Hypoxia modulates the effect of dihydroartemisinin on endothelial cells

D’Alessandro, Sarah; Basilico, Nicoletta; Corbett, Yolanda; Scaccabarozzi, Diletta; Omodeo‐Salè, Fausta; Saresella, Marina; Marventano, Ivana; Vaillant, Michel; Olliaro, Piero; Taramelli, Donatella

doi:10.1016/j.bcp.2011.06.002

Cited by 27 publications

(8 citation statements)

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“…In contrast, TCTP protein levels were almost unchanged at 24 h, but were greatly reduced in MDA cells treated for 48 h with 50 μM DHA (Figure 1D ), indicating the inhibitory effect of DHA on TCTP protein expression levels, as previously reported [ 26 , 31 ]. However, a slight increase of TCTP levels was observed after 72 h, likely due to the DHA short half-life as reported by in vivo [ 32 ] and in vitro studies [ 33 , 34 ] which suggest that DHA may cause severe damage during the first hours of exposure in breast cancer cells. Similar results were also obtained in SKBR3 cells treated with 50 μM DHA ( Figure S1B–C ).…”

Section: Resultsmentioning

confidence: 71%

Phospho-TCTP as a therapeutic target of dihydroartemisinin for aggressive breast cancer cells

et al. 2015

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Upregulation of Translationally Controlled Tumor Protein (TCTP) is associated with poorly differentiated aggressive tumors, including breast cancer, but the underlying mechanism(s) are still debated. Here, we show that in breast cancer cell lines TCTP is primarily localized in the nucleus, mostly in the phosphorylated form.The effects of Dihydroartemisinin (DHA), an anti-malaria agent that binds TCTP, were tested on breast cancer cells. DHA decreases cell proliferation and induces apoptotic cell death by targeting the phosphorylated form of TCTP. Remarkably, DHA enhances the anti-tumor effects of Doxorubicin in triple negative breast cancer cells resulting in an increased level of apoptosis. DHA also synergizes with Trastuzumab, used to treat HER2/neu positive breast cancers, to induce apoptosis of tumor cells.Finally, we present new clinical data that nuclear phospho-TCTP overexpression in primary breast cancer tissue is associated with high histological grade, increase expression of Ki-67 and with ER-negative breast cancer subtypes. Notably, phospho-TCTP expression levels increase in trastuzumab-resistant breast tumors, suggesting a possible role of phospho-TCTP as a new prognostic marker.In conclusion, the anti-tumor effect of DHA in vitro with conventional chemotherapeutics suggests a novel therapeutic strategy and identifies phospho-TCTP as a new promising target for advanced breast cancer.

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Section: Resultsmentioning

confidence: 71%

Phospho-TCTP as a therapeutic target of dihydroartemisinin for aggressive breast cancer cells

et al. 2015

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“…On the other hand, DHA enhanced the toxicity of cisplatinum in lung adenocarcinoma cells in vivo and this effect was accompanied by reduced expression of HIF-1α and VEGF and reduced tumor microvessel density (25). Interestingly, this anti-angiogenic effect of DHA was attributed to growth inhibition of endothelial cells and depended on the level of tissue oxygenation and the drug concentration (26). Thus, the anti-angiogenic effects described above differ from our findings where DHA was almost similarly active under normoxic and hypoxic conditions in all three colon cancer cell lines examined (see Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin is a Hypoxia-Active Anti-Cancer Drug in Colorectal Carcinoma Cells

et al. 2014

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Tumor hypoxia is one main biological factor that drives resistance to chemotherapy and radiotherapy. To develop a novel strategy for overcoming hypoxia-induced therapy resistance, we examined the anti-neoplastic activity of the reactive oxygen donor dihydroartemisinin (DHA) in human colon cancer cell lines in normoxia and severe hypoxia. In addition, we analyzed the involvement of the intrinsic apoptosis pathway for DHA-mediated cytotoxicity in HCT116 cells in short-term and long-term in vitro assays. When applied at lower concentrations (≤25 μM), DHA induced apoptosis in Colo205, HCT15, and HCT116 cells, whereas necrotic cell death was increased when cells were treated with higher DHA concentrations (50 μM). However, no preference for DHA-induced apoptosis or necrosis could be detected between the treatment under normoxic or hypoxic conditions. Moreover, DHA potently reduced clonogenic survival of HCT116 cells in normoxia and hypoxia. Treatment of HCT116 cells with 25 μM DHA resulted in activation of Bax under normoxic and hypoxic conditions. Interestingly, cytochrome c release from the mitochondria and caspase-activation were observed only under normoxic conditions, whereas, under hypoxic conditions DHA induced a caspase-independent apoptosis-like cell death. However, under both conditions, generation of reactive oxygen species was an important mediator of DHA-induced toxicity. Further molecular analysis suggests that DHA-mediated cell death involves different sets of pro-apoptotic Bcl-2 family members. The pronounced cytotoxic activity of DHA in severe hypoxia as well as normoxia offers new perspectives for targeting the hypoxic tumor cell fraction to improve treatment outcome for cancer patients.

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“…The fatty acid composition of the lipid fractions was analysed by gas liquid chromatography according to Corsetto et al [ 20 ]. The levels of thiobarbituric acid reactive substances were used to determinate the lipid peroxidation, as previously reported [ 21 ] and expressed as pmoles of malondialdehyde (MDA).…”

Section: Methodsmentioning

confidence: 99%

Differential induction of malaria liver pathology in mice infected with Plasmodium chabaudi AS or Plasmodium berghei NK65

Scaccabarozzi

Deroost

Corbett

et al. 2018

Malar J

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BackgroundCerebral malaria and severe anaemia are the most common deadly complications of malaria, and are often associated, both in paediatric and adult patients, with hepatopathy, whose pathogenesis is not well characterized, and sometimes also with acute respiratory distress syndrome (ARDS). Here, two species of murine malaria, the lethal Plasmodium berghei strain NK65 and self-healing Plasmodium chabaudi strain AS which differ in their ability to cause hepatopathy and/or ARDS were used to investigate the lipid alterations, oxidative damage and host immune response during the infection in relation to parasite load and accumulation of parasite products, such as haemozoin.MethodsPlasma and livers of C57BL/6J mice injected with PbNK65 or PcAS infected erythrocytes were collected at different times and tested for parasitaemia, content of haemozoin and expression of tumour necrosis factor (TNF). Hepatic enzymes, antioxidant defenses and lipids content and composition were also evaluated.ResultsIn the livers of P. berghei NK65 infected mice both parasites and haemozoin accumulated to a greater extent than in livers of P. chabaudi AS infected mice although in the latter hepatomegaly was more prominent. Hepatic enzymes and TNF were increased in both models. Moreover, in P. berghei NK65 infected mice, increased lipid peroxidation, accumulation of triglycerides, impairment of anti-oxidant enzymes and higher collagen deposition were detected. On the contrary, in P. chabaudi AS infected mice the antioxidant enzymes and the lipid content and composition were normal or even lower than uninfected controls.ConclusionsThis study demonstrates that in C57BL/6J mice, depending on the parasite species, malaria-induced liver pathology results in different manifestations, which may contribute to the different outcomes. In P. berghei NK65 infected mice, which concomitantly develop lethal acute respiratory distress syndrome, the liver tissue is characterized by an excess oxidative stress response and reduced antioxidant defenses while in P. chabaudi AS infected mice hepatopathy does not lead to lipid alterations or reduction of antioxidant enzymes, but rather to inflammation and cytokine burst, as shown earlier, that may favour parasite killing and clearance of the infection. These results may help understanding the different clinical profiles described in human malaria hepatopathy.Electronic supplementary materialThe online version of this article (10.1186/s12936-017-2159-3) contains supplementary material, which is available to authorized users.

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Hypoxia modulates the effect of dihydroartemisinin on endothelial cells

Cited by 27 publications

References 66 publications

Phospho-TCTP as a therapeutic target of dihydroartemisinin for aggressive breast cancer cells

Phospho-TCTP as a therapeutic target of dihydroartemisinin for aggressive breast cancer cells

Dihydroartemisinin is a Hypoxia-Active Anti-Cancer Drug in Colorectal Carcinoma Cells

Differential induction of malaria liver pathology in mice infected with Plasmodium chabaudi AS or Plasmodium berghei NK65

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