Artesunate: A Holistic Cancer Treatment – Part 2

This is a continuation of the three part series on the wholistic cancer treatments artesunate are other artemisinins.

Are wholistic cancer treatments with artesunate and other artemisinins effective?

I will let the evidence speak for itself. Just facts. No opinion. There is too much opinion out there already masquerading as fact.

EFFERTH T, ZACCHINO S, GEORGIEV MI, LIU L, WAGNER H, PANOSSIAN A. NOBEL PRIZE FOR ARTEMISININ BRINGS PHYTOTHERAPY INTO THE SPOTLIGHT. PHYTOMEDICINE. 2015 DEC 1;22(13):A1-3. DOI: 10.1016/J.PHYMED.2015.10.003.

Since Dr. Youyou Tu’s discovery and isolation of artemisinin from sweet wormwood, the research on artemisinin and its various derivatives in the treatment of cancer has exploded. The image to the left shows how the worldwide research of artemisinins in cancer has outpaced all other topics of research on artemisinins [1]. In addition, artesunate, artemisinin, and other artemisinins are safe and effective against malaria in clinical trials [2] [3]. In fact, artesunate is now the gold-standard in the treatment of malaria infection worldwide. But this is about cancer—what evidence is there that artesunate and other artemisinins are effective against cancer? A wide variety of study types including pre-clinical, clinical trials, and yes even the golden-calf of evidence-based medicine that is the randomized, double-blind, placebo-controlled trials [4], have shown artesunate, artemisinin, and other artemisinins to be clinically effective against a wide variety of cancer types that include:

These are just the cancer types that have been studied. Artesunate and other artemisinins will likely prove to be effective against most, if not all, cancer types with the addition of further studies and clinical trials.

The mechanism of actions against cancer is equally diverse. In today’s growing environment of online censorship in the name of fake or misleading news, it is important to document the evidence behind the anti-cancer mechanisms of artesunate and other artemisinins. I will let the science lead the way, not opinion or bias’ as seen by the faux-scientists who censor through the long arms of social media and the internet in the name of science. The active politicization of science and medicine will be the death of science and medicine. I am afraid that the obituary of science and medicine is already being written. As, a result, patients will suffer from a lack of innovation and discovery. Why? For no other reason but profits and control. Sadly, nothing to do with the patient.

The specific anti-cancer benefits of artesunate include:

Out of control proliferation and growth are synonymous with cancer. Specific effects include inhibition of the PI3K/Akt/mTOR pathway, inhibition of COX-2, inhibition of Prostaglandins (particularly PGE-2), cancer cell cycle arrest growth at G2/M and G0/G1 phases, decreased expression of the proliferative index Ki67, inhibition of Nitric Oxide (NO) production, and decrease in HIF-1alpha levels.

Programmed cell death, called apoptosis, is a key regulatory step the body can use to limit and eliminate abnormal cell and/or cancer cell growth. Cancer often circumvents this regulatory ability to eliminate abnormal cells. This is key in cancer cell survival. Specific effects include inhibition of STAT3 (a down-stream cytokine signal, considered an oncogene, that promotes growth and stimulation of other oncogenes), activation of caspase-3, caspase-8, and cascade-9 that stimulate and execute the signal of cell death through apoptosis, increase in Bcl-Rambo levels, decrease in Bcl-2 levels, decreased Bcl-xl levels, increase in the tumor suppressor gene expression of p21 and p53, increase in Bax levels, inhibition of survivin, decrease in PI3K expression, decrease in Akt expression, decrease in TGF-beta, decrease in cyclin-B1, and cancer cell cycle growth arrest in the G2/M phase.

A new term for most. Artesunate and other artemisinin derivatives have been shown to trigger a unique pathway for programmed cell death of cancer cells using iron. Cancer collects high iron and ferritin for replication—called the ferritin or Fe pool. Think of this pooling, not as the energy to build a new cell, but the supplies to build a new cell. Take the building of a new house as an analogy. The energy capacity to build a new house is a well feed work crew and machinery that has an appropriate energy supply, whether electric or gas. The ferritin and/or iron pool is the nails, the cement for foundation, 2 x 4 wood for framing… A new house, or cancer cell, requires both an adequate energy supply with additional building materials to build that house or that new cancer cell. Artesunate binds to this free, available iron (Fe) and ferritin within the cancer cell that then overwhelms the cancer detoxification capacity that then triggers apoptosis (programmed cell destruction) of the cancer cell. Apoptosis driven by ferritin or iron is called ferroptosis.

Angiogenesis is the massive blood vessel growth that is so important to cancer survival and spread. In many ways, it is cancer’s lifeline for survival and the superhighway to spread. Specific effects include a decrease in HIF-1alpha levels, downregulation of Vascular Endothelial Growth Factor Receptor (VEGFR), inhibition of Nitric Oxide (NO) production, and increase in epigenetic expression of angiogenesis inhibitors.

Remember, 90% of morbidity and mortality in cancer occurs as a result of metastasis. A treatment that reduces cancer metastasis would be a definitive approach to reducing cancer mortality. The opposite is true, a therapy i.e. chemotherapy…that increases cancer metastasis would be an approach to increase cancer mortality. Specific effects of artesunate against metastasis include inhibition of NO production in a dose-dependent manner, inactivation of the genetic transcription inflammatory factor NF-kappaB, decrease in MMP-2 and MMP-9 expression, and increase E-cadherin expression.

  • Epigenetics 40 [53]

Epigenetics is defined as the expression of the genetic code—DNA. Epigenetics is translated “above genetics”. The field of epigenetics is becoming an important therapeutic target to change our genetic expression to promote healing and not dis-ease. No longer is DNA seen as a fixed contributor to cancer or dis-ease, but through the prism of epigenetics, DNA expression is amendable, adaptable…simply, it can be changed. This of course could be for the better or for the worse. In the case for cancer in this blog post, I will focus on the alteration of genetic expression for the good—anti-cancer. Specific anti-cancer epigenetic changes induced by artesunate include a decrease in Epidermal Growth Factor Receptor (EGFR) transcription. The human epidermal growth factor type II, also known as HER-2, is important in the treatment in breast and a few other cancer types [54]. This is why the drugs Herceptin and Perjeta are prescribed. This HER-2 receptor is a member of the EGFR family. Artesunate and other artemisinins also have been shown to increase p21 tumor suppressor gene transcription, increase p53 tumor suppressor gene transcription, and increase in Beclin-1 transcription.

  • Mitochondria 11 [55]

Mitochondria are the powerhouses of the cell. These organelles are present in every cell and are responsible for the energy production of the cell. The ability to make energy is critical to cell survival. This is critical in cancer development and progression as mitochondria become corrupted, dysfunctional, which leads to the altered cellular energy pathway described by Otto Warburg (aerobic glycolysis) that appropriately carries his name—Warburg effect. Artesunate disrupts (depolarization) the membrane potential of cancer cell mitochondria which leads to the disruption in the energy supply, destruction of the mitochondria, and eventually to the demise of the cancer cell. Interestingly, this does not occur in healthy, non-cancer cells.

Artesunate, artemisinin, and other derivatives have been shown to increase radiation effectiveness by acting as a sensitizing signal when used in conjunction with radiation therapy. Thus, artesunate is an effective adjunct therapy when used in conjunction with radiation. This is effective against a wide variety of cancer types including cervical cancer, esophageal cancer, lung cancer…

Artesunate and other artemisinins have been shown to increase chemotherapy efficacy by acting as a sensitizing signal in conjunction with chemotherapy. Thus, as in radiation, artesunate is an effective adjunct therapy when used in conjunction with chemotherapy. Artesunate and other artemisinins have shown to augment chemotherapy in both in vitro and in vivo studies in a wide variety of cancer types including lung cancer, ovarian cancer, liver cancer…

Treatment resistance is a major contributor to treatment failure, cancer recurrence, and cancer mortality. Chemo resistance is the loss of cancer sensitivity to chemotherapy. The prevention and reversal of cancer treatment resistance would be significant in the ability to improve cancer treatment effectiveness and success. Artemisinin, artesunate, and dihydroartemisinin have been shown to restore chemotherapy killing effects in cancer that was previously chemotherapy-resistant. I just talked to a potential patient that had been on chemotherapy for > 10 months and treatment resistance had set in—despite continued treatment, cancer growth increased and metastasis developed. According to published evidence, the addition of artesunate could be a way to restore the cancer-killing effects of chemotherapy by restoring cancer sensitivity to chemotherapy.

  • Modification of the immune system

Due to its significance in cancer treatment, artesunate and other artemisinins will be discussed individually in the next blog post.

Artesunate doesn’t just have direct wide-spread anti-cancer effects, but it functions as an adjunct therapy that makes other therapies, including conventional (as shown above), work that much better.

Beyond these wonderful, broad anti-cancer effects of artesunate and other artemisinins, artesunate, in particular, is anti-viral [67] and an effective counter to cytokine storm. Studies (animal and human) have shown artesunate calms the cytokine storm associated with sepsis [68] [69] [70] and in malaria [71]. It is the cytokine storm that is the common link between malaria, virus’ like COVID19, and cancer that provides insight into the broad treatment potential with artesunate and other artemisinins.

No opinion. That is the evidence!

______

[1] Efferth T, Zacchino S, Georgiev MI, Liu L, Wagner H, Panossian A. Nobel Prize for artemisinin brings phytotherapy into the spotlight. Phytomedicine. 2015 Dec 1;22(13):A1-3. doi: 10.1016/j.phymed.2015.10.003.

[2] Li Q, Weina P. Artesunate: The Best Drug in the Treatment of Severe and Complicated Malaria. Pharmaceuticals (Basel). 2010;3(7):2322‐2332. Published 2010 Jul 21. doi:10.3390/ph3072322

[3] Li Ying. 2018. Artemisinin and Derivatives: Clinical Studies. Artemisinin-Based and Other Antimalarials. (pp. 353-413). Elsevier.

[4] Krishna S, Ganapathi S, Ster IC, et al. A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer. EBioMedicine. 2014;2(1):82‐90. Published 2014 Nov 15. doi:10.1016/j.ebiom.2014.11.010

[5] 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. Published 2015 May 2. doi:10.18632/oncoscience.160

[6] 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 Chemother Pharmacol. 2010;65(5):895–902.

[7] Kapoor S. Artesunate and its emerging anti-neoplastic effects: beyond its role in attenuating tumor growth in osteosarcomas. J Zhejiang Univ Sci B. 2012;13(12):1029‐1030. doi:10.1631/jzus.B1200288

[8] Xu Q, Li ZX, Peng HQ, Sun ZW, Cheng RL, Ye ZM, Li WX. Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo. J Zhejiang Univ-Sci B (Biomed & Biotechnol) 2011;12(4):247–255. doi: 10.1631/jzus.B1000373.

[9] Willoughby JA Sr, 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. J Biol Chem. 2009;284(4):2203‐2213. doi:10.1074/jbc.M804491200

[10] Wang Z, Wang C, Wu Z, Xue J, Shen B, Zuo W, Wang Z, Wang SL. Artesunate Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor. Biol Pharm Bull. 2017;40(4):479-485. doi: 10.1248/bpb.b16-00908.

[11] Hamacher-Brady A, Stein HA, Turschner S, Toegel I, Mora R, Jennewein N, Efferth T, Eils R Brady NR. Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. J Biol Chem. 2011;286(8):6587–6601.

[12] Ding X, Yue W, Chen H. Effect of artesunate on apoptosis and autophagy in tamoxifen resistant breast cancer cells (TAM-R). Translational Cancer Research. Sept 2019;8(5). doi: 10.21037/tcr.2019.08.41

[13] Zhang Z.Y., Yu S.Q., Miao L.Y., Huang X.Y., Zhang X.P., Zhu Y.P., Xia X.H., Li D.Q. 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;6:134–138. doi: 10.3736/jcim20080206.

[14] Tong Y, Liu Y, Zheng H, et al. Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling. Oncotarget. 2016;7(21):31413‐31428. doi:10.18632/oncotarget.8920

[15] Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, Schuler G. Artesunate in the treatment of metastatic uveal melanoma–first experiences. Oncol Rep. 2005 Dec;14(6):1599-603.

[16] Chen X, Wong YK, Lim TK, Lim WH, Lin Q, Wang J, Hua Z. Artesunate activates the intrinsic apoptosis of HCT116 cells through the suppression of fatty acid synthesis and the NF-κB pathway. Molecules. 2017;22:1272.

[17] Zhang P, Luo HS, Li M, Tan SY. Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2. Onco Targets Ther. 2015;8:845‐854. Published 2015 Apr 16. doi:10.2147/OTT.S81041

[18] Lin R, Zhang Z, Chen L, Zhou Y, Zou P, Feng C, Wang L, Liang G. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells. Cancer Lett. 2016;381:165–175.

[19] Liu L, Zuo LF, Guo JW. Reversal of multidrug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109/ABCG2 cell line. Oncol Lett. 2013;6(5):1475‐1481. doi:10.3892/ol.2013.1545

[20] Liu L, Zuo LF, Zuo J, Wang J. Artesunate induces apoptosis and inhibits growth of Eca109 and Ec9706 human esophageal cancer cell lines in vitro and in vivo. Molecular Medicine Reports. 2015.12:1465-1472. DOI: 10.3892/mmr.2015.3517

[21] Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer. 2007 Sep 15;121(6):1360-5.

[22] Ramirex I et al. Repurposing Artesunate, an anti-malarial, for ovarian cancer treatment: Mechanistic insights from cell line models. 2015. Gynecologic Oncology;137(207).

[23] Greenshields AL, Shepherd TG, Hoskin DW. Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate. Mol Carcinog. 2017 Jan;56(1):75-93. doi: 10.1002/mc.22474.

[24] Konstat-Korzenny E, Ascencio-Aragón JA, Niezen-Lugo S, Vázquez-López R. Artemisinin and Its Synthetic Derivatives as a Possible Therapy for Cancer. Med Sci (Basel). 2018;6(1):19. Published 2018 Feb 27. doi:10.3390/medsci6010019

[25] 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.

[26] Sukhai MA, Prabha S, Hurren R, Rutledge AC, Lee AY, Sriskanthadevan S, Sun H, Wang X, Skrtic M, Seneviratne A, Cusimano M, Jhas B, Gronda M, et al. Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors. J Clin Invest. 2013;123(1):315–328.

[27] Singh N., Verma K. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch. Oncol. 2002;2002:279–280.

[28] Jeong DE, Song HJ, Lim S, 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):33046‐33064. doi:10.18632/oncotarget.5422

[29] Zuo W, Wang ZZ, Xue J. Artesunate induces apoptosis of bladder cancer cells by miR-16 regulation of COX-2 expression. Int J Mol Sci. 2014;15(8):14298‐14312. Published 2014 Aug 15. doi:10.3390/ijms150814298

[30] Berdelle N., Nikolova T., Quiros S., Efferth T., Kaina B. Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells. Molecular Cancer Therapeutics. 2011;10(12):2224–2233. doi: 10.1158/1535-7163.MCT-11-0534.

[31] 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. Fundam Clin Pharmacol. 2017 Jun;31(3):301-310. doi: 10.1111/fcp.

[32] 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. J Bioenerg Biomembr. 2020 Apr;52(2):113-121. doi: 10.1007/s10863-020-09823-x.

[33] Zhu, S., Liu, W., Ke, X., Li, J., Hu, R., Cui, H., & Song, G. (2014). Artemisinin reduces cell proliferation and induces apoptosis in neuroblastoma. Oncology Reports, 32, 1094-1100. https://doi.org/10.3892/or.2014.3323

[34] Crespo-Ortiz MP, Wei MQ. Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. J Biomed Biotechnol. 2012;2012:247597. doi:10.1155/2012/247597

[35] Avalle L, Camporeale A, Camperi A, Poli V. STAT3 in cancer: A doubled edge sword. Cytokine. 2017 Oct;98:42-50. doi: 10.1016/j.cyto.2017.03.018.

[36] Yu, H., Lee, H., Herrmann, A. et al. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14:736–746. https://doi.org/10.1038/nrc3818

[37] Olsson M, Zhivotovsky B. Caspases and cancer. Cell Death Differ. 2011;18(9):1441‐1449. doi:10.1038/cdd.2011.30

[38] Tan M, Rong Y, Su Q, Chen Y. Artesunate induces apoptosis via inhibition of STAT3 in THP-1 cells. Leukemia Research. Nov 2017;62:98-103.

[39] Zhang P, Luo H, Li M, Tan S. Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2. OncoTargets and Therapy. Apr 2015; 2015(8):845—854.

[40] 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. Oct 2011; https://doi.org/10.1371/journal.pone.0026500

[41] Morrissey C, Gallis B, Solazzi JW, et al. Effect of artemisinin derivatives on apoptosis and cell cycle in prostate cancer cells. Anticancer Drugs. 2010;21(4):423‐432. doi:10.1097/CAD.0b013e328336f57b

[42] Wang K, Zhang Z, Wang M, et al. Role of GRP78 inhibiting artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells. Drug Des Devel Ther. 2019;13:2135‐2144. Published 2019 Jul 2. doi:10.2147/DDDT.S199459

[43] Song Y, Yang H, Lin R, Jiang K, Wang BM. The role of ferroptosis in digestive system cancer. Oncol Lett. 2019;18(3):2159‐2164. doi:10.3892/ol.2019.10568

[44] Krusche B, Arend J, Efferth T. Synergistic inhibition of angiogenesis by artesunate and captopril in vitro and in vivo. Evid Based Complement Alternat Med. 2013;2013:454783. doi:10.1155/2013/454783

[45] Li Q, Weina P, Hickman M. Feb 6 2013. The Use of Artemisinin Compounds as Angiogenesis Inhibitors to Treat Cancer. Research Directions in Tumor Angiogenesis. DOI: 10.5772/54109

[46] 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. Vascular Pharmacology. 2007;47(2-3):131–138.

[47] Huang XJ, Li CT, Zhang WP, Lu YB, Fang SH, Wei EQ. Dihydroartemisinin potentiates the cytotoxic effect of temozolomide in rat C6 glioma cells. Pharmacology. 2008;82(1):1–9.

[48] Anfosso L, Efferth T, Albini A, Pfeffer U. Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins. Pharmacogenomics Journal. 2006;6(4):269–278.

[49] Cathcart J, Pulkoski-Gross A, Cao J. Targeting matrix metalloproteinases in cancer: Bringing new life to old ideas. Genes and Disease. Mar 2015;2(1):26-34. https://doi.org/10.1016/j.gendis.2014.12.002

[50] Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432:332-337.

[51] Weifeng T, Feng S, Xiangji L, et al. Artemisinin inhibits In vitro and In vivo invasion and metastasis of human hepatocellular carcinoma cells. Phytomedicine. 2011;18(2-3):158–162.

[52] Hwang YP, Yun HJ, Kim HG, Han EH, Lee GW, Jeong HG. Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCα/Raf/MAPKs and NF-κB/AP-1-dependent mechanisms. Biochemical Pharmacology. 2010;79(12):1714–1726.

[53] Chen K, Shou LM, Lin F, Duan WM, Wu MY, Xie X, Xie YF, Li W, Tao M. Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells. Anticancer Drugs. Jul 2014;25(6):652-62. doi: 10.1097/CAD.0000000000000089.

[54] Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. doi:10.1155/2014/852748

[55] Li W, Mo W, Shen D, et al. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet. 2005;1(3):e36. doi:10.1371/journal.pgen.0010036

[56] Zhao Y, Jiang W, Li B, Yao Q, Dong J, Cen Y, Pan X, Li J, Zheng J, Pang X, Zhou H. 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;11:2039–2046.

[57] Luo J, Zhu W, Tang Y, et al. Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo. Radiat Oncol. 2014;9:84. Published 2014 Mar 25. doi:10.1186/1748-717X-9-84

[58] Fei Z, Gu W, Xie R, Su H, Jiang Y. Artesunate enhances radiosensitivity of esophageal cancer cells by inhibiting the repair of DNA damage. Oct 2018 J Pharmacol Sci;138(2):131-137. doi: 10.1016/j.jphs.2018.09.011.

[59] Wang Z, Wang Q, He T, Li W, Liu Y, Wang Y, Wang Q, Chen J. The combination of artesunate and carboplatin exerts a synergistic anti-tumour effect on non-small cell lung cancer. Clin Exp Pharmacol Physiol. 2020 Feb 19. doi: 10.1111/1440-1681.13287

[60] Wang B, Hou D, Liu Q, et al. Artesunate sensitizes ovarian cancer cells to cisplatin by downregulating RAD51. Cancer Biol Ther. 2015;16(10):1548‐1556. doi:10.1080/15384047.2015.1071738

[61] 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. Clin. Cancer Res. 2008;14:5519–5530. doi: 10.1158/1078-0432.CCR-08-0197.

[62] Reiter C, Capci Karagoz A, Frohlich T, Klein V, Zeino M, Viertel K, Held J, Mordmuller B, Emirdag-Ozturk S, Anil H, Efferth T, Tsogoeva SB. Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonol-derived hybrid molecules against Plasmodium falciparum and multidrug-resistant human leukemia cells. Eur. J. Med. Chem. 2014;75:403–412.

[63] Reiter C, Herrmann A, Capci A, Efferth T, Tsogoeva SB. Bioorg. New artesunic acid homodimers: potent reversal agents of multidrug resistance in leukemia cells. Med. Chem. 2012;20:5637–5641.

[64] Das AK. Anticancer Effect of AntiMalarial Artemisinin Compounds. Ann Med Health Sci Res. 2015;5(2):93‐102. doi:10.4103/2141-9248.153609

[65] Papanikolaou X, Johnson S, Garg T, et al. Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis. Oncotarget. 2014;5(12):4118‐4128. doi:10.18632/oncotarget.1847

[66] Ma L, Fei H. Antimalarial drug artesunate is effective against chemoresistant anaplastic thyroid carcinoma via targeting mitochondrial metabolism. J Bioenerg Biomembr. 2020 Apr;52(2):123-130. doi: 10.1007/s10863-020-09824-w.

[67] Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJG, Marschall M. The Antiviral Activities of Artemisinin and Artesunate. Sept 2008. Clinical Infectious Diseases;47(6):804–811,https://doi.org/10.1086/591195

[68] Kuang M, Qin R, Cen Y, Shang S. Artesunate Attenuates Pro-Inflammatory Cytokine Release from Macrophages by Inhibiting TLR4-Mediated Autophagic Activation via the TRAF6-Beclin1-PI3KC3 Pathway. May 2018. Cellular Physiology and Biochemistry 47(2):475-488. DOI: 10.1159/000489982

[69] Li B, Zhang R, Li J, Zhang L, Ding G, Luo P, et al. (2008). Antimalarial artesunate protects sepsis model mice against heat-killed Escherichia coli challenge by decreasing TLR4, TLR9 mRNA expressions and transcription factor NF-kappa B activation. Int Immunopharmacol 8: 379-389.

[70] Li B, Yu M, Pan X, Ren C, Peng W, Li X, Jiang W, Zheng J, Zhou H: Artesunate reduces serum lipopolysaccharide in cecal ligation/puncture mice via enhanced LPS internalization by macrophages through increased mRNA expression of scavenger receptors. Int J Mol Sci 2014;15:1143-1161.

[71] Miranda AS, Brant F, Rocha NP, et al. Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria. Malar J. 2013;12:388. Published 2013 Nov 2. doi:10.1186/1475-2875-12-388

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