Artesunate induces G0/G1 cell cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells

Jiang, Zhongyong; Chai, Jin; Chuang, Henry; Li, Shifeng; Wang, Tianran; Cheng, Yi; Chen, Wensheng; Zhou, Dujin

doi:10.1097/cad.0b013e328350e8ac

Cited by 58 publications

(41 citation statements)

References 24 publications

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“…The results therefore suggest that the mechanism inhibiting cell proliferation depends on the artesunate concentration. This is also supported by our real-time proliferation analysis, where only cells treated with artesunate at concentrations of 10 M or less, which were possibly arrested in G 0 phase, spontaneously reinitiated proliferation after 40 to 50 h. Of note, artesunate and dihydroartemisinin have previously been described to decrease the numbers of cells in S phase in A431 human epidermoid carcinoma cells (43), cells of the human leukemia cell line K562 (44), and cells of the murine myeloma cell line SP2/0 (45). Interestingly, while some found simultaneously increased numbers of cells in G 0 /G 1 phase (43) (45), others described increased numbers of cells in G 2 /M phase (46).…”

Section: Discussionsupporting

confidence: 66%

“…Interestingly, while some found simultaneously increased numbers of cells in G 0 /G 1 phase (43) (45), others described increased numbers of cells in G 2 /M phase (46). Apparently, artesunate also induced apoptosis in many cancer cell lines (43,45,46). Since we did not detect any sub-G 1 -phase fraction when performing flow cytometry, we concluded that artesunate at 10 and 40 M does not induce apoptosis in RPTECs.…”

Section: Discussionmentioning

confidence: 48%

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Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

Sharma

Marschall

Henriksen

et al. 2014

Antimicrob Agents Chemother

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dPolyomavirus BK (BKV) causes polyomavirus-associated nephropathy (PyVAN) and hemorrhagic cystitis (PyVHC) in renal and bone marrow transplant patients, respectively. Antiviral drugs with targeted activity against BKV are lacking. Since the antimalarial drug artesunate was recently demonstrated to have antiviral activity, the possible effects of artesunate on BKV replication in human primary renal proximal tubular epithelial cells (RPTECs), the host cells in PyVAN, were explored. At 2 h postinfection (hpi), RPTECs were treated with artesunate at concentrations ranging from 0.3 to 80 M. After one viral replication cycle (approximately 72 hpi), the loads of extracellular BKV DNA, reflecting viral progeny production, were reduced in a concentrationdependent manner. Artesunate at 10 M reduced the extracellular BKV load by 65%; early large T antigen mRNA and protein expression by 30% and 75%, respectively; DNA replication by 73%; and late VP1 mRNA and protein expression by 47% and 64%, respectively. Importantly, the proliferation of RPTECs was also inhibited in a concentration-dependent manner. At 72 hpi, artesunate at 10 M reduced cellular DNA replication by 68% and total metabolic activity by 47%. Cell impedance and lactate dehydrogenase measurements indicated a cytostatic but not a cytotoxic mechanism. Flow cytometry and 5-ethynyl-2=-deoxyuridine incorporation revealed a decreased number of cells in S phase and suggested cell cycle arrest in G 0 or G 2 phase. Both the antiproliferative and antiviral effects of artesunate at 10 M were reversible. Thus, artesunate inhibits BKV replication in RPTECs in a concentration-dependent manner by inhibiting BKV gene expression and genome replication. The antiviral mechanism appears to be closely connected to cytostatic effects on the host cell, underscoring the dependence of BKV on host cell proliferative functions.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 48%

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

Sharma

Marschall

Henriksen

et al. 2014

Antimicrob Agents Chemother

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“…Interestingly, the effect on total metabolic activity was not reversed up to 96 hpt. The explanation for this apparent discrepancy is probably linked to a cell cycle arrest in G 0 or G 2 , as previously demonstrated in other cells (39,(54)(55)(56). When the effect of artesunate waned, a high proportion of the synchronized cells moved into the S phase and incorporated BrdU in their DNA, whereas the metabolic activity was still reduced due to reduced cell numbers.…”

Section: Discussionmentioning

confidence: 60%

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

Sharma

Marschall

Rinaldo

2014

Antimicrob Agents Chemother

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The human JC polyomavirus (JCPyV) causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). A growing number of patients with induced or acquired immunosuppression are at risk for infection, and no effective antiviral therapy is presently available. The widely used antimalarial drug artesunate has shown broad antiviral activity in vitro but limited clinical success. The aim of this study was to investigate the effect of artesunate on JCPyV replication in vitro. The permissivity for JCPyV MAD-4 was first compared in four cell lines, and the monkey kidney cell line COS-7 was selected. Artesunate caused a concentration-dependent decrease in the extracellular JCPyV DNA load 96 h postinfection, with a 50% effective concentration (EC 50 ) of 2.9 M. This effect correlated with a decreased expression of capsid protein VP1 and a reduced release of infectious viral progeny. For concentrations of <20 M, transient reductions in cellular DNA replication and proliferation were seen, while for higher concentrations, some cytotoxicity was detected. A selective index of 16.6 was found when cytotoxicity was calculated based on cellular DNA replication in the mock-infected cells, but interestingly, cellular DNA replication in the JCPyV-infected cells was more strongly affected. In conclusion, artesunate is efficacious in inhibiting JCPyV replication at micromolar concentrations, which are achievable in plasma. The inhibition at EC 50 probably reflects an effect on cellular proteins and involves transient cytostatic effects. Our results, together with the favorable distribution of the active metabolite dihydroartemisinin to the central nervous system, suggest a potential use for artesunate in patients with PML.

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“…Artesunate, is a derivative of artemisinin isolated from Artemisia annua L, has been used to treat malaria, especially against cerebral malaria (Padilla-Camberos et al, 2010;Bachmeier et al, 2011;Berdelle et al, 2011;Jin et al, 2011;Mota et al, 2011;Jiang et al, 2012;Zhou et al, 2012), new report shown that it has a variety of biological activities, such as hepatoprotective, antioxidative, antiinflammatory, antidiabetic, antiallergic, and antibacterial effects (Li et al, 2009;Bat-Chen et al, 2010;Du et al,…”

Section: Introductionmentioning

confidence: 99%

The Synergistic Anticancer Effect of Artesunate Combined with Allicin in Osteosarcoma Cell Line in Vitro and in Vivo

Jiang¹,

Huang²,

Wang³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Artesunate, extracted from Artemisia annua, has been proven to have anti-cancer potential. Allicin, diallyl thiosulfinate, the main biologically active compound derived from garlic, is also of interest in cancer treatment research. This object of this report was to document synergistic effects of artesunate combined with allicin on osteosarcoma cell lines in vitro and in vivo. Methods: After treatment with artesunate and allicin at various concentrations, the viability of osteosarcoma cells was analyzed by MTT method, with assessment of invasion and motility, colony formation and apoptosis. Western Blotting was performed to determine the expression of caspase-3/9, and activity was also detected after drug treatment. Moreover, in a nude mouse model established with orthotopic xenograft tumors, tumor weight and volume were monitored after drug administration via the intraperitoneal (i.p.) route. Results: The viability of osteosarcoma cells in the combination group was significantly decreased in a concentration and time dependent manner; moreover, invasion, motility and colony formation ability were significantly suppressed and the apoptotic rate was significantly increased through caspase-3/9 expression and activity enhancement in the combination group. Furthermore, suppression of tumor growth was evident in vivo. Conclusion: Our results indicated that artesunate and allicin in combination exert synergistic effects on osteosarcoma cell proliferation and apoptosis.

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Artesunate induces G0/G1 cell cycle arrest and iron-mediated mitochondrial apoptosis in A431 human epidermoid carcinoma cells

Cited by 58 publications

References 24 publications

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

Antiviral Effects of Artesunate on Polyomavirus BK Replication in Primary Human Kidney Cells

Antiviral Effects of Artesunate on JC Polyomavirus Replication in COS-7 Cells

The Synergistic Anticancer Effect of Artesunate Combined with Allicin in Osteosarcoma Cell Line in Vitro and in Vivo

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