Artesunate sensitizes ovarian cancer cells to cisplatin by downregulating RAD51

Wang, Bingliang; Hou, Dong; Liu, Qiao; Wu, Tingting; Guo, Haiyang; Zhang, Xiyu; Zou, Yongxin; Liu, Zhaojian; Liu, Jinsong; Wei, Jian‐Jun; Gong, Yaoqin; Shao, Changshun

doi:10.1080/15384047.2015.1071738

Cited by 66 publications

(56 citation statements)

References 24 publications

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“…Thus, mitochondrial apoptosis occurs from the iron-dependent generation of cytotoxic oxidative stress [14], [15], [16], [17]. Artesunate also induces oxidative DNA damage, sustained DNA double-strand breaks, and the damage response in cancer cells [18], [19], [20]. These effects were clearly observed in cisplatin-sensitive and -resistant HNC cells in our study.…”

Section: Discussionsupporting

confidence: 61%

“…Artemisinins enhanced anticancer toxicity by utilizing ferrous iron to generate radicals that could kill cancer cells [14], [15]. Artesunate also induces lysosomal ROS-mediated mitochondrial apoptosis and targets the DNA damage and repair systems in conventional chemotherapeutic drug-resistant cancer cells [16], [17], [18], [19], [20]. Furthermore, a recent report suggested that artesunate induced iron-dependent, ROS-producing mitochondrial stress and non-caspase apoptosis [21].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, artesunate downregulates RAD51 and increases γH2AX formation, which results in sensitizing ovarian cancer cells to cisplatin [20]. However, the molecular mechanisms regulating cancer cell death and artesunate resistance remain unclear.…”

Section: Introductionmentioning

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: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

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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“…ARS increased significantly the incidence rates of MN containing both whole chromosomes and centric fragments, demonstrating its ability to act by means of aneugenic and clastogenic events. ARS is known to induce oxidative DNA damage and DNA double‐strand breaks in healthy and cancer cells, and such effects have been widely associated with an increase of ROS levels (Berdelle et al, ; Li et al, ; Wang et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, a number of cancer cell lines were observed to respond to ARS by decreasing cell viability and increasing cell death (Greenshields, Shepherd, & Hoskin, ; Li et al, ; Pang, Qin, Wu, Wang, & Chen, ; Roh, Kim, Jang, & Shin, ). Similarly, incubation with ARS led to oxidative DNA damage, induction of DNA double‐strand breaks and increase of micronuclei (MN) frequency in both cancer cell lines and normal cells, including human lymphocytes (Aquino et al, ; Aquino, Ferreira, & Luis, ; Berdelle, Nikolova, Quiros, Efferth, & Kaina, ; Li et al, ; Mota et al, ; Wang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

Mota

Garcia

Bonfim

et al. 2019

J of Applied Toxicology

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Artesunate (ARS) is a semi‐synthetic derivative of artemisinin, used as an outstanding antimalarial drug, which also displays antitumor, anti‐inflammatory and immunosuppressive effects. In spite of the numerous reports showing the antitumor activity of ARS, the particular mechanisms associated with its cytotoxicity and genotoxicity in non‐neoplastic human cells remain unclear. Here we aimed to verify the specific chromosome damages and the changes in markers of oxidative‐nitrosative stress and apoptosis triggered by ARS exposure in human peripheral blood lymphocytes. Cultures were incubated in the presence of ARS and the number of binucleated cells was determined. To discriminate between micronuclei (MN) containing a whole chromosome or an acentric chromosome, the MN test was employed in combination with the fluorescence in situ hybridization assay. Alterations in the levels of superoxide anion (O2−) and nitric oxide (NO) were measured by the nitroblue tetrazolium and Griess assay, respectively. Changes in the expression of the apoptotic markers were assessed by immunocytochemistry. We found that ARS induced a significant formation of both centromere‐positive MN (C+ MN) and centromere‐negative MN (C– MN). These alterations were accompanied by an increase in both cellular levels of O2− and total NO production, and a remarkable enhancement in the expression of the apoptotic markers cytochrome c and caspases 8 and 9. Together these findings reveal that ARS induces changes in the oxidative‐nitrosative status of human lymphocytes, which are followed by apoptosis and clastogenic and aneugenic effects.

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Platinum‐Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment

et al. 2022

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Triggering receptor expressed on myeloid cells‐2 (TREM2) is a key pro‐tumorigenic marker of tumor‐infiltrating macrophages, showing potent immunosuppressive activity in tumor microenvironment. A platinum(IV) complex OPA derived from oxaliplatin (OP) and artesunate (ART) exhibited direct cytotoxicity against human colon cancer cells and immunomodulatory activity to inhibit TREM2 on macrophages in vitro and vivo. Furthermore, OPA deterred the tumor growth in mouse models bearing MC38 colorectal tumor by reducing the number of CD206+ and CX3CR1+ immunosuppressive macrophages; it also promoted the expansion and infiltration of immunostimulatory dendritic, cytotoxic T, and natural killer cells. OPA is the first small‐molecular TREM2 inhibitor capable of relieving immunosuppressive tumor microenvironment and enhancing chemical anticancer efficiency of a platinum drug, thus showing typical characteristics of a chemoimmunotherapeutic agent.

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Artesunate sensitizes ovarian cancer cells to cisplatin by downregulating RAD51

Cited by 66 publications

References 24 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

Markers of oxidative‐nitrosative stress induced by artesunate are followed by clastogenic and aneugenic effects and apoptosis in human lymphocytes

Platinum‐Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment

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