; 10(04): 279-280.
     Google Scholar
  76. Wang Z, Hu W, Zhang J-L, Wu X-H, Zhou H-J. Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity. FEBS Open Bio. 2012; 2: 103-112.
     Google Scholar
  77. Deng DA, Xu CH, Cai JC. Derivatives of arteannuin B with antileukemia activity. Yao Xue Xue Bao. 1992; 27(4): 317-20.
     Google Scholar
  78. Drenberg CD, Buaboonnam J, Orwick SJ, Hu S, Li L, Fan Y, et al. Evaluation of artemisinins for the treatment of acute myeloid leukemia. Cancer Chemother Pharmacol. 2016; 77(6): 1231-43.
     Google Scholar
  79. Fox JM, Moynihan JR, Mott BT, Mazzone JR, Anders NM, Brown PA, et al. Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. Oncotarget. 2016; 7(6): 7268-79.
     Google Scholar
  80. Efferth T, Giaisi M, Merling A, Krammer PH, Li-Weber M. Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells. PloS One. 2007; 2(8): e693.
     Google Scholar
  81. Chen S, Gan S, Han L, Li X, Xie X, Zou D, et al. Artesunate induces apoptosis and inhibits the proliferation, stemness, and tumorigenesis of leukemia. Annals of Translational Medicine. 2020; 8(12).
     Google Scholar
  82. Sieber S, Gdynia G, Roth W, Bonavida B, Efferth T. Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol. 2009; 35(1): 149-58.
     Google Scholar
  83. Våtsveen TK, Myhre MR, Steen CB, Walchli S, Lingjærde OC, Bai B, et al. Artesunate shows potent anti-tumor activity in B-cell lymphoma. Journal of Hematology & Oncology. 2018; 11(1): 1-2.
     Google Scholar
  84. Holien T, Olsen OE, Misund K, Hella H, Waage A, Rø TB, et al. Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. European Journal of Haematology. 2013; 91(4): 339-46.
     Google Scholar
  85. Morrissey C, Gallis B, Solazzi JW, Kim BJ, Gulati R, Vakar-Lopez F, et al. Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells. Anti-Cancer Drugs. 2010; 21(4): 423.
     Google Scholar
  86. Wang Z, Wang C, Wu Z, Xue J, Shen B, Zuo W, et al. Artesunate suppresses the growth of prostatic cancer cells through inhibiting androgen receptor. Biological and Pharmaceutical Bulletin. 2017; 40(4): 479-85.
     Google Scholar
  87. Sundar SN, Marconett CN, Doan VB, Willoughby JA, Firestone GL, Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells. Carcinogenesis. 2008; 29(12): 2252-8.
     Google Scholar
  88. Tin AS, Sundar SN, Tran KQ, Park AH, Poindexter KM, Firestone GL. Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes. Anti-Cancer Drugs. 2012; 23(4): 370-9.
     Google Scholar
  89. Greenshields AL, Fernando W, Hoskin DW. The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells. Exp Mol Pathol. 2019; 107: 10-22.
     Google Scholar
  90. Pirali M, Taheri M, Zarei S, Majidi M, Ghafouri H. Artesunate, as a HSP70 ATPase activity inhibitor, induces apoptosis in breast cancer cells. Int J Biol Macromol. 2020; 164: 3369-3375.
     Google Scholar
  91. Chen W, Qi H, Wu C, Cui Y, Liu B, Li Y, Wu J. Effect of dihydroartemisinin on proliferation of human lung adenocarcinoma cell line A549. Zhonqquo Fei Ai Za Zhi. 2005; 8(2): 85-8.
     Google Scholar
  92. Liao K, Li J, Wang Z. Dihydroartemisinin inhibits cell proliferation via AKT/GSK3β/cyclinD1 pathway and induces apoptosis in A549 lung cancer cells. Int J Clin Exp Pathol. 2014; 7(12): 8684-91.
     Google Scholar
  93. Zhao Y, Jiang W, Li B, Yao Q, Dong J, Cen Y, et al. Artesunate enhances radiosensitivity of human non-small cell lung cancer A549 cells via increasing NO production to induce cell cycle arrest at G2/M phase. Int Immunopharmacol. 2011; 11(12): 2039-46.
     Google Scholar
  94. Ma H, Yao Q, Zhang AM, Lin S, Wang XX, Wu Li, et al. The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model. Molecules. 2011; 16(12): 10556-69.
     Google Scholar
  95. Rasheed SA, Efferth T, Asangani IA, Allgayer H. First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer. 2010; 127(6): 1475-85.
     Google Scholar
  96. Ganguli A, Choudhury D, Datta S, Bhattacharya S, Chakrabart G. Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis. Biochimie. 2014; 107 Pt B: 338-49.
     Google Scholar
  97. Zhang ZY, Yu SQ, Miao LY, Huang XY, Zhang XP, Zhu YP, et al. Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial. Zhong Xi Yi Jie He Xue Bao. 2008; 6(2): 134-8.
     Google Scholar
  98. Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, et al. Artesunate in the treatment of metastatic uveal melanoma-first experiences. Oncol Rep. 2005; 14(6): 1599-603.
     Google Scholar
  99. Buommino E, Baroni A, Canozo N, Petrazzuolo M, Nicoletti R, Vozza A, et al. Artemisinin reduces human melanoma cell migration by down-regulating alpha V beta 3 integrin and reducing metalloproteinase 2 production. Invest New Drugs. 2009; 27(5): 412-8.
     Google Scholar
  100. Cabello CM, Lamore SD, Bair WB 3rd, Qiao S, Azimian S, Lesson JL, et al. The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis. Invest New Drugs. 2012; 30(4): 1289-301.
     Google Scholar
  101. Berköz M, Özkan-Yılmaz F, Özlüer-Hunt A, Krosniak M, Türkmen Ö, Korkmaz D, et al. Artesunate inhibits melanoma progression in vitro via suppressing STAT3 signaling pathway. Pharmacological Reports. 2021; 73(2): 650-63.
     Google Scholar
  102. Geng B, Zhu Y, Yuan Y, Bai J, Dou Z, Sui A, et al. Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis. Frontiers in Oncology. 2021: 3131.
     Google Scholar
  103. Jeong da E, Song HJ, Lim S, Lee SJJ, Lim JE, Nam D-H, et al. Repurposing the anti-malarial drug artesunate as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation of tumor growth, metastasis, and angiogenesis. Oncotarget. 2015; 6(32): 33046-64.
     Google Scholar
  104. Markowitsch SD, Schupp P, Lauckner J, Vakhrusheva O, Slade KS, Mager R, et al. Artesunate inhibits growth of sunitinib-resistant renal cell carcinoma cells through cell cycle arrest and induction of ferroptosis. Cancers. 2020; 12(11): 3150.
     Google Scholar
  105. Juengel E, Markowitsch S, Erb HH, Efferth T, Haferkamp A. Artesunate reduces tumor growth in sunitinb-resistant renal cell carcinoma cells. Cancer Res. 2019; 79(13 Suppl): Abstract nr 3805.
     Google Scholar
  106. Anfosso L, Efferth T, Albini A, Pfeffer U. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. The Pharmacogenomics Journal. 2006; 6(4): 269-78.
     Google Scholar
  107. Hou J, Wang D, Zhang R, Wang H. Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clinical Cancer Research. 2008; 14(17): 5519-30.
     Google Scholar
  108. Li Y, Lu J, Chen Q, Han S, Shao H, Chen P, et al. Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling. Arch Toxicol. 2019; 93(11): 3367-3383.
     Google Scholar
  109. Weifeng T, Feng S, Xiangji L, Changqing S, Zhiquan Q, Huazhong Z, et al. Artemisinin inhibits in vitro and in vivo invasion and metastasis of human hepatocellular carcinoma cells. Phytomedicine.2011; 18(2-3): 158-62.
     Google Scholar
  110. 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): 55-9.
     Google Scholar
  111. Nandi D, Cheema PS, Singal A, Bharti H, Nag A. Artemisinin Mediates Its Tumor-Suppressive Activity in Hepatocellular Carcinoma Through Targeted Inhibition of FoxM1. Front Oncol. 2021; 11: 751271.
     Google Scholar
  112. Deng XR, Liu ZX, Liu F, Pan L, Yu HP, Jiang JP, et al. Holotransferrin enhances selective anticancer activity of artemisinin against human hepatocellular carcinoma cells. J Huazhong Univ Sci Technolog Med Sci. 2013; 33(6): 862-865.
     Google Scholar
  113. Wu L, Pang Y, Qin G, Xi G, Wu S, Wang X, et al. Farnesylthiosalicylic acid sensitizes hepatocarcinoma cells to artemisinin derivatives. PLoS One. 2017; 12(2).
     Google Scholar
  114. Vandewynckel YP, Laukens D, Geerts A, Vanhoe C, Descamps B, Colle I, et al. Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent. Eur J Gastroenterol Hepatol. 2014; 26(8): 861-70.
     Google Scholar
  115. Hao L, Guo Y, Peng Q, Zhang Z, Ji J, Liu Y, et al. Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma. Phytomedicine. 2022; 96: 153913.
     Google Scholar
  116. Im E, Yeo C, Lee HJ, Lee EO. Dihydroartemisinin induced caspase-dependent apoptosis through inhibiting the specificity protein 1 pathway in hepatocellular carcinoma SK-Hep-1 cells. Life Sci. 2018; 192: 286-292.
     Google Scholar
  117. Qin G, Zhao C, Zhang L, Liu H, Quan Y, Chai L, et al. Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells. Apoptosis. 2015; 20(8): 1072-86.
     Google Scholar
  118. Yao X, Zhao CR, Yin H, Wang K, Gao JJ. Synergistic antitumor activity of sorafenib and artesunate in hepatocellular carcinoma cells. Acta Pharmacol Sin. 2020; 41(12): 1609-1620.
     Google Scholar
  119. Jiang Z, Wang Z, Chen L, Zhang C, Liao F, et al. Artesunate induces ER-derived-ROS-mediated cell death by disrupting labile iron pool and iron redistribution in hepatocellular carcinoma cells. Am J Cancer Res. 2021; 11(3): 691-711.
     Google Scholar
  120. Krishna S, Ganapathi S, Ster IC, Saeed MEM, Cowan M, Finlayson C, et al. A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer. EBioMedicine. 2015; 2(1): 82-90.
     Google Scholar
  121. Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/b-catenin pathway. Int. J. Cancer. 2007; 121: 1360–1365.
     Google Scholar
  122. Lu M, Sun L, Zhou J, Yang J. Dihydroartemisinin induces apoptosis in colorectal cancer cells through the mitochondrial-dependent pathway. Tumour Biol. 2014; 35(6): 5307-14.
     Google Scholar
  123. Lu M, Sun L, Zhou J, Zhao Y, Deng X. Dihydroartemisinin-induced apoptosis is associated with inhibition of sarco/endoplasmic reticulum calcium ATPase activity in colorectal cancer. Cell Biochem Biophys. 2015; 73(1): 137-45.
     Google Scholar
  124. Fröhlich T, Ndreshkjana B, Muenzner JK, Reiter C, Hofmeister E, Mederer S, et al. Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer. ChemMedChem. 2017; 12(3): 226/234.
     Google Scholar
  125. Zhao F, Wang H, Kunda P, Chen X, Liu QL, Liu T. Artesunate exerts specific cytotoxicity in retinoblastoma cells via CD71. Oncology Reports. 2013; 30(3): 1473-82.
     Google Scholar
  126. Li X, Zhou Y, Liu Y, Zhang X, Chen T, Chen K, et al. Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer. EBioMedicine. 2016; 14: 44-54.
     Google Scholar
  127. Wu B, Hu K, Li S, Zhu J, Gu L, Shen H, et al. Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer. Oncology Reports. 2012; 27(1): 101-108.
     Google Scholar
  128. Zhang ZS, Wang J, Shen YB, Guo CC, Sai KE, Chen FR, et al. Dihydroartemisinin increases temozolomide efficacy in glioma cells by inducing autophagy. Oncology Letters. 2015; 10(1): 379-83.
     Google Scholar
  129. Karpel-Massler G, Westhoff MA, Kast RE, DwucetA, Nonnemacher L, Wirtz CR, et al. Artesunate enhances the antiproliferative effect of temozolomide on U87MG and A172 glioblastoma cell lines. Anticancer Agents Med Chem. 2014; 14(2): 313-8.
     Google Scholar
  130. Reichert S, Reinboldt V, Hehlgans S, Effarth T, Rödel C, Ridel F. A radiosensitizing effect of artesunate in glioblastoma cells is associated with a diminished expression of the inhibitor of apoptosis protein survivin.. Radiother Oncol. 2012; 103(3): 394-401.
     Google Scholar
  131. Que Z, Wang P, Hu Y, Xue Y, Liu X, Qu C, et al. Dihydroartemisin inhibits glioma invasiveness via a ROS to P53 to β-catenin signaling. Pharmacol Res. 2017; 119: 72-88.
     Google Scholar
  132. Rinner B, Siegl V, Pürstner P, Efferth T, Brem B, Greger H, et al. Activity of novel plant extracts against medullary thyroid carcinoma cells. Anticancer Res. 2004; 24(2A): 495-500.
     Google Scholar
  133. Ma L, Fei H. Antimalarial drug artesunate is effective against chemoresistant anaplastic thyroid carcinoma via targeting mitochondrial metabolism. Journal of Bioenergetics and Biomembranes. 2020; 52(2): 123-30.
     Google Scholar
  134. Xu Z, Liu X, Zhuang D. Artesunate inhibits proliferation, migration, and invasion of thyroid cancer cells by regulating the PI3K/AKT/FKHR pathway. Biochemistry and Cell Biology. 2022; 100(1): 85-92.
     Google Scholar
  135. Zhang HT, Wang YL, Zhang J, Zhang QX. Artemisinin inhibits gastric cancer cell proliferation through upregulation of p53. Tumour Biol. 2014; 35(2): 1403-9.
     Google Scholar
  136. Wang L, Liu L, Wang J, Chen Y. Inhibitory effect of artesunate on growth and apoptosis of gastric cancer cells. Archives of Medical Research. 2017; 48(7): 623-30.
     Google Scholar
  137. Zhang P, Luo HS, Li M, Tan SY. Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2. OncoTargets and Therapy. 2015; 8: 845.
     Google Scholar
  138. Tang C, Ao PY, Zhao YQ, Huang SZ, Jin Y, Liu JJ, et al. Effect and mechanism of dihydroartemisinin on proliferation, metastasis and apoptosis of human osteosarcoma cells. J Biol Regul Homeost Agents. 2015; 29(4): 881-7.
     Google Scholar
  139. Tang C, Zhao Y, Huang S, Jin Y, Liu J, Luo J, et al. Influence of Artemisia annua extract derivatives on proliferation, apoptosis and metastasis of osteosarcoma cells. Pak J Pharm Sci. 2015; 28(2 Suppl): 773-9.
     Google Scholar
  140. Xu Q, Li ZX, Peng HQ, Sun ZW, Cheng RL, Ye ZM, Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ Sci B. 2011; 12(4): 247-55.
     Google Scholar
  141. Ji Y, Zhang YC, Pei LB, Shi LL, Yan JL, Ma XH. Anti-tumor effects of dihydroartemisinin on human osteosarcoma. Mol Cell Biochem. 2011; 351(1-2): 99-108.
     Google Scholar
  142. Hosoya K, Murahari S, Laio A, London CA, Couto CG, Kisseberth WC. Biological activity of dihydroartemisinin in canine osteosarcoma cell lines. Am J Vet Res. 2008; 69(4): 519-26.
     Google Scholar
  143. Liu Y, Wang W, Xu J, Li L, Dong Q, Shi Q, et al. Dihydroartemisinin inhibits tumor growth of human osteosarcoma cells by suppressing Wnt/β-catenin signaling. Oncol Rep. 2013; 30(4): 1723-30.
     Google Scholar
  144. Odaka Y, Xu B, Luo Y, Shen T, Shang C, Wu Y, et al. Dihydroartemisinin inhibits the mammalian target of rapamycin-mediated signaling pathways in tumor cells. Carcinogenesis. 2014; 35(1): 192-200.
     Google Scholar
  145. Beccafico S, Morozzi G, Marchetti MC, Riccardi C, Sidoni A, Donat R, et al. Artesunate induces ROS- and p38 MAPK-mediated apoptosis and counteracts tumor growth in vivo in embryonal rhabdomyosarcoma cells. Carcinogenesis. 2015; 36(9): 1071-83.
     Google Scholar
  146. Dell'Eva R, Pfeffer U, Vené R, Anfosso L, Forlani A, Albini A, Efferth T. Inhibition of angiogenesis in vivo and growth of Kaposi's sarcoma xenograft tumors by the anti-malarial artesunate. Biochem Pharmacol. 2004; 68(12): 2359-66.
     Google Scholar
  147. Jia J, Qin Y, Zhang L, Guo C, Wang Y, Yue X, et al. Artemisinin inhibits gallbladder cancer cell lines through triggering cell cycle arrest and apoptosis. Mol Med Rep. 2016; 13(5): 4461-8.
     Google Scholar
  148. Chen H, Sun B, Pan S, Jiang H, Sun X. Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivo. Anti-cancer drugs. 2009; 20(2): 131-40.
     Google Scholar
  149. Chen H, Sun B, Pan SH, Li J, Xue DB, Meng QH, et al. Study on anticancer effect of dihydroartemisinin on pancreatic cancer]. Zhonghua wai ke za zhi. 2009; 47(13): 1002-1005.
     Google Scholar
  150. Chen H, Sun B, Wang S, Pan S, Gao Y, Bai X, et al. Growth inhibitory effects of dihydroartemisinin on pancreatic cancer cells: involvement of cell cycle arrest and inactivation of nuclear factor-κB. Journal of Cancer Research and Clinical Oncology. 2010; 136(6): 897-903.
     Google Scholar
  151. Wang SJ, Gao Y, Chen H, Kong R, Jiang HC, Pan SH, et al. Dihydroartemisinin inactivates NF-κB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo. Cancer Letters. 2010; 293(1): 99-108.
     Google Scholar
  152. Chen H, Sun B, Wang S, Pan S, Gao Y, Bai X, et al. Dihydroartemisinin inhibits angiogenesis in pancreatic cancer by targeting the NF-κB pathway. J Cancer Res Clin Oncol. 2010; 136(6): 897-903.
     Google Scholar
  153. Wang SJ, Sun B, Pan SH, Chen H, Kong R, Li J, et al. Experimental study of the function and mechanism combining dihydroartemisinin and gemcitabine in treating pancreatic cancer. Zhonghua wai ke za zhi. 2010; 48(7): 530-4.
     Google Scholar
  154. Kong R, Jia G, Cheng ZX, Wang YW, Mu M, Wang SJ, et al. Dihydroartemisinin enhances Apo2L/TRAIL-mediated apoptosis in pancreatic cancer cells via ROS-mediated up-regulation of death receptor 5. PloS One. 2012; 7(5): e37222.
     Google Scholar
  155. Youns M, Efferth T, Reichling J, Fellenberg K, Bauer A, Hoheisel JD. Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells. Biochemical Pharmacology. 2009; 78(3): 273-83.
     Google Scholar
  156. Batty KT, Davis TM, Thu LT, Binh TQ, Anh TK, Ilett KF. Selective highperformance liquid chromatographic determination of artesunate and alpha- and beta- dihydroartemisinin in patients with falciparum malaria. J Chromatogr B Biomed Appl. 1996; 677: 345-50.
     Google Scholar
  157. 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.
     Google Scholar
  158. Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends in Biochemical Sciences. 2014; 39(2): 91-100.
     Google Scholar
  159. Luo J. KRAS mutation in pancreatic cancer. InSeminars in oncology 2021; 48(1): 10-18.
     Google Scholar
  160. Du JH, Zhang HD, Ma ZJ, Ji KM. Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemotherapy and Pharmacology. 2010; 65(5): 895-902.
     Google Scholar
  161. Noori S, Hassan Z, Farsam V. Artemisinin as a Chinese medicine, selectively induces apoptosis in pancreatic tumor cell line. Chinese Journal of Integrative Medicine. 2014; 20(8): 618-23.
     Google Scholar
  162. Wang K, Zhang Z, Wang M, Cao X, Qi J, Wang D, et al. Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Drug Design, Development and Therapy. 2019; 13: 2135.
     Google Scholar
  163. Niu Z, Wang M, Zhou L, Yao L, Liao Q, Zhao Y. Elevated GRP78 expression is associated with poor prognosis in patients with pancreatic cancer. Scientific Reports. 2015; 5(1): 1-2.
     Google Scholar
  164. Yuan XP, Dong M, Li X, Zhou JP. GRP78 promotes the invasion of pancreatic cancer cells by FAK and JNK. Molecular and Cellular Biochemistry. 2015; 398(1): 55-62.
     Google Scholar
  165. Dauer P, Sharma NS, Gupta VK, Durden B, Hadad R, Banerjee S, et al. ER stress sensor, glucose regulatory protein 78 regulates redox status in pancreatic cancer thereby maintaining “stemness”. Cell Death & Disease. 2019; 10(2): 1-3.
     Google Scholar
  166. Gifford JB, Huang W, Zeleniak AE, Hindoyan A, Wu H, Donahue TR, et al. Expression of GRP78, master regulator of the unfolded protein response, increases chemoresistance in pancreatic ductal adenocarcinoma. Molecular Cancer Therapeutics. 2016; 15(5): 1043-52.
     Google Scholar
  167. Gopal U, Mowery Y, Young K, Pizzo SV. Targeting cell surface GRP78 enhances pancreatic cancer radiosensitivity through YAP/TAZ protein signaling. Journal of Biological Chemistry. 2019; 294(38): 13939-52.
     Google Scholar
  168. Thakur PC, Miller-Ocuin JL, Nguyen K, Matsuda R, Singhi AD, Zeh HJ, et al. Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer. Journal of Translational Medicine. 2018; 16(1): 1-9.
     Google Scholar
  169. Palmeira A, Sousa E, Köseler A, Sabirli R, Gören T, Türkçüer İ, et al. Preliminary virtual screening studies to identify GRP78 inhibitors which may interfere with SARS-CoV-2 infection. Pharmaceuticals. 2020; 13(6): 132.
     Google Scholar
  170. Liu Y, Cui YF. Synergism of cytotoxicity effects of triptolide and artesunate combination treatment in pancreatic cancer cell lines. Asian Pacific Journal of Cancer Prevention. 2013; 14(9): 5243-8.
     Google Scholar
  171. Chen X, Kang R, Kroemer G, Tang D. Targeting ferroptosis in pancreatic cancer: a double-edged sword. Trends in Cancer. 2021; 7(10): 891-901.
     Google Scholar
  172. Du Jh, Li Jx, Zhang Hd. An oncosis-like cell death of pancreatic cancer Panc-1 cells induced by artesunate is related to generation of reactive oxygen species. China Oncology. 2000.
     Google Scholar
  173. Chen G, Guo G, Zhou X, Chen H. Potential mechanism of ferroptosis in pancreatic cancer. Oncology Letters. 2020; 19(1): 579-87.
     Google Scholar
  174. Wu J, Xu MD, Wang WJ, Shen M, Zhang Y, Qian J, et al. Artesunate Represses the Growth and Metastasis of Pancreatic Cancer Cells but Upregulates the Expression Levels of Proangiogenic Genes Through Inhibition of Protein Phosphatase 2A. Lancet. 2019.
     Google Scholar
  175. Zhang F, Gosser DK Jr, Meshnick SR. Hemin-catalyzed decomposition of artemisinin. Biochem Pharmacol. 1992; 43(8): 1805-9.
     Google Scholar
  176. Kapetanaki S, Varotsis C. Ferryl-oxo heme intermediate in the antimalarial mode of action of artemisinin. FEBS Lett. 2000; 474(2-3): 238-41.
     Google Scholar
  177. Sibmooh N, Udomsangpetch R, Kujoa A, Chantharaksri U, Mankhetkorn S. Redox reaction of artemisinin with ferrous and ferric ions in aqueous buffer. Chem Pharm Bull (Tokyo). 2001; 49(12): 1541-6.
     Google Scholar
  178. Hampton MB, Orrenius S. Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Letters. 1997; 414(3): 552-6.
     Google Scholar
  179. Ju HQ, Gocho T, Aguilar M, Wu M, Zhuang ZN, Fu J, et al. Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Molecular Cancer Therapeutics. 2015; 14(3): 788-98.
     Google Scholar
  180. Donadelli M, Costanzo C, Beghelli S, et al. Synergistic inhibition of pancreatic adenocarcinoma cell growth by trichostatin A and gemcitabine. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2007; 1773(7): 1095-106.
     Google Scholar
  181. Arora S, Bhardwaj A, Singh S, Srivastava SK, McCellan S, Nirodi CS, et al. An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through reactive oxygen species-dependent, nuclear factor κB-and hypoxia-inducible factor 1α-mediated up-regulation of CXCR4. Journal of Biological Chemistry. 2013; 288(29): 21197-207.
     Google Scholar
  182. Sui X, Zhang R, Liu S, Duan T, Zhai L, Zhang M, et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer. Frontiers in Pharmacology. 2018: 1371.
     Google Scholar
  183. Wang M, Wey S, Zhang Y, Ye R, Lee AS. Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxidants & Redox Signaling. 2009; 11(9): 2307-16.
     Google Scholar
  184. Meshnick SR, Yang YZ, Lima V, Kuypers F, Kamchonwongpaisan S, Yuthavong Y. Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu). Antimicrobial Agents and Chemotherapy. 1993; 37(5): 1108-14.
     Google Scholar
  185. Elford HL, Freese M, Passamani E, Morris HP. Ribonucleotide Reductase and Cell Proliferation: I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas. Journal of Biological Chemistry. 1970; 245(20): 5228-33.
     Google Scholar
  186. Chen G, Luo Y, Warncke K, Sun Y, Yu DS, Fu H, et al. Acetylation regulates ribonucleotide reductase activity and cancer cell growth. Nature Communications. 2019; 10(1): 1-6.
     Google Scholar
  187. Greene BL, Kang G, Cui C, Bennati M, Nocera DG, Drennan CL, et al.. Ribonucleotide reductases: structure, chemistry, and metabolism suggest new therapeutic targets. Annual Review of biochemistry. 2020; 89: 45-75.
     Google Scholar
  188. Cerqueira NM, Fernandes PA, Ramos MJ. Understanding ribonucleotide reductase inactivation by gemcitabine. Chemistry–A European Journal. 2007; 13(30): 8507-15.
     Google Scholar
  189. Pereira S, Fernandes PA, Ramos MJ. Mechanism for ribonucleotide reductase inactivation by the anticancer drug gemcitabine. Journal of Computational Chemistry. 2004; 25(10): 1286-94.
     Google Scholar
  190. Jordheim LP, Guittet O, Lepoivre M, Galmarini CM, Dumontet C, Increased expression of the large subunit of ribonucleotide reductase is involved in resistance to gemcitabine in human mammary adenocarcinoma cells. Molecular Cancer Therapeutics. 2005; 4(8): 1268-76.
     Google Scholar
  191. Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Research. 2004; 64(11): 3761-6.
     Google Scholar
  192. Minami K, Shinsato Y, Yamamoto M, Takahashi H, Zhang S, Nishizawa Y, et al. Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors. Journal of Pharmacological Sciences. 2015; 127(3): 319-25.
     Google Scholar
  193. Yokoi K, Fidler IJ. Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine. Clinical Cancer Research. 2004; 10(7): 2299-306.
     Google Scholar
  194. Schniewind B, Christgen M, Kurdow R, Haye S, Kremer B, Kalthoff H, et al. Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria‐mediated apoptosis. International Journal of Cancer. 2004; 109(2): 182-8.
     Google Scholar
  195. Binenbaum Y, Na’ara S, Gil Z. Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resistance Updates. 2015; 23: 55-68.
     Google Scholar
  196. Ilamathi M, Prabu PC, Ayyappa KA, Sivaramakrishnan V. Artesunate obliterates experimental hepatocellular carcinoma in rats through suppression of IL-6-JAK-STAT signalling. Biomedicine & Pharmacotherapy. 2016; 82: 72-9.
     Google Scholar
  197. Ilamathi M, Santhosh S, Sivaramakrishnan V. Artesunate as an anti-cancer agent targets stat-3 and favorably suppresses hepatocellular carcinoma. Current Topics in Medicinal Chemistry. 2016; 16(22): 2453-63.
     Google Scholar
  198. Kuang M, Cen Y, Qin R, Shang S, Zhai Z, Liu C, et al. Artesunate attenuates pro-inflammatory cytokine release from macrophages by inhibiting TLR4-mediated autophagic activation via the TRAF6-Beclin1-PI3KC3 pathway. Cellular Physiology and Biochemistry. 2018; 47(2): 475-88.
     Google Scholar
  199. Dolivo D, Weathers P, Dominko T. Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics. Acta Pharmaceutica Sinica B. 2021; 11(2): 322-39.
     Google Scholar
  200. Lai L, Chen Y, Tian X, Li X, Zhang X, Lei J, et al. Artesunate alleviates hepatic fibrosis induced by multiple pathogenic factors and inflammation through the inhibition of LPS/TLR4/NF-κB signaling pathway in rats. European Journal of Pharmacology. 2015; 765: 234-41.
     Google Scholar
  201. Longxi P, Buwu F, Yuan W, Sinan G. Expression of p53 in the effects of artesunate on induction of apoptosis and inhibition of proliferation in rat primary hepatic stellate cells. PLoS One. 2011; 6(10): e26500.
     Google Scholar
  202. Bai R, Zhang H, Huang C. Effect of Artesunate on Akt/GSK-3β/β-catenin signal pathway in human hepatic stellate cells. China Pharmacist. 2017: 1192-5.
     Google Scholar
  203. Nong X, Rajbanshi G, Chen L, Li J, Li Z, Liu T, et al. Effect of artesunate and relation with TGF-β1 and SMAD3 signaling on experimental hypertrophic scar model in rabbit ear. Archives of Dermatological Research. 2019; 311(10): 761-72.
     Google Scholar
  204. Wang C, Xuan X, Yao W, Huang G, Jin J. Anti-profibrotic effects of artesunate on bleomycin-induced pulmonary fibrosis in Sprague Dawley rats. Molecular Medicine Reports. 2015; 12(1): 1291-7.
     Google Scholar
  205. Liu Y, Huang G, Mo B, Wang C. Artesunate ameliorates lung fibrosis via inhibiting the Notch signaling pathway. Experimental and Therapeutic Medicine. 2017; 14(1): 561-6.
     Google Scholar
  206. Wan Q, Chen H, Li X, Yan L, Sun Y, Wang J. Artesunate inhibits fibroblasts proliferation and reduces surgery-induced epidural fibrosis via the autophagy-mediated p53/p21waf1/cip1 pathway. European Journal of Pharmacology. 2019; 842: 197-207.
     Google Scholar