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Targeted treatment of cancer with artemisinin and artemisinin-tagged iron-carrying compounds
Abstract
Artemisinin is a chemical compound that reacts with iron to form free radicals which can kill cells. Cancer cells require and uptake a large amount of iron to proliferate. They are more susceptible to the cytotoxic effect of artemisinin than normal cells. Cancer cells express a large concentration of cell surface transferrin receptors that facilitate uptake of the plasma iron-carrying protein transferrin via endocytosis. By covalently tagging artemisinin to transferrin, artemisinin could be selectively picked up and concentrated by cancer cells. Futhermore, both artemisinin and iron would be transported into the cell in one package. Once an artemisinin-tagged transferrin molecule is endocytosed, iron is released and reacts with artemisinin moieties tagged to transferrin. Formation of free radicals kills the cancer cell. The authors have found that artemisinin-tagged transferrin is highly selective and potent in killing cancer cells. Thus, artemisinin and artemisinin-tagged iron-carrying compounds could be developed into powerful anticancer drugs.
... ARTs, by reacting with iron in the malignant cells destroy them, but normal cells unsaturated with iron remain virtually unaffected by these agents [20][21][22]. Thus ARTs may provide targeted anticancer therapy, making the tumor cells selectively more susceptible to the cytotoxic effects [23]. ...
... ARTs, by reacting with iron in the malignant cells destroy them, but normal cells unsaturated with iron remain virtually unaffected by these agents [20][21][22]. Thus ARTs may provide targeted anti-cancer therapy, making the tumor cells selectively more susceptible to the cytotoxic effects [23]. ...
Artemisinin (ART) and dihydroartemisinin (DHA) are anti-malaria drugs but also exhibit huge anticancer potential based on ferroptosis driven by iron-dependent lipid peroxidation. This study was conducted on primary (SW480), metastatic (SW620) colon cancer, and noncancerous HaCaT cells at pharmacologically relevant drug concentrations (1–8 µM) and in the presence of holotransferrin (TRFi 50 µM) and linoleic acid (LA 20, 40 µM) at physiological levels. ART and DHA showed the growth inhibitory potency which was significantly increased in the presence of LA or/and TRFi. The IC50 for ART or DHA, LA40 and TRFi combination in both cancer cell lines ranged 0.14–0.69 µM whereas no cytotoxic effect was observed for HaCaT cells (SI = 202–480). Almost all experimental settings revealed late apoptosis in both cancer cell lines, but not in normal cells. The percentage of late apoptotic cells increased with LA concentrations and was intensified after TRFi addition. The strongest pro-apoptic effect was exhibited by ART or DHA, LA40, and TRFi combination. More interestingly, we found a stimulatory effect of TRFi on IL-6 synthesis. The present study using LA and TRFi which are inherent blood components revealed high antitumor artemisinin activity in concentrations achievable after drug administration to cancer patients without toxic effects on normal cells.
... Medicinal plants have served as a constant source of remedies for a variety of diseases over centuries. Plants have been a rich source of antimicrobial and anthelmintic agents and their products are used medicinally in different parts of the world as sources of many potent and safe drugs, including anthelmintics (Lai et al., 2005;Abdul-Ghani et al., 2011;Harvey et al., 2015;Irum et al., 2015). This study was therefore designed to investigate the anthelmintic efficacies of three medicinal plants, namely, Annona senegalensis, Cochlospermum planchonii, and Sarcocephalus latifolius against H. contortus. ...
Aim of study: To investigate the in vitro anthelmintic efficacies of three plants, Annona senegalensis (AS), Cochlospermum planchonii (CP), and Sarcocephalus latifolius (SL), used by livestock farmers in Northern Nigeria, to treat gastrointestinal nematode infections in ruminants.
Area of study: Makurdi, Benue State, Nigeria.
Materials and methods: The plants were selected through a structured questionnaire administered to livestock farmers in Northern Nigeria. Aqueous and acetone leaf (AS and SL) and root (CP) extracts of these plants were investigated for their anthelmintic activity against Haemonchus contortus using the egg hatch inhibition assay at concentration levels of 0.3125 to 10 mg/mL in 2.5% dimethyl sulfoxide.
Main results: A probit log-dose response analysis showed that acetone extract of CP achieved 100% egg hatch inhibition similar to the commercial drug at all tested concentrations after 48 hours of incubation, while AS demonstrated 88.7% egg hatch inhibition. Acetone extract of SL had less than 50% egg hatch inhibition at all tested concentrations. On the other hand, the aqueous extract of CP and SL both exhibited 100% inhibition at 5 and 10 mg/mL of the tested concentrations, while AS had less than 50% egg hatch inhibition at all tested concentrations.
Research highlights: This study identified CP, AS, and SL as medicinal plants with rich sources of molecules that have potential value in the development of novel anthelmintic drugs.
... Due to the great effect of artemisinin in treating malaria, researchers have set off an upsurge of artemisinin research. The research on artemisinin is not limited to antimalarial effect; it also focuses on its efficacy as antivirus, antitumor, anti-inflammatory, and antiparasitic (except malaria) (4,5). Many artemisinin derivatives have been developed to improve the oral bioavailability, short half-life, and low solubility of artemisinin (6)(7)(8)(9). ...
Objective
Artemisinin is an organic compound that comes from Artemisia annua. Artemisinin treatment is the most important and effective method for treating malaria. Bibliometric analysis was carried out to identify the global research trends, hot spots, scientific frontiers, and output characteristics of artemisinin from 2000 to 2021.
Methods
Publications and their recorded information from 2000 to 2021 were retrieved through the Web of Science Core Collection (WoSCC). Using VOSviewer and Citespace, the hotspots and trends of studies on artemisinin were visualized.
Results
A total of 8,466 publications were retrieved, and for the past 22 years, the annual number of publications associated with artemisinin kept increasing. The United States published most papers. The H-index and number of citations of the United States ranked first. The University of Oxford and MALARIA JOURNAL were the most productive affiliation and journal, respectively. A paper written by E.A. Ashley in 2011 achieved the highest global citation score. Keywords, such as “malaria,” “artesunate,” “plasmodium-falciparum,” “ in-vitro ,” “artemisinin resistance,” “plasmodium falciparum,” “resistance,” and “artemether-lumefantrine,” appeared most frequently. The research on artemisinin includes clinical research and animal and cell experiments.
Conclusion
The biosynthesis, drug resistance mechanism, and combination of artemisinin have become more popular than before. Studies on artemisinin treating coronavirus disease 2019 (COVID-19) have been carried out, and good research results have been obtained.
... Artemisinin metabolized can be tested by HPLC using human plasma and saliva sample [31,32] . HPLC-UV (ultraviolet light detection) is the widely adopted technique to define pharamacokinetics by reducing specificity. ...
Malaria and cancers still existed as a prevalent life-threatening ailment lacking vaccine owing to numerous pharmacological drawbacks such as high toxicity, low solubility and low efficiency. Artemisinin is a semisynthate derived from Artemisia annua an herb with immense therapeutic potential most commonly employed for treating malaria, renal ailments and cancer. The poor solubility of this bioactives makes it less efficient in therapeutic applications. However, the advancement of nanotechnological interventions like nano drug delivery/carrier system improves therapeutic efficiency via target site delivery, precision in dosage, slow release of nanobioactives, and reduced toxicity optimally. Artemisinin drug compounds possess the ability to control immunity response and such capability has beneficial impacts in treating cancer and malaria. In recent years, nanostructures like liposomes, carbon nano tubes (CNTs), Polymeric nanoparticles improves drug efficiency and known to exploit in treating parasitic effect of malaria in humans. Consequently, nanobioformulations are novel and innovative strategy for significant therapeutic approach towards life threatening human ailments. However, there is still a need for researchers to refine the study towards nullifying the direct and indirect toxicity of nanodrugs to human body.
... The mechanism of action of artemisinin compounds as anticancer is anti-angiogenic, anti-inflammatory, anti-metastatic, and inhibiting cancer cell growth. It is known that artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals (20,21). ...
Intoduction: Breast cancer is a significant healthcare problem worldwide. Surgery remains the treatment of choice combined with other modalities such as chemotherapy, radiation, and immunotherapy such as Artemisia vulgaris (AV). Selective cytotoxicity of AV is intended as a supplementation to Adriamycin-Cyclophosphamide, improving the response rate of chemotherapy in adenocarcinoma mammae.
Method: This study used a "Post-test only control group design" on 24 females C3H mice that were randomly selected and divided into four groups: group K (control), P1 (chemotherapy), P2 (extract), and P3 (combination). Adenocarcinoma mammae come from the inoculation of donor mice. Chemotherapy of Adriamycin 60 mg / m 2 and Cyclophosphamide 600 mg / m 2 were given in two cycles. AV 13 mg (0.2 ml) was given once daily orally. NF-κB expression and CD34
were evaluated using imunohistochemical staining.
Result: The expression of NF-κB and microvascular density of CD 34 were obtained in groups of K, P1, P2, P3 Statistical analysis showed significant decrease in the expression of NF-κB between groups K and P1, P2, P3. Correlation analysis between NF-κB expression with CD 34 was found to have significant correlation (p = 0,039 and r = 0,897).
Conclusion:
Artemisia vulgaris can reduce angiogenesis by decreasing NF-κB expression and the microvascular density CD34 of adenocarcinoma mammae of C3H mice treated with Adriamycin-Cyclophosphamide chemotherapy and can improve the effectivity.
... (Derda et al. 2016). Lai et al. (2005) discovered that artemisinin and artemisinin-tagged iron-carrying compounds could be developed into powerful anticancer drugs. Njuguna et al. (2012) stated that artemisinin and its derivatives have revealed its potential use in treating other infectious and noninfectious diseases. ...
Artemisia annua L. (Chinese wormwood herb, Asteraceae) synthesizes artemisinin, which is known as qinghaosu, considers as a unique sesquiterpene endoperoxide lactone. In traditional Chinese medicine, it has been used for the treatment of fevers and haemorrhoides. More researches on Artemisia annua L. and its derivatives, especially artemisinin and other metabolites will help to increase the knowledge and value of A. annua and its constituents. Phenolics from Artemisia annua consists of coumarins, flavones, flavonols, phenolic acids, and miscellaneous. Artemisinin has attracted much attention from scientists due to its potent antimalarial properties as secondary metabolites. Moreover, more attentions are focusing on the roles of artemisinin and its derivatives in treating obesity and metabolic diseases. They also have anti-bacterial, anti-inflammatory, anti-tumor, anti-protozoa, anti-helminthic, anti-fungal, anti-angiogenic and antiproliferation properties. The most important derivatives of Artemisia annua L. are arteether, artemether, artemiside, artemisinin, artemisone, artesunate, and dihydroartemisinin. Artemisinin also use against some cancers such as liver cancer, brain glioma, leukemia, nasopharyngeal cancer, gallbladder cancer, gastric cancer, cervical cancer, lung cancer, breast cancer and colon cancer. This important gift from ancient Chinese traditional medicine can guarantee health of people all around the world. Further researches should be done on the new advances and development of artemisinin and its derivatives as potential natural medicine in the global fight against so many diseases, malaria included.
Background
Anaplastic thyroid cancer (ATC) is a rare subtype of thyroid tumors with a high mortality rate. Targeted therapies against ATC are ineffective and mostly transient. Artemisinin has shown excellent anti-tumor activity in several cancers, but its effects on ATC are still unknown.
Objective
To evaluate the effects of artemisinin on ATC cells and assess the mechanism underlying drug resistance.
Methods
The viability and proliferation rates of the artemisinin-treated CAL-62 and BHT-101 cells were analyzed by MTT and EdU incorporation assays. The protein expression levels were determined by tandem mass tag (TMT) labeling quantitative proteomics and western blotting.
Results
Artemisinin treatment significantly decreased the expression levels of COX2 and COX7A2 and increased that of COX14, YEM1l1, ALAS1, and OAT after 48h. In addition, FTL was upregulated in the CAL-62 cells and downregulated in BHT-101 cells. The CAL-62 cells showed transient and reversible resistance to artemisinin, which was correlated to time-dependent changes in HIF1, PDK1, and PDHA levels.
Conclusion
Artemisinin targets the mitochondrial respiratory chain proteins in ATC cells. CAL-62 cells show transient resistance to artemisinin via PDH downregulation, indicating that PDH activation may enhance the cytotoxic effects of artemisinin on ATC cells.
Ferroptosis-based nanomedicine has drawn increasing attention in antitumor therapy because of the advantages of this unconventional mode of apoptosis, but the difficulties of delivery to the tumor site and surface-to-core penetration after arrival seriously hinder further clinical transformation and application. Herein, we propose an unprecedented strategy of injecting magnetic nanodroplets (MNDs) to solve these two longstanding problems. MNDs are nanocarriers that can carry multifunctional drugs and imaging materials. MNDs can effectively accumulate in the tumor site by active tumor targeting (multifunctional drugs) and passive tumor targeting (enhanced permeability and retention effect), allowing diffusion of the MNDs from the surface to the core through mild-temperature magnetic fluid hyperthermia (MHT) under multimodal imaging guidance. Finally, the ferroptosis pathway is activated deep within the tumor site through the drug release. This approach was inspired by the ability of mild-temperature MHT to allow MNDs to quickly pass through the blood vessel-tumor barrier and deeply penetrate the tumor tissue from the surface to the core to amplify the antitumor efficacy of ferroptosis. This strategy is termed as “thermoferroptosis sensitization”. Importantly, this behavior can be performed under the guidance of multimodal imaging, making the design of MNDs for cancer therapy safer and more reasonable.
Uterine corpus endometrial carcinoma (UCEC) is the most prevalent gynecologic cancer in developed countries and lacks efficient therapeutic strategies. Artesunate (ART), a well-modified derivate of artemisinin, exerts potent anti-cancer effects apart from its classical anti-malaria feature. Autophagy is a universal double-edged process in cell survival, and CD155 is a novel immune checkpoint highly expressed in numerous cancers. However, the relationships among ART, autophagy, and CD155 remain unclear in UCEC. In this study, we discovered that ART not only inhibited proliferation and migration, promoted apoptosis, but also induced autophagy in UCEC cells. Meanwhile, ART-induced autophagy elevated the level of CD155 in UCEC cells, thereby enhancing the cytotoxicity of natural killer cell line (NK92) by modulating the interactions between CD155 and its receptors in NK92 cells via upregulation of co-stimulator CD226 and downregulation of co-inhibitor TIGIT. Additionally, ART regulated CD155 partially via ATG5, and knockdown of ATG5 dampened the expression of CD155 in UCEC cells, thus decreasing the cytotoxicity of NK92 cells. Therefore, this study demonstrated the dual anti-cancer effects of ART as it could induce cell-killing directly and indirectly, which provides novel insights into the anti-cancer mechanisms of ART on UCEC.
This review covers developments in relation to artemisinin-based antimalarial agents. Topics covered include a brief introduction to the history and treatment of malaria, and more recently, drug resistant malaria; the discovery of the naturally occurring novel peroxidic antimalarial artemisinin; artemisinin biosynthesis. metabolism and biotransformations; the diversity of proposed mechanisms of action: pharmacokinetics: the insight into structure-toxicity relationships; the total syntheses and the progress made in the syntheses of its analogs; and, ultimately the contribution of these efforts towards rational drug design in order to access potent, non-toxic antimalarial drugs based on artemisinin.
Lactoferrin (Lf), an iron-sequestering glycoprotein, predominates in mucosal secretions, where the level of free extracellular iron (10 ⁻¹⁸ M) is not sufficient for bacterial growth. This represents a mechanism of resistance to bacterial infections by prevention of colonization of the host by pathogens. In this study we were able to show that Streptococcus pneumoniae specifically recognizes and binds the iron carrier protein human Lf (hLf). Pretreatment of pneumococci with proteases reduced hLf binding significantly, indicating that the hLf receptor is proteinaceous. Binding assays performed with 63 clinical isolates belonging to different serotypes showed that 88% of the tested isolates interacted with hLf. Scatchard analysis showed the existence of two hLf-binding proteins with dissociation constants of 5.7 × 10 ⁻⁸ and 2.74 × 10 ⁻⁷ M. The receptors were purified by affinity chromatography, and internal sequence analysis revealed that one of the S. pneumoniae proteins was homologous to pneumococcal surface protein A (PspA). The function of PspA as an hLf-binding protein was confirmed by the ability of purified PspA to bind hLf and to competitively inhibit hLf binding to pneumococci. S. pneumoniae may use the hLf-PspA interaction to overcome the iron limitation at mucosal surfaces, and this might represent a potential virulence mechanism.
AIM: To obtain an efficient delivery system for transporting endostatin gene to mouse liver tumor xenografts by administration of aerosol.
METHODS: Recombinant plasmid pcDNA3.0/endostatin containing human endostatin gene together with signal peptide from alkaline phosphatase were transferred into human umbilical vein endothelial cell (HUVEC) by transferrin (TF)-liposome-endostatin complex. Western blot was used to detect the expression of human endostatin in transfected HUVEC cells and its medium. After the tumor-bearing mice were administrated with TF-liposome-endostatin complex, the lung tissue was analyzed by immunohistochemical method for expression of endostatin and the tumors were treated with CD-31 antibody to detect the density of microvesseles in tumor tissues. The inhibition of tumor growth was estimated by the weight of tumors from groups treated with different doses of TF-liposome-endostatin complex. DNA fragmentation assay was used to detect the apoptosis of the cells from primary liver tumor.
RESULTS: Western blot analysis and immunohistochemical method confirmed the expression of endostatin protein in vitro and in vivo. After the tumor sections were treated with CD-31 antibody, the positive reaction cells appeared brown while the negative cells were colorless. The positively stained area of the TF-liposome-endostatin treated group was significantly smaller (P < 0.01, 645.8 ± 5.2 μm²) than that of the control group (1325.4 ± 98.5 μm²). The data showed a significant inhibition of angiogenesis. After administration of TF-liposome-endostatin, comparing with the control group administrated with TF-liposome-pcDNA3.0, liver tumor growth in the mice treated with 50, 250 and 500 mg DNA/kg was inhibited by 36.6%, 40.8%, and 72.8%, respectively (P < 0.01). And a typical DNA fragmentation of apoptosis was found in the cells from tumor tissues of the mice treated with TF-liposome-endostatin but none in the control group.
CONCLUSION: Endostatin gene could be efficiently transported into the mice with TF-liposome-DNA delivery system by administration of aerosol. TF-liposome-mediated endostatin gene therapy strongly inhibited angiogenesis and the growth of mouse xenograft liver tumors. It also could promote the development of apoptosis of tumors without direct influence on tumor cells.
Keywords: $[Keywords]
Citation: Li X, Fu GF, Fan YR, Shi CF, Liu XJ, Xu GX, Wang JJ. Potent inhibition of angiogenesis and liver tumor growth by administration of an aerosol containing a transferrin-liposome-endostatin complex. World J Gastroenterol 2003; 9(2): 262-266
Artemisinic acid and arteannuin B are biogenetic precursors of artemisinin, an important antimalarial produced by the herb Artemisia annua. These compounds have been screened for antimicrobial activity against a range of organisms. All the three compounds are active against different bacteria and certain fungal species.
This chapter discusses the synthesis and structure-activity relationships of peroxidic antimalarials based on artemisinin. Synthetic methodology has been developed for introducing substituents at C-9, O- 11 (as N-R), and C-3 via a total synthetic intermediate; for substitution of carbon for oxygen at O-13 by a separate route; and for a variety of simplified, tricyclic versions of artemisinin. Analogues accrued from these studies have been bioassayed and their structure-activity relationship is discussed in the chapter. However, in terms of rational design, these relationships are complex and the bioassay data more easily utilized by computer aided pharmacophore modeling. Accordingly, with a dataset of over 200 artemisinin analogues, various comparative molecular field analysis (CoMFA) pharmacophore models have been developed based on: (a) the conformational hypotheses that the active conformation of the analogues is the globally minimized structure (b) the conformational hypotheses that the active conformation of the analogues is based on their interaction with the proposed molecular target in the parasite, hemin; (c) the assumption that enantiomers have identical activity; and (d) the assumption that enantiomers have differing activities.
Cellular iron uptake is mediated by binding of transferrin with specific surface receptors and internalization of the Fe-transferrin-receptor complex. This has been examined as a possible pathway for carrying into leukaemic cells a ribosome-inactivating protein (RIP), SO-6, derived from Saponaria officinalis. Purified human differic transferrin was conjugated with SO-6 and a pool of proteins was obtained, with variable numbers of SO-6 molecules linked to a single transferrin molecule. Human erythroleukaemic K562 cells were grown in the presence of human transferrin, SO-6 and human transferrin conjugated with SO-6. The conjugate was found to be internalized via binding with transferrin receptor. Whereas the presence of unconjugated human transferrin and SO-6 in the medium did not significantly influence K562 cell growth, the conjugated proteins displayed an inhibitory activity on cell proliferation. This was maximal after 72 h at a transferrin concentration of 10-9m, with about 50% of cells being killed. Bovine transferrin, present in fetal calf serum, did not appear to compete with human diferric transferrin in binding to K562 cells in suspension culture. In a clonogenic assay, colony formation by leukaemic cells was not influenced by free SO-6 or transferrin, whereas the conjugated proteins were markedly inhibitory (about 100% at 10-9m). Our findings indicate that SO-6 can be efficiently carried into mammalian cells via the transferrin-transferrin receptor cycle and exert its ribosome inactivating activity. This is in keeping with the existence of an alternative pathway of transferrin endocytosis in addition to the classic acidic endosome pathway. From a practical viewpoint, conjugates between transferrin and SO-6 can be useful tools for studying the expression of transferrin receptors, and deserve also to be investigated for a possible use in cancer therapy.
Artemisinin is a sesquiterpene lactone with an endoperoxide function essential for its antimalarial activity against chloroquine-resistant strains of Plasmodium falciparum. The mechanism of action of this paradigm molecule for endoperoxide-containing antimalarial drugs is still open to debate. Are the artemisinin derivatives only responsible for oxidative stress or are they able to alkylate heme and parasite proteins? The characterization of a covalent artemisinin-heme model adduct supports the role of C-centered radicals generated by the reductive activation of the peroxidic bond of this class of drugs. Artemether (an artemisinin analogue) and BO7 (a synthetic antimalarial trioxane) are also able to alkylate a porphyrin cycle.
Artemisinin and its derivatives, which have been known as antimalarial drugs, have also demonstrated their cytotoxicity against tumor cells. It has been proposed that antitumor activity depends on the lipophilicity of functional group on artemisinin derivatives. Solution structures of two artemisinin derivatives as antitumor drug candidates, deoxoartemisinin and carboxypropyldeoxoartemisinin, were determined by NMR spectroscopy to elucidate structure–activity relationship. According to biological assay, antitumor efficiencies are not dependent upon lipophilicity. Instead, these compounds demonstrated their distinctive structural features of boat/chair conformation and capability to interact with receptors, as they have different efficiencies on antitumor activity. Especially, carboxypropyl moiety or carbonyl moiety in artemisinin derivatives influences the conformation and stability of ring structure. Although the detailed mechanism of antitumor activity by artemisinin derivatives has not been addressed, we suggest that antitumor activity is not determined only with lipophilicity and that artemisinin derivatives have specific target proteins in each type of cancer.