ARTEMISININ

Very limited number of clinical trials, which mainly used the prescription form artesunate. A small pilot study in prostate cancer using pulsed oral artemisinin 300–400 mg three times a day every other week for 3–24 months showed some encouraging indications.

Similarly an older study in lung cancer reported extended disease free progression with artesunate, a derivative of artemisinin. And another small trial in colorectal cancer also reported positive tendencies with artesunate. Dose and effect research shows artemisinin may be best pulsed one week on one week off, as resistance develops to the active compounds actions.Of those patients who have previously undergone RP, 2/5 (40%) had improved PSA kinetics after artemisinin therapy.

TYPICAL ABSORPTION LEVELS

20-40%

EXAMPLES OF IMPROVED OUTCOMES

PENDING

PRE-DIAGNOSIS OR PREVENTION

Highlighted Studies

Median artemisinin dosing was for 11.5 months .. in this group of 5 patients. Patients 7 and 24 had favorable PSA kinetics (measured from baseline to end of therapy with artemisinin, defined as PSADT >1 year and PSAV <0.75 ng/mL/year).. Two patients in this group met the primary outcome measure…. 2/4 patients (50%) had favorable outcomes. No patient was known to have required additional radiation or hormone therapy. There was no evidence of metastatic disease or other severe outco...

There were no significant differences in the short-term survival rate [lung cancer] MST and 1-year survival rate between the trial group and the control group, which were 45.1% and 34.5%, 44 weeks and 45 weeks, 45.1% and 32.7%, respectively. The DCR [disease control rate] of the trial group [with artesunate] (88.2%) was significantly higher than that of the control group (72.7%), and the trial group’s TTP time to progression (24 weeks) was significantly longer than that of the control g...

20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively…the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the p...

Combination of artemisinin and its derivatives with traditional chemotherapeutic drugs can significantly enhance the anti-cancer effect of other chemotherapy drugs without any obvious adverse effects. Especially, in the cancer cells with chemotherapeutic drug resistance, artemisinin has shown significant antitumor activity, suggesting that artemisinin has the potential to be a combined chemotherapy drugs to reduce resistance of cancer cells with traditional chemotherapy drugs

TABLE OF REFERENCES

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URL	Rating	Highlight	Highlight 2	Dose mg/kg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541447/	2	This pilot study provides preliminary evidence to suggest that high-dose, pulsed oral artemisinin therapy may have activity in patients with CaP. A larger controlled trial is warranted to confirm these preliminary beneficial effects.	In all cases, pure artemisinin was dosed on a schedule of 7 days on, then 7 days off. This is based on research showing that artemisinin absorption stops after approximately 5–7 days in men.4 This is due to upregulation of intestinal CYP2D6, which completely blocks absorption after a few days. Based on the dosing of artemisinin in malaria patients, a daily dose of 400 mg three times a day (tid) was used during on-treatment weeks. One CaP patient (for simplicity’s sake not included in this study as he underwent radiation therapy) developed mild numbness and tingling in the feet at this dose after several months of treatment, and so all subsequent patients to that event were treated with 300 mg tid. No further obvious adverse effects of artemisinin occurred at this dose	300-400mg doses 3x per day once every 2 weeks
https://pubmed.ncbi.nlm.nih.gov/18241646/	2	The DCR of the trial group (88.2%) was significantly higher than that of the control group (72.7%) (P<0.05), and the trial group's TTP (24 weeks) was significantly longer than that of the control group (20 weeks) (P<0.05). No significant difference was found in toxicity between the two groups	Artesunate can be used in the treatment of NSCLC. Artesunate combined with NP can elevate the short-term survival rate and prolong the TTP of patients with advanced NSCLC without extra side effects.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4484515/	2	During a median follow up of 42 months, there were 6 recurrences in the placebo group and 1 recurrence in an artesunate recipient. Fig. 4 illustrates results from a Cox's proportional hazards model. The hazard ratio of first disease recurrence is 0.16 (95% CI (0.02, 1.3)) in the artesunate group compared with placebo. The survival beyond 2 years in the artesunate group is estimated at 91% (95% CI (54%, 98%)) whilst surviving the first recurrence in the placebo group is only 57%	The recurrence-free survival probability was also higher after artesunate compared with placebo (at 3 years 0.89 compared with 0.5; Fig. 3) although confidence intervals for these estimates overlap (HR 0.16, p = 0.091, Supplementary Table 1) because of the small numbers of patients and therefore events included in this study. Till this analysis, there have been no deaths in artesunate recipients (despite some patients having relatively poor prognosis), and 3 deaths in placebo recipients.
https://www.sciencedirect.com/science/article/pii/S0753332219322358?via%3Dihub	1	We demonstrated that ART exhibited anti-cancer eﬀ ;ects of RCC. The drug inhibited cell proliferation, migration and metastasis. Combination of ART and AKT inhibitor enhanced anti-cancer effects of ART. These ﬁndings provide novel insights into potential and combinational therapeutic strategies for ccRCC.	1) ART inhibited tumor cell proliferation, migration and invasion; 2) ART suppressed AKT and ERK1/2 signaling pathway; 3) combination of ART and AKT inhibitor VIII enhanced the anti-cancer effects of ART; 4) ART reduced tumorigenesis in vivo.	20mg/kg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718674/	1	DHA exhibited remarkable and specific inhibitory effects on STAT3 activation via selectively blocking Jak2/STAT3 signaling. Besides, DHA significantly inhibited HNSCC growth both in vitro and in vivo possibly through induction of apoptosis and attenuation of cell migration.	DHA also synergized with cisplatin in tumor inhibition in HNSCC cells. Our findings demonstrate that DHA is a putative STAT3 inhibitor that may represent a new and effective drug for cancer treatment and therapeutic sensitization in HNSCC patients.	50mg/kg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684509/	1	Artemisinin's anticancer effect is likely to be mediated via inhibition of the PI3K/AKT/mTOR pathway. Artemisinin also induced mitochondrial membrane potential loss and apoptosis of UM cells, having no significant toxic effect on normal retinal neuronal cells RGC-5 and epithelial cells D407. These findings and the reported safety of artemisinin's clinical dosage strongly suggest the therapeutic potential of artemisinin in the prevention and treatment of uveal melanomas.	Further study of artemisinin action in vivo showed that it was able to inhibit tumor growth in an UM subcutaneous mouse model. Artemisinin effect was shown to be dose-dependent as it significantly reduced the growth of UM melanoma tumors by almost 50% in the animals treated with the lower dose and 75% in the animals receiving a higher dose. The body weights of the animals receiving artemisinin were not affected further suggesting that it was able to affect tumor growth without having a toxic effect	20 or 40
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741748/	1	Artesunate possesses several characteristics that make it a promising angiogenesis inhibitor for cancer, including its anti-tumor activity, its anti-angiogenic efficacy, its low overall toxicity, and its highly selective toxicity to cancer cells. Given the anti-angiogenic activities described here, ART appears to be well-suited for adjuvant therapy in combination with classical TKIs for the treatment of highly angiogenic RCC.	ART may be useful for angioprevention, which is a strategy based on nontoxic drugs that can be taken for extended periods or even as life-long treatments to control tumor growth and metastasis	100mg/ kg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058767/	1	By affecting multiple targets in Wnt/β-catenin pathway, a developmental pathway influencing the clinical outcomes of early-diagnosed lung cancer patients, ART, DHA, and ARTS markedly suppressed lung tumorigenesis and exerted a perfect effect on inhibiting tumor metastasis. Therefore, ART and its derivatives are excellent chemopreventive candidates with high bioavailability, low toxicity, and significant anti-tumor efficacy	To further explore the anti-tumor effectiveness of ART, DHA, and ARTS in vivo and also the implied risk of toxicity after biotransformation, A549 xenograft model was applied. Compared with the control group, without altering the body weight of mice, ART, DHA, and ARTS significantly decreased tumor volume and tumor weight	60
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258160/	1	ARS and DHA could suppress TGF-β signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-β signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo.	ARS and DHA could suppress TGF-β signaling, thus inactivated cancer-associated fibroblasts, and finally inhibited cancer growth and metastasis. Therefore, artemisinin derivatives might be potential therapeutic agents for the treatment of breast cancer.	100mg/kg per day
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349987/	1	Low concentration DHA also inhibited Warburg effect in NSCLC cells. Mechanically, DHA negatively regulates NF-κB signaling to inhibit the GLUT1 translocation. Blocking the NF-κB signaling largely abolishes the inhibitory effects of DHA on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Furthermore, GLUT1 knockdown significantly decreased the inhibition of invasion, and migration by DHA	DHA could be a useful agent for inhibiting tumor metastasis in NSCLC. Also, GLUT1 modulation via NF-κB inactivation could be a critical cancer targeted strategy. On the basis of our findings, further in-depth researches including clinical trials are required	50 or 100mg/ kg
https://www.hindawi.com/journals/omcl/2021/9911537/#discussion	1	Results suggest the potential use of artemisinin in the prevention of UM progression. By acting in PI3K/AKT/mTOR, a pathway with recognized importance in cancer, artemisinin was shown to be able to impair the migration, invasion, and proliferation of UM cells.	Artemisinin also induced mitochondrial membrane potential loss and apoptosis of UM cells, having no significant toxic effect on normal retinal neuronal cells RGC-5 and epithelial cells D407. These findings and the reported safety of artemisinin’s clinical dosage strongly suggest the therapeutic potential of artemisinin in the prevention and treatment of uveal melanomas.	40mg/kg
https://www.sciengine.com/ABBS/doi/10.1093/abbs/gmw082	1	In vivo experiments also showed that the antitumor effect of Onc was markedly enhanced by DHA in mouse xenograft models. No obvious adverse effect was observed after the treatment. The density of microvasculature in the tumor tissues treated with Onc/DHA combination was lower than those treated with Onc or DHA alone. The above results are consistent with the results of the matrigel plug test for angiogenesis suppression using the Onconase/DHA combinatio	In our study, the combination of Onc and DHA synergistically inhibited the proliferation of NSCLC and MSTO cells and showed enhanced antitumor effects in mouse xenograft models. The synergistic antitumor effect of Onc and DHA allows a reduction in the drug dose, leading to lower side effects. The synergistic effect also means an enhanced antitumor activity at the same dose, thus suggesting a wide antitumor application.	20mg/kg
https://www.nature.com/articles/srep19074#Sec11	1	More importantly, we demonstrated that DHA inhibited breast tumor-induced osteolysis through inhibiting the proliferation, migration and invasion of MDA-MB-231 cells via modulating AKT signaling pathway. In conclusion, DHA effectively inhibited osteoclastogenesis and prevented breast cancer-induced osteolysis.	We also demonstrated that DHA can inhibit AKT activation, thus leading to inhibited proliferation and enhancing apoptosis in breast cancer cells. This finding suggests a universal mode of action of DHA is related to AKT activation. In conclusion, this study described a natural compound DHA can effectively inhibit osteoclastogenesis and prevented breast cancer-induced bone osteolysis through the suppression of the AKT signaling cascade.	100mg/kg
https://jgo.amegroups.com/article/view/68983/html	1	Artemisinin could inhibit the proliferation, metastasis, and glycolysis of esophageal squamous cell carcinoma (ESCC), and this was verified by the expression of key metastatic proteins (N-cadherin) and key enzymes of glycolysis [hypoxia-inducible factor-1α (HIF-1α), pyruvate kinase M2 (PKM2)]. Through network pharmacology, we found the potential therapeutic target of artemisinin, HIF-1α. The results of molecular docking showed that artemisinin could directly target HIF-1α and promote its degradation.	Artemisinin can target HIF-1α to reduce the level of glycolysis and inhibit the development of EC, which may become a targeted drug for the treatment of EC.
https://www.nature.com/articles/3780754#Abs1	1	Artemisinin down-regulated hypoxia-inducible factor-1α and vascular endothelial growth factor (VEGF) expression, which control endothelial cell growth. The data of the present study suggest that the antiangiogenic activity of artemisinin and the increase in tissue permeability for cytostatics may be exploited for anticancer treatment.	Artemisinin dose dependently inhibited angiogenesis in embryoid bodies and raised the level of intracellular reactive oxygen species. Furthermore impaired organization of the extracellular matrix component laminin and altered expression patterns of matrix metalloproteinases 1, 2, and 9 were observed during the time course of embryoid body differentiation. Consequently accelerated penetration kinetics of the fluorescent anthracycline doxorubicin
https://www.spandidos-publications.com/10.3892/or.2014.3323	1	Results revealed that artemisinin inhibited cell proliferation and tumor growth, with cell cycle arrest and apoptosis induction in neuroblastoma cells. Since artemisinin has been used for the treatment of malaria for an extensive period of time, a large body of data regarding clinical tests and adverse drug reactions in patients are available. Therfore, artemisinin may serve as a potential new therapeutic agent for the treatment of neuroblastoma.	Previous studies have shown that artemisinin induced apoptosis in pancreatic tumor cells (36), lung adenocarcinoma cells , liver cancer cells, and non-small cell lung cancer cells. In the present study, we first demonstrated that artemisinin induced the cell death and apoptosis of neuroblastoma cells at a lower dose than that for clinical usage	100mg/kg
https://aacrjournals.org/clincancerres/article/14/17/5519/72734/Experimental-Therapy-of-Hepatoma-with-Artemisinin	1	ART and DHA have significant anticancer effects against human hepatoma cells, regardless of p53 status, with minimal effects on normal cells, indicating that they are promising therapeutics for human hepatoma used alone or in combination with other therapies.ART and DHA inhibited tumor growth and modulated tumor gene expression consistent with in vitro observations. DHA increased the efficacy of the chemotherapeutic agent gemcitabine.	ART and DHA exerted the greatest cytotoxicity to hepatoma cells but significantly lower cytotoxicity to normal liver cells. The compounds inhibited cell proliferation, induced G1-phase arrest, decreased the levels of cyclin D1, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, and E2F1, and increased the levels of Cip1/p21 and Kip1/p27. They induced apoptosis, activated caspase-3, increased the Bax/Bcl-2 ratio and poly(ADP-ribose) polymerase, and down-regulated MDM2.	50 and 100mg/kg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9247850/	1	In summary, here we report that ART controls the functional polarization of MDSCs through PI3K/AKT, mTOR, and MAPK pathways and inhibition of MDSCs by ART may provide a novel therapeutic strategy to enhance anti-PD-L1 cancer immunotherapy.	Our data show that targeting blockade of MDSCs by ART further enhances anti-PD-L1 immunotherapy (Figures 5(a) and 5(d)). Most patients with melanoma and hepatocellular carcinoma initially respond to but later become resistant to anti-PD-L1 tumor immunotherapy [6, 53]. The main reason for this resistance is the presence of tumor immunosuppressive microenvironment which mainly consists of MDSCs, tumor-associated macrophages (TAMs), and Tregs [54]. In our experiments, combinating ART and anti-PD-L1 antibody significantly decrease the percentages of MDSC	50 and 100mg/kg
https://www.researchgate.net/publication/321191593_Dihydroartemisinin_selectively_inhibits_PDGFRa-positive_ovarian_cancer_growth_and_metastasis_through_inducing_degradation_of_PDGFRa_protein	1	The results from the present study may have high potential for translation to clinical practice. Our results uncovered a previously unknown target of DHA responsible for its effects on cell growth and migration in ovarian cancer cells. We speculate that the inhibition of PDGFRα by DHA is important for its actions on not only cell growth, proliferation and migration, but also apoptosis and angiogenesis [14, 49], which would facilitate the rational design of effective DHA-based cancer therapy	Considering that ART compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive cancer patients. We also believe that the results from the current study will facilitate the discovery of novel DHA-based, PDGFRα-targeting agents for the treatment of ovarian cancer, and possibly for other cancers as well.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629082/	1	Angiogenesis inhibitors have been shown to retard tumor growth and vascularization of prostate cancer cells in vivo, and artemisinin and its derivatives show similar anti-angiogenic effects...Results suggest that artemisinin is a very potent anti-cancer compound that exhibits unique effects on the cell cycle regulation of human prostate cancer cells. As such, artemisinin has the potential to be developed as a potent anti-prostate cancer therapeutic.	Our data corroborate these findings in that LNCaP xenografts excised from BALB/c mice treated with artemisinin showed little to no vascularization and appeared bloodless, whereas xenografts taken from the control mice were much larger and highly vascularized and sanguinary (data not shown). This result suggests that artemisinin may affect multiple pathways associated with tumor proliferation in vivo in addition to the control of cell cycle progression.	100
https://www.researchgate.net/publication/321191593_Dihydroartemisinin_selectively_inhibits_PDGFRa-positive_ovarian_cancer_growth_and_metastasis_through_inducing_degradation_of_PDGFRa_protein/link/5a142b04aca27240e308622e/download	1	ART compounds are currently clinically used drugs with favorable safety profiles, the results from this study will potentate their use in combination with clinically used PDGFRα inhibitors, leading to maximal therapeutic efficacy with minimal adverse effects in PDGFRα-positive cancer patients. We also believe that the results from the current study will facilitate the discovery of novel DHA-based, PDGFRα-targeting agents for the treat- ment of ovarian cancer, and possibly for other cancers as well.	that the PDGFRα expression was significantly enhanced in the tumor cells ovarian cancer patients with high metastasis (Figure 6a and Supplementary figure S7; Supplementary Table S3). These results indicated that PDGFRα may be a prognostic biomarker and a poten- tial therapeutic target for ovarian cancer. Discussion In the present study, we identified and validated PDGFRα as a novel molecular target for DHA, which was based on the following major findings. First, DHA selectively inhibits the growth and migration of PDGFRα-positive ovarian cancer cells. Second, DHA inhibited PDGFRα expression via promoting its pro- tein degradation. Third, following PDGFRα down- regulation by DHA, the downstream PI3K/AKT and MAPK/ERK signaling pathways were inactivated and the EMT was repressed, resulting in suppression of the tumor growth and migratio	25mg/ kg and adjunct
https://www.sciencedirect.com/science/article/pii/S075333222300656X#sec0015	1	The absolute bioavailability of ART, deoxyartemisinin and 10-deoxoartemisinin after oral (100 mg/kg) and intravenous (5 mg/kg) administration was 12.2; 1.60; and 26.1%, respectively	The bioavailability of artesunate, ART, and artemether after oral administration was 30% due to high first-pass metabolism. Artesunate reaches peak levels within minutes while artemether peaks in 2–6 h....Both are extensively metabolized and converted to DHA which has a plasma half-life of 1–2 h [92].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484515/	1	Artesunate has anti-proliferative properties in CRC and is generally well tolerated......During a median follow up of 42 months, there were 6 recurrences in the placebo group and 1 recurrence in an artesunate recipient	Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC.	Artesunate 200mg/ day for two weeks before surgery
https://ar.iiarjournals.org/content/37/11/5995#sec-3	1	ARTs represent an efficacious antimalarial drug group with an excellent safety profile. Their anticancer properties have been documented in multiple preclinical and clinical studies. ARTs effectively reduce the growth of solid tumours by inhibition of angiogenesis, induction of apoptosis and ferroptosis, production of reactive oxygen species and induction of cell-cycle arrest	The chemosensiting effect of artesunate and dihydroartemisinin suggests the use of ARTs as an add-on therapy in combination with conventional chemotherapeutics and it is to be studied in future clinical trials. ARTs may represent one of many examples of power hidden in natural sources and after many years of research may become new promising anticancer drugs, hopefully developed and introduced to clinical use in the near future.
https://onlinelibrary.wiley.com/doi/10.1002/kjm2.12684?af=R	1	DHA treatment induced significant apoptosis and ferroptosis through ROS accumulation and as a result, an increase in the sensitivity of A549-GR cells to gefitinib was observed. These results provide new insights on the research against EGFR-TKI drug resistance	The combined treatment of DHA and gefitinib resulted in inhibition of proliferation of A549, H1975, and HCC827 cells, and ROS accumulation and a remarkable induction of apoptosis was observed in A549-GR cells. DHA significantly induced apoptosis and ferroptosis in a dose-dependent manner and exhibited high cellular toxicity on A549-GR cells when combined with gefitinib.