Artesunate shows potent anti-tumor activity in B-cell lymphoma

Våtsveen, Thea Kristin; Myhre, Marit Renée; Steen, Chloé B.; Wälchli, Sébastien; Lingjærde, Ole Christian; Bai, Baoyan; Dillard, Pierre; Theodossiou, Theodossis A.; Holien, Toril; Sundan, Anders; Inderberg, Else Marit; Smeland, Erlend B.; Myklebust, June Helen; Oksvold, Morten P.

doi:10.1186/s13045-018-0561-0

Cited by 72 publications

(59 citation statements)

References 49 publications

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“…It also exerts anti-tumor activities through the loss of mitochondrial membrane potential, Bcl-2 down-regulation, Bax up-regulation, and caspase-3 activation in human gastric cancer SGC-7901 and HGC-27, esophageal cancer Eca109 and Ec9706 cells, and breast cancer MCF-7 xenograft mice [673,681,683]. In addition, gene expression analysis identifies that ER stress is the most relevant pathway for the anti-tumor activity of artesunate in B-cell lymphoma [689]. Interestingly, artesunate selectively inhibits cell growth through iron-dependent and ROS-mediated ferroptosis in human head and neck cancer HN9 cells [690].…”

Section: Artesunatementioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including antiproliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

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Section: Artesunatementioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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“…These compounds, generally used for the treatment of malarial infections, have recently found additional use as antineoplastic agents 40,41 . Although the MoA is not fully understood, their cytotoxicity appears to rely on an iron/heme-dependent activation step and subsequent generation of Reactive Oxygen species (ROS) 42 .…”

Section: Genetic Screening Identifies Known and Novel Slc-drug Associmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Gottardi

César-Razquin

Παπακώστας

et al. 2019

Preprint

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The activity and potency of a drug is inherently affected by the metabolic state of its target cell.Solute Carriers (SLCs) represent the largest family of transmembrane transporters in humans and constitute major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of individual chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in the haploid human cell line HAP1 using a set of 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using a SLC-focused CRISPR/Cas9 lentiviral library, we identified transporters whose absence induced resistance to the drugs tested. Among the hundreds of drug-SLC relationships identified, we confirmed the role of the folate transporter SLC19A1 on the activity of antifolates and of SLC29A1 on several nucleoside analogs. Among the newly discovered dependencies, we identified the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the compounds screened suggested a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provided an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.

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“…Furthermore, in recent years, several additional activities beyond anti-malarial activity have been observed [22,61]. In this respect, pre-clinical studies on artesunate have demonstrated anti-tumor activity against many different cancers including colon caancer [29], lung adenocarcinoma [31], pancreatic cancer [33], breast cancer [62] and different hematological malignancies [30,32,63]. The present study adds MCPyV-positive MCC to this list as we demonstrate the capability of artesunate to restrict growth of virus-positive MCC cells in vitro as well as in xenotransplantation mouse models in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that artesunate-induced death is not preceded by DNA fragmentation, a well-known characteristic of apoptosis [40]. Hence, apoptosis, a frequently described result of artesunate treatment in cancer cells [29][30][31]41], seems not to represent a crucial mechanism in these MCPyV-positive MCC cell lines. Only for MKL-2, no difference could be observed between the two dose response curves suggesting a possible contribution of apoptotic cell death.…”

Section: No Signs Of Apoptotic Cell Death Are Induced By Artesunate Imentioning

confidence: 96%

“…This cytotoxicity was ascribed to artesunate impacting a multitude of signaling pathways and cell death modes [22]. For the latter, induction of apoptosis [29][30][31] or ferroptotic cell death [32][33][34] have been reported most frequently. Importantly, besides these anti-cancer effects, it also exerts anti-viral activities towards a broad range of viruses [35,36].…”

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confidence: 99%

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Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Sarma

Willmes

Angerer

et al. 2020

Cancers

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Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate-a drug used to treat malaria-has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.Cancers 2020, 12, 919 2 of 15 cells [6], and subsequent studies confirmed that approximately 80% of all MCC cases are associated with MCPyV [7]. Importantly, the integration patterns suggest that clonal expansion of the tumor cells occurs after MCPyV integration sustaining the assumption that viral proteins are causal for tumorigenesis [6,8,9]. Moreover, in MCPyV-positive MCC cells, expression of the viral oncoproteins small and Large T-antigen (sT and LT) can be detected, and these proteins are essential for growth of the tumor cells [10,11] qualifying them as potential therapeutic targets.The five-year overall survival rate for patients with MCC is only about 40%, although the relative survival rate (compared to an age-and sex-matched population) is 54% [12]. Primary MCCs are excised by surgery, and adjuvant radiotherapy of the primary tumor location and the lymph node region is recommended [13]. Until recently, the metastatic disease was treated preferentially with various, not-standardized chemotherapeutic regimens, all of which could not improve survival of the patients significantly [14]. Recently, however, antibodies targeting the immune suppressive protein programmed cell death protein 1 (PD-1) or its ligand PD-L1 have demonstrated high response rates of 56 in first-line and 32% in second-line treatment, respectively for patients with stage IV disease [15,16]. Indeed, the PD-L1 targeting antibody Avelumab was the first treatment for metastatic MCC approved both in the US and European Union [17]. Importantly, data avail...

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Artesunate shows potent anti-tumor activity in B-cell lymphoma

Cited by 72 publications

References 49 publications

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

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