Therapeutic effects of artesunate in hepatocellular carcinoma

Vandewynckel, Yves-Paul; Laukens, Debby; Geerts, Anja; Vanhove, Christian; Descamps, Benedicte; Colle, Isabelle; Devisscher, Lindsey; Bogaerts, Eliene; Paridaens, Annelies; Verhelst, Xavier; Steenkiste, Christophe Van; Libbrecht, Louis; Lambrecht, Bart N.; Janssens, Sophie; Vlierberghe, Hans Van

doi:10.1097/meg.0000000000000066

Cited by 39 publications

(23 citation statements)

References 21 publications

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“…Artesunate has been successfully repurposed as an anticancer drug for various cancer types [10], [11], [12], [13]. The role of artesunate as an effective anticancer drug is under active examination in phase I–II clinical trials [43], [44].…”

Section: Discussionmentioning

confidence: 99%

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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%

“…Artesunate has been repurposed as an anticancer drug that induces cell death by reactive oxygen species (ROS) production [10], [11], [12], [13]. Artemisinins enhanced anticancer toxicity by utilizing ferrous iron to generate radicals that could kill cancer cells [14], [15].…”

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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“…The endoplasmic reticulum (ER) is a major regulator of cancer cell proliferation, metastasis, angiogenesis, and chemotherapy resistance . Cancer cells often exhibit higher rates of protein synthesis than non‐cancer cells, which raises their ER protein load and leads to higher basal levels of ER stress . To handle this ER stress, cancer cells often employ the unfolded protein response (UPR).…”

Section: Figurementioning

confidence: 99%

A Rhenium Isonitrile Complex Induces Unfolded Protein Response‐Mediated Apoptosis in Cancer Cells

King

Marker

Swanda

et al. 2019

Chemistry A European J

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Complexes of the element Re have recently been shown to possess promising anticancer activity through mechanisms of action that are distinct from the conventional metal‐based drug cisplatin. In this study, we report our investigations on the anticancer activity of the complex [Re(CO)3(dmphen)(p‐tol‐ICN)]+ (TRIP) in which dmphen=2,9‐dimethyl‐1,10‐phenanthroline and p‐tol‐ICN=para‐tolyl isonitrile. TRIP was synthesized by literature methods and exhaustively characterized. This compound exhibited potent in vitro anticancer activity in a wide variety of cell lines. Flow cytometry and immunostaining experiments indicated that TRIP induces intrinsic apoptosis. Comprehensive biological mechanistic studies demonstrated that this compound triggers the accumulation of misfolded proteins, which causes endoplasmic reticulum (ER) stress, the unfolded protein response, and apoptotic cell death. Furthermore, TRIP induced hyperphosphorylation of eIF2α, translation inhibition, mitochondrial fission, and expression of proapoptotic ATF4 and CHOP. These results establish TRIP as a promising anticancer agent based on its potent cytotoxic activity and ability to induce ER stress.

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“…Artemisinin cotreatment has been shown to synergize with or enhance the effects of various conventional chemotherapy drugs in a range of cancer types (Table ). These include DNA alkylating and intercalating agents including cisplatin, carboplatin, doxorubicin, temozolomide, the antimetabolite cytarabine, as well as kinase inhibitors such as sorafenib and midostaurin . The application of the artemisinin–temozolomide combination in gliomas has been shown by multiple reports to be especially efficacious.…”

Section: Potential Application In Cancer Therapymentioning

confidence: 99%

“…These include DNA alkylating and intercalating agents including cisplatin, 113,166,167 carboplatin, 168 doxorubicin, 161,169,170 temozolomide, 124,171,172 the antimetabolite cytarabine, 131,161 as well as kinase inhibitors such as sorafenib and midostaurin. 73,161,173 The application of the artemisinin-temozolomide combination in gliomas has been shown by multiple reports to be especially efficacious.…”

Section: Artemisinin In Combinational Therapymentioning

confidence: 99%

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

Wong

Kalesh

et al. 2017

Medicinal Research Reviews

187

140

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Therapeutic effects of artesunate in hepatocellular carcinoma

Abstract: These findings indicate that artesunate could offer a new approach to the therapy of hepatocellular carcinoma. Clinical trials with artesunate as monotherapy or in combination with current hypoxia-inducing approaches are necessary.

Cited by 39 publications

References 21 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

A Rhenium Isonitrile Complex Induces Unfolded Protein Response‐Mediated Apoptosis in Cancer Cells

Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action

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