Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells

Eling, Nils; Reuter, Lukas; Hazin, John; Hamacher-Brady, Anne; Brady, Nathan R.

doi:10.18632/oncoscience.160

Cited by 429 publications

(312 citation statements)

References 56 publications

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“…Recent clinical trials indicated that the tumor suppression action of ART on advanced breast cancer, 14) colorectal cancer 15) and pancreatic cancer cells. 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: Discussionmentioning

confidence: 99%

<i>Artesunate</i> 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: Discussionmentioning

confidence: 99%

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

Wang¹,

Wang²,

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Artesunate selectively induces ferroptosis in K-Ras-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines, but not human pancreatic ductal epithelial cells or wild-type K-Ras PDAC cells. 18 This process can be blocked by the iron chelator deferoxamine, whereas it is enhanced by exogenous lysosomal form of iron. 18 In addition to iron chelator deferoxamine, the ROS inhibitors (e.g., trolox and ferrostatin-1), but not necrostatin-1, significantly inhibit artesunate-induced ferroptosis in PDAC cells.…”

Section: Morphologymentioning

confidence: 99%

“…18 This process can be blocked by the iron chelator deferoxamine, whereas it is enhanced by exogenous lysosomal form of iron. 18 In addition to iron chelator deferoxamine, the ROS inhibitors (e.g., trolox and ferrostatin-1), but not necrostatin-1, significantly inhibit artesunate-induced ferroptosis in PDAC cells. 18 Another study shows that 10 artemisinin derivatives, including artesunate, altered numerous iron-related gene mRNA levels, which contributes to cell death in cancer cells.…”

Section: Morphologymentioning

confidence: 99%

“…4 However, induction of ferroptosis may exist in a both Rasdependent and -independent manner. Artesunate induces pancreatic cancer death in a Ras-dependent manner, 18 whereas it induces leukemia cell death in a Ras-independent manner. 23 Indeed, several normal Ras wild-type cells such as kidney tubule cells, T cells, and fibroblasts are sensitive to erastin.…”

Section: Molecular Biologymentioning

confidence: 99%

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Ferroptosis: process and function

et al. 2016

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Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

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“…Abbreviations: ACSL4, acyl-CoA synthetase long-chain family member 4; CARS, cysteinyl tRNA synthetase; CBS, cystathionine-β-synthase; CGL, cystathionine-γ-lyase; FTH1, ferritin heavy chain 1; GPX, glutathione peroxidase; GPX4, glutathione peroxidase 4; GSH, glutathione; G6PD, glucose-6-phosphate dehydrogenase; IPP, isopentenyl pyrophosphate; L-ROS, lipid-based reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; NCOA4, nuclear receptor coactivator 4; NOX, NADPH oxidase; NRF2, nuclear factor E2-related factor 2; PGD, 6-phosphogluconate dehydrogenase; PUFAs, polyunsaturated fatty acids; RCD, regulated cell death; Sec, selenocysteine; Sec-tRNA [ (15,25,26). The metabolic peculiarities of ferroptosis vary among different types of cancer cell.…”

Section: Introductionmentioning

confidence: 99%

Metabolic networks in ferroptosis (Review)

et al. 2018

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Abstract.Ferroptosis is an iron-dependent and peroxidation-driven form of cell death associated with multiple metabolic disorders and disrupted homeostasis. A number of metabolic processes and homeostasis are affected by ferroptosis. The molecules that regulate ferroptosis are involved in metabolic pathways that regulate cysteine exploitation, glutathione state, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation and iron homeostasis. The present review summarizes the metabolic networks involved in ferroptosis based on previous studies, and discusses the function of ferroptosis in pathological processes, including cancer. Finally, the clinical significance of ferroptosis is highlighted, to provide evidence for further studies.

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Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells

Cited by 429 publications

References 56 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

Ferroptosis: process and function

Metabolic networks in ferroptosis (Review)

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