A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer

Krishna, Sanjeev; Ganapathi, S; Ster, Irina Chis; Saeed, Mohamed E.M.; Cowan, M; Finlayson, Caroline; Kovacsevics, Hajnalka; Jansen, Herwig; Kremsner, Peter G.; Efferth, Thomas; Kumar, Devinder

doi:10.1016/j.ebiom.2014.11.010

Cited by 166 publications

(109 citation statements)

References 35 publications

(38 reference statements)

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“…The role of artesunate as an effective anticancer drug is under active examination in phase I–II clinical trials [43], [44]. The selective killing of cancer cells but not normal cells may be the major advantage of artesunate, which is already known to be generally safe and well tolerated, even in the fetus during first-trimester pregnancies [45].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…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.…”

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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“…In 2009, the combined effects of artesunate and rituximab on malignant B-cells were reported [12]. Clinical pilot phase I/II trials in veterinary tumors and human cancer patients demonstrated that the artemisinin derivative artesunate possesses clinical anticancer activity at tolerable side effects [13,14,15]. It can be speculated that not only artemisinin-type drugs, but also other endoperoxides may reveal anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation

et al. 2017

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The 6-epimer of the plakortide H acid (1), along with the endoperoxides plakortide E (2), plakortin (3), and dihydroplakortin (4) have been isolated from a sample of the Caribbean sponge Plakortis halichondrioides. To perform a comparative study on the cytotoxicity towards the drug-sensitive leukemia CCRF-CEM cell line and its multi-drug resistant subline CEM/ADR5000, the acid of plakortin, namely plakortic acid (5), as well as the esters plakortide E methyl ester (6) and 6-epi-plakortide H (7) were synthesized by hydrolysis and Steglich esterification, respectively. The data obtained showed that the acids (1, 2, 5) exhibited potent cytotoxicity towards both cell lines, whereas the esters showed no activity (6, 7) or weaker activity (3, 4) compared to their corresponding acids. Plakortic acid (5) was the most promising derivative with half maximal inhibitory concentration (IC50) values of ca. 0.20 µM for both cell lines.

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A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer

Cited by 166 publications

References 35 publications

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

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

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

Cytotoxicity of Endoperoxides from the Caribbean Sponge Plakortis halichondrioides towards Sensitive and Multidrug-Resistant Leukemia Cells: Acids vs. Esters Activity Evaluation

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