Dihydroartemisinin induces apoptosis in colorectal cancer cells through the mitochondria-dependent pathway

Lü, Min; Sun, Luhaoran; Zhou, Jin; Yang, Jing

doi:10.1007/s13277-014-1691-9

Cited by 44 publications

(32 citation statements)

References 25 publications

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“…Consistent with previous studies in yeast (43) and tumor cells (45, 46), our findings support the mitochondrion as a target of artemisinin. We observed both a decrease in membrane potential and altered morphology in wild type parasites treated with ART and a stable decrease in membrane potential and altered morphology in resistant populations, suggesting these changes are a long-term adaptation to the presence of drug.…”

Section: Discussionsupporting

confidence: 93%

“…Treatment of yeast with ART results in mitochondrial membrane depolarization, suggesting that ART is activated by the electron transport system which leads to oxidative stress and membrane damage (44). Inhibition of mitochondrial function in tumor cells treated with ART derivatives has also been shown to promote cell death due to apoptosis (45). In human tumor cells, it is proposed that mitochondrial heme activates the endoperoxide group of artemisinin and interaction with the electron transport chain generates reactive oxygen species leading to cell death (46).…”

Section: Introductionmentioning

confidence: 99%

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Evolution of resistance in vitro reveals a novel mechanism of artemisinin activity in Toxoplasma gondii

Rozenberg

Luth

Winzeler

et al. 2019

Preprint

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250)Artemisinins are effective against a variety of parasites and provide the first line of treatment for malaria. Laboratory studies have identified several mechanisms for artemisinin resistance in Plasmodium falciparum, including mutations in Kelch13 that are associated with delayed clearance in some clinical isolates, although other mechanisms are likely involved. To explore other potential mechanisms of resistance in parasites, we took advantage of the genetic tractability of T. gondii, a related apicomplexan parasite that shows moderate sensitivity to artemisinin. Resistant populations of T. gondii were selected by culture in increasing drug concentrations and whole genome sequencing identified several non-conservative point mutations that emerged in the population and were fixed over time. Genome editing using CRISPR/Cas9 was used to introduce point mutations conferring amino acids changes in a serine protease homologous to DegP and a serine/threonine protein kinase of unknown function. Single and double mutations conferred a competitive advantage over wild type parasites in the presence of drug, despite not changing EC 50 values. Additionally, the evolved resistant lines showed dramatic amplification of the mitochondrial genome, including genes encoding cytochrome b and cytochrome oxidase I. Consistent with prior studies in yeast and mammalian tumor cells that implicate the mitochondrion as a target of artemisinins, treatment of wild type parasites with artemisinin decreased mitochondrial membrane potential, and resistant parasites showed altered morphology and decreased membrane potential. These findings extend the repertoire of mutations associated with artemisinin resistance and suggest that the mitochondrion may be an important target of inhibition in T. gondii. Significance (120)Artemisinins provide important therapeutic agents for treatment of malaria and have potential for use in other infections and in cancer. Their use is threatened by the potential for resistance development, so understanding their mechanism of action and identifying genetic changes that alter sensitivity are important for improving clinical outcomes. Our findings suggest that mutations in novel targets can contribute to the emergence of parasites with increased tolerance to artemisinin treatment and that such mutations can confer a fitness advantage even in the absence of a notable shift in EC 50 . Our findings also support the idea that inhibition of mitochondrial function may be an important target in T.gondii, as previously suggested by studies in yeast and human cancer cells.P. falciparum. The ART mechanism of action against tumor cells is also uncertain, but has been linked to oxidative stress, DNA damage, decreased cell replication, and activation of cell death pathways including apoptosis (41, 42). Studies in Baker's yeast (S. cerevisiae) implicate the mitochondria as a target of ART, and consistent with this model, growth on fermentable carbon sources results in genome sequence, as its assembly has been complicated by th...

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Evolution of resistance in vitro reveals a novel mechanism of artemisinin activity in Toxoplasma gondii

Rozenberg

Luth

Winzeler

et al. 2019

Preprint

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“…DHA has previously been reported to have anti-cancer properties; however, the specificity of activity and the concentrations needed for efficacy have remained unclear (32–35, 45). Furthermore, how DHA kills cancer cells has been linked to a number of mechanisms (32–36, 45).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, how DHA kills cancer cells has been linked to a number of mechanisms (32–36, 45). The treatment of mouse BCR-ABL + B-ALL cells and MEF cells with DHA treatment induces the activation of a genetic program that is similar to the ER stress pathway as well as the pro-apoptotic protein NOXA.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABL+ B-Lineage Acute Lymphoblastic Leukemia

Budhraja

Turnis

Churchman

et al. 2017

Clinical Cancer Research

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Purpose BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1 to promote viability and are resistant to BH3-mimetic agents such as navitoclax (ABT-263) that targets BCL-2, BCL-XL, and BCL-W. However, the survival of most normal blood cells and other cell types are also dependent on Mcl-1. Despite the requirement for MCL-1 in these cell types, initial reports of MCL-1-specific BH3-mimetics have not described any overt toxicities associated with single-agent use, but these agents are still early in clinical development. Therefore, we sought to identify FDA-approved drugs that could sensitize leukemic cells to ABT-263. Experimental Design A screen identified dihydroartemisinin (DHA), a water-soluble metabolite of the anti-malarial artemisinin. Using mouse and human leukemic cell lines, and primary patient-derived xenografts, the effect of DHA on survival was tested and mechanistic studies were carried out to discover how DHA functions. We further tested in vitro and in vivo whether combining DHA with ABT-263 could enhance the response of leukemic cells to combination therapy. Results DHA causes the down-modulation of MCL-1 expression by triggering a cellular stress response that represses translation. The repression of MCL-1 renders leukemic cells highly sensitive to synergistic cell death induced by ABT-263 in a mouse model of BCR-ABL+ B-ALL both in vitro and in vivo. Furthermore, DHA synergizes with ABT-263 in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL in culture. Conclusions Our findings suggest that combining DHA with ABT-263 can improve therapeutic response in BCR-ABL+ B-ALL.

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“…It has been frequently employed to induce the apoptosis of leukaemia, breast cancer and lung cancer cells (Gu, ). However, its influence on prostate cancer, to the best of our knowledge, has seldom been assessed (Chen, Chen, Wang, Gao, & Hu, ; Lu, Sun, Zhou, & Yang, ). In the present study, the apoptosis of PC‐3 cells was induced by using different doses of DHA.…”

Section: Introductionmentioning

confidence: 99%

Effects of dihydroartemisinin on HSP70 expression in human prostate cancer PC‐3 cells

Kong

et al. 2019

Andrologia

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We aimed to evaluate the effects of dihydroartemisinin (DHA) on heat‐shock protein 70 (HSP70) expression in human prostate cancer PC‐3 cells and to examine the molecular mechanism. The viability of PC‐3 cells following treatment with 25, 50, 100 and 200 μmol/L DHA for 48 hr was detected by flow cytometry and MTT assay. The expression of HSP70 mRNA was detected by RT‐qPCR. The expression levels and locations of HSP70, caspase‐3 and apoptosis‐inducing factor (AIF) were detected with immunofluorescence assay. With 100 μmol/L HSP70 inhibitor quercetin as positive control and dimethyl sulphoxide (DMSO) as solvent control, the protein expressions of HSP70, apoptotic protease activating factor‐1 (Apaf‐1) and AIF were detected by Western blot. DHA promoted PC‐3 cell apoptosis dose‐dependently. With increasing DHA dose, the expression of HSP70 mRNA significantly decreased (p < 0.05). DHA did not change the location of HSP70 or AIF. Compared with control and DMSO groups, the expression of HSP70 protein significantly decreased, and those of Apaf‐1, caspase‐3 and AIF significantly increased following treatment with DHA and quercetin for 48 hr. In conclusion, DHA inhibits the expression of HSP70 and induces the apoptosis of PC‐3 cells. The results provide valuable experimental evidence for prostate cancer therapies using DHA.

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Dihydroartemisinin induces apoptosis in colorectal cancer cells through the mitochondria-dependent pathway

Cited by 44 publications

References 25 publications

Evolution of resistance in vitro reveals a novel mechanism of artemisinin activity in Toxoplasma gondii

Evolution of resistance in vitro reveals a novel mechanism of artemisinin activity in Toxoplasma gondii

Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABL+ B-Lineage Acute Lymphoblastic Leukemia

Effects of dihydroartemisinin on HSP70 expression in human prostate cancer PC‐3 cells

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