Artesunate and Artemisinin-based Drugs

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Mode of action: interaction with iron

Artemisinin’s anticancer activity is believed to occur when it comes in contact with iron. Cancer cells concentrate iron for use in cellular division (the malaria parasite also collects high concentrations of iron). Artemisinin’s contact with iron triggers the release of free radicals between cells that destroy cancer cells. Because of this “ferroptosis” effect, iron is often administered several hours before artemisinin to enhance targeting the cancer cells while sparing normal cells.¹Hu Y, Guo N et al. The potential mechanisms by which artemisinin and its derivatives induce ferroptosis in the treatment of cancer. Oxidative Medicine and Cellular Longevity. 2022 Jan 4;2022:1458143; Crespo-Ortiz MP, Wei MQ. Antitumor activity of artemisinin and its derivatives: from a well-known antimalarial agent to a potential anticancer drug. Journal of Biomedicine and Biotechnology. 2012;2012:247597. In addition, several other pathways for the anti-cancer modes of action of artesunate and artemisinin derivatives have been studied. These include growth inhibition through cell cycle arrest, apoptosis of cancer cells, inhibition of angiogenesis, disruption of cell migration and modulation of nuclear receptor responsiveness.²Firestone GL, Sundar SN. Anticancer activities of artemisinin and its bioactive derivatives. Expert Reviews in Molecular Medicine. 2009 Oct 30;11:e32.

Preclinical evidence

Notable preclinical evidence is listed here; clinical evidence is in How can artemisinin-based drugs help you? What the research says ›

Improving treatment outcomes

Cancer as a whole

• Artesunate enhanced the anticancer activity of doxorubicin, temozolomide, and erlotinib and sensitized tumor cells to cisplatin in preclinical studies.³Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Dihydroartemisinin (DHA) enhanced anticancer activity of doxorubicin, cisplatin, carboplatin, temozolomide, gemcitabine, cytarabine, and dexamethasone in preclinical studies.⁴Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Ethacrynic acid and L-buthionine sulfoximine sensitized MSV-HL13 cells to artesunate in preclinical studies.⁵Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.

Brain cancer

• Artesunate and dihydroartemisinin (DHA) each sensitized glioblastoma cells to radiotherapy in preclinical trials.⁶Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artemether enhanced the anticancer activity of VCAM1 shRNA against glioblastoma cells in preclinical trials.⁷Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artemisone enhanced the anticancer activity of oxaliplatin against glioma cells in preclinical trials.⁸Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.

Breast cancer 

• Artemisone enhanced the anticancer activity of either oxaliplatin, gemcitabine, or thalidomide against breast cancer cells in preclinical trials.⁹Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artesunate enhanced apoptosis in MCF-7 breast cancer cells in vitro via lysosome-dependent mitochondrial outer membrane permeabilization.¹⁰Hamacher-Brady A, Stein HA et al. Artesunate activates mitochondrial apoptosis in breast cancer cells via iron-catalyzed lysosomal reactive oxygen species production. Journal of Biological Chemistry. 2011 Feb 25;286(8):6587-601.
• Resistance to artesunate was induced in highly metastatic breast cancer cell line (MDA-MB-231) but not in a cell line that was less tumorogenic (MDA-MB-468) in preclinical trials.¹¹Bachmeier B, Fichtner I et al. Development of resistance towards artesunate in MDA-MB-231 human breast cancer cells. PLOS ONE. 2011;6(5):e20550.
• Anticancer activity in breast cancer cell lines treated with artemisinin derivatives¹²Kumar MS, Yadav TT, Khair RR, Peters GJ, Yergeri MC. Combination therapies of artemisinin and its derivatives as a viable approach for future cancer treatment. Current Pharmaceutical Design. 2019;25(31):3323–3338.

Cervical cancer

• Artesunate sensitized cervical cancer cells to radiotherapy in preclinical trials.¹³Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artesunate enhanced the anticancer activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against cervical cancer cells in preclinical studies.¹⁴Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• DHA enhanced the anticancer activity of PARK7 siRNA or p8 siRNA against cervical cancer cells in preclinical trials.¹⁵Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.

Colorectal cancer

• Dihydroartemisinin (DHA) enhanced the anticancer activity of VCAM1 shRNA or p8 siRNA against colon cancer cells in preclinical trials.¹⁶Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artemisone enhanced the anticancer activity of either oxaliplatin, gemcitabine, or thalidomide against colon cancer cells in preclinical trials.¹⁷Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• DHA exerted an anticancer effect against several CRC cell lines and restored cancer cell sensitivity to 5-FU in a p53 knockout CRC HCT116 cell line in preclinical studies.¹⁸Yao Z, Bhandari A et al. Dihydroartemisinin potentiates antitumor activity of 5-fluorouracil against a resistant colorectal cancer cell line. Biochemical and Biophysical Research Communications. 2018;501(3):636–642.
• Many artemisinin derivatives have been synthesized and show cytotoxic activity against HCT116 and WM-266-4 CRC cell lines in vitro.¹⁹Wang LL, Kong L et al. Design and synthesis of novel artemisinin derivatives with potent activities against colorectal cancer in vitro and in vivo. European Journal of Medicinal Chemistry. 2019;182:111665.
• Synthesized thymoquinone-artemisinin hybrid drugs selectively decreased the viability of HCT116 and HT29 CRC cell lines in vitro. The hybrid labeled 7a performed better than 5-fluorouracil at suppressing these cell lines in vitro.²⁰Fröhlich T, Ndreshkjana B et al. Synthesis of novel hybrids of thymoquinone and artemisinin with high activity and selectivity against colon cancer. ChemMedChem. 2017;12(3):226–234.
• Artesunate inhibited proliferation of HCT116 CRC cell lines in vitro and in vivo (in mice) by inducing apoptosis and autophagy. When autophagy was pharmacologically blocked, apoptosis was increased even further.²¹Jiang F, Zhou JY, Zhang D, Liu MH, Chen YG. Artesunate induces apoptosis and autophagy in HCT116 colon cancer cells, and autophagy inhibition enhances the artesunate‑induced apoptosis. International Journal of Molecular Medicine. 2018;42(3):1295–1304.
• Dihydroartemisinin (DHA) reduced viability of HCT116 CRC cell lines in vitro. The study suggests the mechanisms include G1 cell cycle arrest, apoptotic cell death, accumulation of reactive oxygen species (ROS).²²Lu M, Sun L, Zhou J, Yang J. Dihydroartemisinin induces apoptosis in colorectal cancer cells through the mitochondria-dependent pathway. Tumor Biology. 2014;35(6):5307–5314.
• Orally administered artesunate reduced pre-neoplastic changes comparable to aspirin in rats treated with dimethylhydrazine (DMH) to induce colon carcinogenesis. It could not be determined if a control group was included in the study.²³Verma S, Das P, Kumar VL. Chemoprevention by artesunate in a preclinical model of colorectal cancer involves down regulation of β-catenin, suppression of angiogenesis, cellular proliferation and induction of apoptosis. Chemico-Biological Interactions. 2017;278:84–91.
• Artesunate significantly inhibited HCT116 CRC cell viability in a dose dependent manner. The study suggested that the mechanisms of action included suppressing the fatty acid biosynthetic pathway and activating the mitochondrial apoptosis pathway.²⁴Chen X, Wong YK 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.
• 10-(4-phenyl-1H-1,2,3- triazol)-artemisinin (5a) controlled acquired drug resistance and recovered the anticancer effect of paclitaxel on cancer cells in vitro.²⁵Lee DH, Hasanuzzaman M et al. 10-phenylpyrazole artemisinin is a novel P-glycoprotein inhibitor that suppresses the overexpression and function of P-glycoprotein. Current Pharmaceutical Design. 2018;24(46):5590–5597.
• Anticancer activity in colorectal cancer cell lines treated with artemisinin derivatives²⁶Kumar MS, Yadav TT, Khair RR, Peters GJ, Yergeri MC. Combination therapies of artemisinin and its derivatives as a viable approach for future cancer treatment. Current Pharmaceutical Design. 2019;25(31):3323–3338.

Endometrial cancer

• Artemisinin inhibited proliferation of human Ishikawa endometrial cancer cells.²⁷Tran KQ, Tin AS, Firestone GL. Artemisinin triggers a G1 cell cycle arrest of human Ishikawa endometrial cancer cells and inhibits cyclin-dependent kinase-4 promoter activity and expression by disrupting nuclear factor-κB transcriptional signaling. Anticancer Drugs. 2014 Mar;25(3):270-81.

Endothelial cancer

• Artesunate enhanced cytotoxic activity of captopril against HUVEC endothelial cells in preclinical studies²⁸Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.

Gastric cancer

• Artesunate inhibited the growth of gastric cancer cell lines SGC-7901, BGC-823, and AGS but had no effect on GES-1 cells in vitro and caused a dose dependent tumor regression in mice.²⁹Zhou X, Sun WJ et al. Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. Anticancer Drugs. 2013 Oct;24(9):920-7.

Leukemia

• DHA had a synergistic interaction with 6PGD inhibitors Physcion and S3 against leukemia cells in preclinical studies.³⁰Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70. 
• Artesunate inhibited growth of leukemia cells when used with arsenic trioxide in preclinical studies.³¹Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70. 
• Dihydroartemisinin (DHA) had a synergistic interaction with 6PGD inhibitors physcion and S3 against leukemia cells in preclinical studies³²Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70. 
• DHA had an additive interaction with sodium salicylate against leukemia cells in preclinical studies.³³Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70. 
• DHA enhanced the anticancer action of vitamin C and vitamin D₃ against leukemia cells in preclinical studies.³⁴Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70. 
• Anticancer activity in leukemia cell lines treated with artemisinin derivatives³⁵Kumar MS, Yadav TT, Khair RR, Peters GJ, Yergeri MC. Combination therapies of artemisinin and its derivatives as a viable approach for future cancer treatment. Current Pharmaceutical Design. 2019;25(31):3323–3338.

Liver cancer

• Dihydroartemisinin (DHA) increased efficacy of gemcitabine against human hepatoma cells.³⁶Hou 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 Sep 1;14(17):5519-30.
• DHA enhanced the anticancer activity of p8 siRNA against liver cancer cells in preclinical trials.³⁷Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artesunate inhibited solid tumor growth in vivo and increased survival of mice bearing H22 ascitic liver tumors. There was also evidence of cytotoxicity to human hepatocarcinoma SMMC-7721 cell line in vitro.³⁸Wang Q, Wu LM, Li AY, Zhao Y, Wang NP. [Experimental studies of antitumor effect of artesunate on liver cancer]. [Article in Chinese]. Zhongguo Zhong Yao Za Zhi. 2001 Oct;26(10):707-8, 720.
• Artesunate downregulated vascular endothelial growth factor and placental growth factor expression and reduced viability in HepG2 and BWTG3 cell lines in vitro. It also decreased vessel density and tumor burden in mice (in vivo).³⁹in vitroVandewynckel YP, Laukens D et al. Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent. European Journal of Gastroenterology and Hepatology. 2014 Aug;26(8):861-70.
• Anticancer activity in hepatocellular carcinoma cell lines treated with artemisinin derivatives⁴⁰Kumar MS, Yadav TT, Khair RR, Peters GJ, Yergeri MC. Combination therapies of artemisinin and its derivatives as a viable approach for future cancer treatment. Current Pharmaceutical Design. 2019;25(31):3323–3338.

Lung cancer

• Artesunate and dihydroartemisinin (DHA) each sensitized lung cancer cells to radiotherapy in preclinical trials.⁴¹Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artemisone enhanced the anticancer activity of either oxaliplatin or gemcitabine against pancreatic cancer cells in preclinical trials.⁴²Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artesunate, DHA, and other artemisinin derivatives led to lower colony formation, less proliferation, greater apoptosis, and other anticancer activity in preclinical studies.⁴³Cheong DHJ, Tan DWS, Wong FWS, Tran T. Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Pharmacological Research. 2020 Aug;158:104901. 

Lymphoma

• Artesunate enhanced anticancer activity of rituximab against B-cell lymphoma cells in preclinical studies.⁴⁴Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.

Oral squamous cell carcinoma

• Artemisinin promotes apoptosis in HPV 16 immortalized and transformed human gingival epithelial (IHGK) cells.⁴⁵Yamachika E, Habte T, Oda D. Artemisinin: an alternative treatment for oral squamous cell carcinoma. Anticancer Research. 2004 Jul-Aug;24(4):2153-60.

Ovarian cancer

• Dihydroartemisinin (DHA) enhanced the anticancer activity of p8 siRNA against ovarian cancer cells in preclinical trials.⁴⁶Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artesunate and DHA both inhibited SKOV3 and epithelial ovarian cancer (EOC) cell growth via G2/M cell cycle arrest, induced autophagy and disruption of the NF-kappaB signaling pathway in EOC cells in vitro.⁴⁷Li B, Bu S, Sun J, Guo Y, Lai D. Artemisinin derivatives inhibit epithelial ovarian cancer cells via autophagy-mediated cell cycle arrest. Acta Biochimica et Biophysica Sinica (Shanghai). 2018 Dec 1;50(12):1227-1235.
• DHA significantly inhibited proliferation, migration, and invasion of ovarian cancer cells and induced apoptosis in vitro but had few effects on cell proliferation and apoptosis in human ovarian surface epithelial cells.⁴⁸Liu Y, Gao S et al. Dihydroartemisinin induces apoptosis and inhibits proliferation, migration, and invasion in epithelial ovarian cancer via inhibition of the hedgehog signaling pathway. Cancer Medicine. 2018 Nov;7(11):5704-5715.
• DHA directly targets platelet-derived growth factor receptor-alpha (PDGFR𝛼) to inhibit ovarian cancer cell growth and metastasis.⁴⁹Li X, Ba Q et al. Dihydroartemisinin selectively inhibits PDGFRα-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRα protein. Cell Discovery. 2017 Nov 21;3:17042.
• Artesunate treatment showed strong induction of reactive oxygen species (ROS) and reduced proliferation of ovarian cancer cells in vitro and a decrease of tumor growth in a mouse model of ovarian cancer (in vivo).⁵⁰Greenshields AL, Shepherd TG, Hoskin DW. Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate. Molecular Carcinogenesis. 2017 Jan;56(1):75-93.
• DHA enhanced toxicity to human ovarian cancer cells without appreciable toxicity to normal cells when conjugated with the chemotherapy drug melphalan in ARS4.⁵¹Li X, Zhou Y et al. Preclinical efficacy and safety assessment of artemisinin-chemotherapeutic agent conjugates for ovarian cancer. EBioMedicine. 2016 Dec;14:44-54.
• Combined treatment of DHA and Curcumin synergistically decreased cell viability, arrested cell cycle, and promoted apoptosis in SKOV3 cells in vitro. The combined DHA-curcumin treatment also significantly inhibited tumor growth in mice (in vivo).⁵²Zhao J, Pan Y et al. Dihydroartemisinin and curcumin synergistically induce apoptosis in SKOV3 cells via upregulation of MiR-124 targeting midkine. Cell Physiology and Biochemistry. 2017;43(2):589-601.

Pancreatic cancer

• Artesunate inhibited growth of pancreatic cancer cells when used with triptolide in preclinical studies.⁵³Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70. 
• Dihydroartemisinin (DHA) enhanced the anticancer activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against prostate cancer cells in preclinical studies.⁵⁴Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artemisone enhanced the anticancer activity of either oxaliplatin, gemcitabine, or thalidomide against pancreatic cancer cells in preclinical trials.⁵⁵Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.
• Artesunate produced dose-dependent tumor regression in vivo in a pancreatic cancer xenografts model in mice that was comparable to gemcitabine. In vitro, artesunate demonstrated loss of mitochondrial membrane potential, cell lysis and other cytotoxic activity against Panc-1, BxPC-3 and CFPAC-1 pancreatic cancer cell lines.⁵⁶Du 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 Apr;65(5):895-902.

Prostate cancer

• Dihydroartemisinin (DHA) enhanced the anticancer activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against prostate cancer cells in preclinical studies.⁵⁷Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70.

Renal cell carcinoma

• Artesunate exerted selective cytotoxicity against human renal cell carcinoma (RCC) cell lines Caki-1, 786-0, and SN12C-GFP-SRLu2 and sensitized the cells to sorafenib in vitro. In vivo, anti-tumor, anti-metastatic and anti-angiogenic effects of artesunate were also validated in 786-0 cell line xenografts in mice.⁵⁸Jeong DE, Song HJ 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 Oct 20;6(32):33046-64.

Sarcoma

• Artesunate inhibited growth of osteosarcoma cells when used with allicin in preclinical studies.⁵⁹Efferth T. Cancer combination therapies with artemisinin-type drugs. Biochemical Pharmacology. 2017 Sep 1;139:56-70. 

Artesunate combined with other therapies

• Comprehensive Undermining of Survival Paths (CUSP9) is a treatment made of 9 medications, including artesunate, as an adjunct to temozolomide. The authors believe a trial of CUSP9 is warranted in cases of a recurrence of a glioblastoma.⁶⁰Kast RE, Karpel-Massler G, Halatsch ME. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget. 2014 Sep 30;5(18):8052-82.