mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether

Efferth, Thomas; Olbrich, Armin; Bauer, Rudolf

doi:10.1016/s0006-2952(02)01221-2

Cited by 107 publications

(83 citation statements)

References 9 publications

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“…This indicates that drug resistance genes may be a less important issue if ART is established as a viable anticancer drug. This observation fits well with a recent investigation (Efferth et al, 2002a). ART was more potent than the artemisinin derivatives arteether and artemether, and the number of drug resistance genes in which mRNA expression correlated with the IC 50 values of ART was lower than that for arteether or artemether.…”

Section: Discussionsupporting

confidence: 92%

Molecular Modes of Action of Artesunate in Tumor Cell Lines

Efferth

Sauerbrey²,

Olbrich³

et al. 2003

Mol Pharmacol

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A profound cytotoxic action of the antimalarial, artesunate (ART), was identified against 55 cancer cell lines of the U.S. National Cancer Institute (NCI). The 50% inhibition concentrations (IC 50 values) for ART correlated significantly to the cell doubling times (P ϭ 0.00132) and the portion of cells in the G 0 /G 1 (P ϭ 0.02244) or S cell cycle phases (P ϭ 0.03567). We selected mRNA expression data of 465 genes obtained by microarray hybridization from the NCI data base. These genes belong to different biological categories (drug resistance genes, DNA damage response and repair genes, oncogenes and tumor suppressor genes, apoptosis-regulating genes, proliferation-associated genes, and cytokines and cytokine-associated genes). The constitutive expression of 54 of 465 (ϭ12%) genes correlated significantly to the IC 50 values for ART. Hierarchical cluster analysis of these 12 genes allowed the differentiation of clusters with ART-sensitive or ART-resistant cell lines (P ϭ 0.00017). For exemplary validation, cell lines transduced with 3 of the 12 genes were used to prove a causative relationship. The cDNAs for a deletion-mutated epidermal growth factor receptor (EGFR) and for ␥-glutamylcysteine synthetase increased resistance to ART. The conditional expression of the CDC25A gene using a tetracycline repressor expression vector increased sensitivity toward ART. Multidrug-resistant cells differentially expressing the MDR1, MRP1, or BCRP genes were not cross-resistant to ART. ART acts via p53-dependent andindependent pathways in isogenic p53ϩ/ϩ p21 WAF1/CIP1 ϩ/ϩ, p53Ϫ/Ϫ p21 WAF1/CIP1 ϩ/ϩ, and p53ϩ/ϩ p21 WAF1/CIP1

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Section: Discussionsupporting

confidence: 92%

Molecular Modes of Action of Artesunate in Tumor Cell Lines

Efferth

Sauerbrey²,

Olbrich³

et al. 2003

Mol Pharmacol

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397

290

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“…3A and B) (28)(29)(30). Monomeric and dimeric artemisinins were reported to induce G 1 arrest and apoptosis in cancer cell lines (25,29), activities that correlated with changes in the expression of genes involved in cell proliferation (31). In a panel of 55 cancer cell lines, the cytotoxicity of AS resulted in induction of G 0 /G 1 arrest and changes in expression of cell cycle regulatory proteins (32).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

Roy

Kapoor

et al. 2015

Antimicrob Agents Chemother

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dArtemisinin-derived monomers and dimers inhibit human cytomegalovirus (CMV) replication in human foreskin fibroblasts (HFFs). The monomer artesunate (AS) inhibits CMV at micromolar concentrations, while dimers inhibit CMV replication at nanomolar concentrations, without increased toxicity in HFFs. We report on the variable anti-CMV activity of AS compared to the consistent and reproducible CMV inhibition by dimer 606 and ganciclovir (GCV). Investigation of this phenomenon revealed that the anti-CMV activity of AS correlated with HFFs synchronized to the G 0 /G 1 stage of the cell cycle. In contact-inhibited serum-starved HFFs or cells arrested at early/late G 1 with specific checkpoint regulators, AS and dimer 606 efficiently inhibited CMV replication. However, in cycling HFFs, in which CMV replication was productive, virus inhibition by AS was significantly reduced, but inhibition by dimer 606 and GCV was maintained. Cell cycle analysis in noninfected HFFs revealed that AS induced early G 1 arrest, while dimer 606 partially blocked cell cycle progression. In infected HFFs, AS and dimer 606 prevented the progression of cell cycle toward the G 1 /S checkpoint. AS reduced the expression of cyclin-dependent kinases (CDK) 2, 4, and 6 in noninfected cycling HFFs, while the effect of dimer 606 on these CDKs was moderate. Neither compound affected CDK expression in noninfected contact-inhibited HFFs. In CMV-infected cells, AS activity correlated with reduced CDK2 levels. CMV inhibition by AS and dimer 606 also correlated with hypophosphorylation (activity) of the retinoblastoma protein (pRb). AS activity was strongly associated with pRb hypophosphorylation, while its reduced anti-CMV activity was marked by pRb phosphorylation. Roscovitine, a CDK2 inhibitor, antagonized the anti-CMV activities of AS and dimer 606. These data suggest that cell cycle modulation through CDKs and pRb might play a role in the anti-CMV activities of artemisinins. Proteins involved in this modulation may be identified and targeted for CMV inhibition.A rtemisinins, drugs of choice for malaria therapy, inhibit human cytomegalovirus (CMV) replication (1-4). Artesunate (AS) and the parent compound artemisinin inhibit CMV replication in vitro and in vivo. Variable responses to AS in case reports of CMV-infected patients have been attributed to the dosing regimen, duration of therapy, or tissue penetration of AS (5-8). In our effort to improve and uncover the anti-CMV activities of artemisinins, we reported on in vitro highly selective inhibition of CMV replication with artemisinin-derived dimers, significantly more than with their monomeric counterparts, without increasing toxicity in human foreskin fibroblasts (HFFs) (3, 9). Although similar effects on CMV replication were observed between monomers and dimers (timing of CMV inhibition, effects on DNA replication, and virus yield), dimers inhibited CMV at nanomolar concentrations and had a high slope of the dose-response curve, a measure of cooperativity in binding of multiple ligands to linked bi...

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“…In the present study, we report on antiangiogenic effects of the antimalaria agent artemisinin, which has recently also proven effective against several cancer cell lines (Efferth et al, 2002). Hence, our data suggest that possible future applications for artemisinin in cancer therapies may include the use of this compound as an antiangiogenic agent.…”

Section: Discussionmentioning

confidence: 99%

“…The increased penetration of doxorubicin in the three-dimensional tissue should increase the cytotoxic action of this anticancer agent in solid tumors and supplement the abrogation of tumor growth achieved by inhibition of tumor-induced angiogenesis. Because artemisinin and a number of derivatives of this compound have been recently demonstrated to exert cytostatic or cytotoxic activity against cancer cells (Efferth et al, 2001(Efferth et al, , 2002Posner et al, 2003), these compounds, in addition to their antimalaria action, are likely fulfilling their promise as anticancer agents in the future.…”

Section: Wartenberg Et Almentioning

confidence: 99%

The Antimalaria Agent Artemisinin Exerts Antiangiogenic Effects in Mouse Embryonic Stem Cell-Derived Embryoid Bodies

Wartenberg

Wolf

Budde

et al. 2003

Laboratory Investigation

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SUMMARY:Artemisinin is widely used as an agent to treat malaria; the possible antiangiogenic effects of this compound are unknown. In the present study, the antiangiogenic effects of artemisinin were investigated in mouse embryonic stem cell-derived embryoid bodies, which are a model system for early postimplantation embryos and which efficiently differentiate capillaries. 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 occurred within the tissue, indicating increased tissue permeability. Artemisinin down-regulated hypoxia-inducible factor-1␣ and vascular endothelial growth factor (VEGF) expression, which control endothelial cell growth. The antiangiogenic effects and the inhibition of hypoxia-inducible factor-1␣ and VEGF were reversed upon cotreatment with the free radical scavengers mannitol and vitamin E, indicating that artemisinin may act via reactive oxygen species generation. Furthermore, capillary formation was restored upon coadministration of exogenous VEGF. 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. (Lab Invest 2003, 83:1647-1655.

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mRNA expression profiles for the response of human tumor cell lines to the antimalarial drugs artesunate, arteether, and artemether

Cited by 107 publications

References 9 publications

Molecular Modes of Action of Artesunate in Tumor Cell Lines

Molecular Modes of Action of Artesunate in Tumor Cell Lines

Inhibition of Human Cytomegalovirus Replication by Artemisinins: Effects Mediated through Cell Cycle Modulation

The Antimalaria Agent Artemisinin Exerts Antiangiogenic Effects in Mouse Embryonic Stem Cell-Derived Embryoid Bodies

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