Artesunate induces ROS- and p38 MAPK-mediated apoptosis and counteracts tumor growthin vivoin embryonal rhabdomyosarcoma cells

Beccafico, Sara; Morozzi, Giulio; Marchetti, M. Cristina; Riccardi, Carlo; Sidoni, Angelo; Donato, Rosario; Sorci, Guglielmo

doi:10.1093/carcin/bgv098

Cited by 70 publications

(53 citation statements)

References 43 publications

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“…16) ART increasingly attracts the attention of cancer researchers due to a broad range of anti-cancer activity, such as pro-apoptosis attenuation of tumor growth, metastasis, and angiogenesis. 2,3,17) The present study further supported that ART could dose-dependently suppress tumor growth of prostatic tumor-bearing mice.…”

Section: Discussionsupporting

confidence: 80%

Artesunate Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor

Wang¹,

Wang²,

et al. 2017

Biological & Pharmaceutical Bulletin

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Prostatic cancer (PCa) is a leading cause of cancer related death in males and is often regarded as a kind of androgen-sensitive cancer. Artesunate (ART), a semi-synthetic derivative of the Chinese herb Artemisia annua, is such an anti-cancer agent. However, the effects and mechanism of ART on PCa cells remains unclear. The study aims to elaborate the mechanism of the involvement of androgen receptor (AR) in antiprostatic cancer (PCa) of artesunate (ART). PCa cells 22rvl were used in vivo and in vitro, and the viability and apoptosis were conducted using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, respectively. Ectopic expressions of AR and DNA methyltransferase (DNMT) were detected in cells in overexpression or interference of AR or DNMT3b. ART dose-dependently suppressed tumor growth, inhibited cell viability, enhanced apoptosis, decreased AR expression, and increased the expression and the catalytic activity of DNMT3b in 22rv1 cells either in transplanted mice or in vitro. Furthermore, AR downregulated DNMT3b expression, and overexpression of AR or interference of DNMT3b could reverse ART-induced cytotoxicity and apoptosis in 22rvl cells, whereas overexpression of DNMT3b could not change the effect profiles of ART on the cells. The results indicated that ART suppressed tumor growth of prostatic cancer cells through AR-DNMT3b pathway, underlying ART will allow for the utilization of this Chinese therapeutic agent for the potential treatment of prostate cancer.Key words artesunate; prostatic cancer; androgen receptor; DNA methyltransferase; apoptosis Prostatic cancer (PCa) is the most common cause of cancerrelated death in males. Morbidity and mortality of PCa underscore the need for novel treatment options. Although improved therapies have been recently developed to treat and prevent PCa, prostate cancer still remains refractory disease. Lately, herbs and phytochemicals 1) have been attractive as therapeutic agents for tumorigenesis suppression. Understanding how the production of these Chinese herbs is regulated during cancer progression would help develop new cancer therapeutic strategy.Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua. ART has been revealed remarkable activity against otherwise multidrug-resistant Plasmodium falciparum and P. vivax malaria. With the recognition of ART, it has now been analyzed for its anti-cancer activity in various tissues-specificity. For example, Tran et al. found that enhancement of ART activity could effectively induce the apoptosis of breast cancer cells. 2)Moreover, ART was proved to be as a novel therapeutic agent for metastatic renal cell carcinoma due to its attenuation action on tumor growth, metastasis.3) Recently, Michaelsen et al. clinically treated PCa patients with long-term Artemisia annua capsules via oral administration combined with shortterm ART inj...

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Section: Discussionsupporting

confidence: 80%

Artesunate Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor

Wang¹,

Wang²,

et al. 2017

Biological & Pharmaceutical Bulletin

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“…2B) and were most susceptible to ARS (Fig. 1) in the three HCC cell lines supports the notion that high iron content enhances the antitumor activity of ARS [28,29,31]. Based on the facts that NAC significantly prevent ARS-induced rapid decrease in iron ions level ( Fig.2A and 2B), we speculate that because of the high intracellular iron ions level in HepG2 cells ( Fig.…”

Section: Discussionsupporting

confidence: 79%

Artesunate induces ROS-dependent apoptosis via a Bax-mediated intrinsic pathway in Huh-7 and Hep3B cells

Pang

Qin

et al. 2016

Experimental Cell Research

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“…Recently, artesunate was identified as a specific activator of a novel iron-dependent, caspase-independent, nonapoptotic ferroptosis that killed resistant cancer cells with oncogenic KRAS reprogramming [22]. Artesunate has been tested for its anticancer effects on various types of human malignancies but rarely using HNC cells [12], [14], [16], [17], [18], [19], [21], [23], [24], [25].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis

et al. 2017

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Artesunate, an anti-malarial drug, has been repurposed as an anticancer drug due to its induction of cell death via reactive oxygen species (ROS) production. However, the molecular mechanisms regulating cancer cell death and the resistance of cells to artesunate remain unclear. We investigated the molecular mechanisms behind the antitumor effects of artesunate and an approach to overcome artesunate resistance in head and neck cancer (HNC). The effects of artesunate and trigonelline were tested in different HNC cell lines, including three cisplatin-resistant HNC cell lines. The effects of these drugs as well as the inhibition of Keap1, Nrf2, and HO-1 were assessed by cell viability, cell death, glutathione (GSH) and ROS production, protein expression, and mouse tumor xenograft models. Artesunate selectively killed HNC cells but not normal cells. The artesunate sensitivity was relatively low in cisplatin-resistant HNC cells. Artesunate induced ferroptosis in HNC cells by decreasing cellular GSH levels and increasing lipid ROS levels. This effect was blocked by co-incubation with ferrostatin-1 and a trolox pretreatment. Artesunate activated the Nrf2–antioxidant response element (ARE) pathway in HNC cells, which contributed to ferroptosis resistance. The silencing of Keap1, a negative regulator of Nrf2, decreased artesunate sensitivity in HNC cells. Nrf2 genetic silencing or trigonelline reversed the ferroptosis resistance of Keap1-silenced and cisplatin-resistant HNC cells to artesunate in vitro and in vivo. Nrf2–ARE pathway activation contributes to the artesunate resistance of HNC cells, and inhibition of this pathway abolishes ferroptosis-resistant HNC.Condensed abstractOur results show the effectiveness and molecular mechanism of artesunate treatment on head and neck cancer (HNC). Artesunate selectively killed HNC cells but not normal cells by inducing an iron-dependent, ROS-accumulated ferroptosis. However, this effect may be suboptimal in some cisplatin-resistant HNCs because of Nrf2–antioxidant response element (ARE) pathway activation. Inhibition of the Nrf2–ARE pathway increased artesunate sensitivity and reversed the ferroptosis resistance in resistant HNC cells.

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Artesunate induces ROS- and p38 MAPK-mediated apoptosis and counteracts tumor growthin vivoin embryonal rhabdomyosarcoma cells

Cited by 70 publications

References 43 publications

<i>Artesunate</i> Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor

<i>Artesunate</i> Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor

Artesunate induces ROS-dependent apoptosis via a Bax-mediated intrinsic pathway in Huh-7 and Hep3B cells

Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis

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