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.
Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World Journal of Oncology. 2019; 10(1): 10.
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.
Klein AP. Pancreatic cancer: a growing burden. The Lancet Gastroenterology & Hepatology. 2019; 4(12): 895-6.
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.
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.
Cindy H. Lasker Award Rekindles Debate Over Artemisinin's Discovery. Science. 2011.
Miller LH, Su, X. Artemisinin: Discovery from the Chinese herbal garden. Cell. 2011; 146(6): 855–858.
Jianfang Z. A detailed chronological record of project 523 and the discovery and development of qinghaosu (artemisinin). Strategic Book Publishing; 2013.
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.
Tu, Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med 2011; 17: 1217–1220.
Meshnick SR, Taylor TE, Kamchonwongpaisan S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiological Reviews. 1996; 60(2): 301-15.
WHO guidelines for the treatment of malaria. World Health Organization. Third Edition. [Internet] 2015. Available from: https://apps.who.int/iris/handle/10665/162441
WHO Guidelines for malaria. [Internet] 2022. Available from: https://www.who.int/publications/i/item/guidelines-for-malaria accessed April 4 2022.
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.
Nair MS, Basile DV. Bioconversion of arteannuin B to artemisinin. Journal of Natural Products. 1993; 56(9): 1559-66.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Krishna S, Bustamante L, Haynes RK, Staines HM. Artemisinins: their growing importance in medicine. Trends in Pharmacological Sciences. 2008; 29(10): 520-7.
O’neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin—the debate continues. Molecules. 2010; 15(3): 1705-21.
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.
Dixon SJ. Ferroptosis: bug or feature?. Immunological Reviews. 2017; 277(1): 150-7.
Lei P, Bai T, Sun Y. Mechanisms of ferroptosis and relations with regulated cell death: a review. Frontiers inPhysiology. 2019; 10: 139.
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.
Kong Z, Liu R, Cheng Y. Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomedicine & Pharmacotherapy. 2019;109: 2043-53.
Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. International Journal for Parasitology. 2002; 32(13): 1655-60.
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.
Torti SV, Manz DH, Paul BT, Blanchette-Farra N, Torti FM. Iron and cancer. Annual Review of Nutrition. 2018; 38: 97-125.
Lai H, Sasaki T, Singh NP, Messay A. Effects of artemisinin-tagged holotransferrin on cancer cells. Life Sci. 2005; 76(11): 2277-80.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Kolligs FT, Bommer G, Göke B. Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion. 2002; 66(3): 131-44.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Spiridonov NA, Konovalov DA, Arkhipov VV. Cytotoxicity of some Russian ethnomedicinal plants and plant compounds. Phytother. Res., 2005; 19: 428–432.
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.
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.
Zheng GQ. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med. 1994; 60(1): 54-57.
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.
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.
Singh NP, Verma KB. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Archive of Oncology. 2002; 10(04): 279-280.
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.
Deng DA, Xu CH, Cai JC. Derivatives of arteannuin B with antileukemia activity. Yao Xue Xue Bao. 1992; 27(4): 317-20.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends in Biochemical Sciences. 2014; 39(2): 91-100.
Luo J. KRAS mutation in pancreatic cancer. InSeminars in oncology 2021; 48(1): 10-18.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Chen G, Guo G, Zhou X, Chen H. Potential mechanism of ferroptosis in pancreatic cancer. Oncology Letters. 2020; 19(1): 579-87.
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.
Zhang F, Gosser DK Jr, Meshnick SR. Hemin-catalyzed decomposition of artemisinin. Biochem Pharmacol. 1992; 43(8): 1805-9.
Kapetanaki S, Varotsis C. Ferryl-oxo heme intermediate in the antimalarial mode of action of artemisinin. FEBS Lett. 2000; 474(2-3): 238-41.
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.
Hampton MB, Orrenius S. Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Letters. 1997; 414(3): 552-6.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cerqueira NM, Fernandes PA, Ramos MJ. Understanding ribonucleotide reductase inactivation by gemcitabine. Chemistry–A European Journal. 2007; 13(30): 8507-15.
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.
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.
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.
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.
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.
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.
Binenbaum Y, Na’ara S, Gil Z. Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resistance Updates. 2015; 23: 55-68.
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.
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.
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.
Dolivo D, Weathers P, Dominko T. Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics. Acta Pharmaceutica Sinica B. 2021; 11(2): 322-39.
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.
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.
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.
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.
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.
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.
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.