A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies

Deeken, John F.; Wang, Hongkun; Hartley, Marion L.; Cheema, Amrita K.; Smaglo, Brandon G.; Hwang, Jimmy J.; He, Aiwu Ruth; Weiner, Louis M.; Marshall, John L.; Giaccone, Giuseppe; Liu, Stephen V.; Luecht, Jim; Spiegel, Jay Y.; Pishvaian, Michael J.

doi:10.1007/s00280-018-3533-8

Cited by 72 publications

(58 citation statements)

References 39 publications

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“…Clinical studies are carried out to investigate the safety and efficacy of artesunate in patients with colorectal and breast cancers, and advanced solid tumor malignancies [698][699][700][701]. A phase I study is performed to evaluate the safety and the maximum tolerated dose of artesunate in patients with metastatic breast cancer, the oral administration of artesunate is safe and 2.2-3.9 mg/kg per day is well tolerated [701].…”

Section: Artesunatementioning

confidence: 99%

“…A phase I study is performed to evaluate the safety and the maximum tolerated dose of artesunate in patients with metastatic breast cancer, the oral administration of artesunate is safe and 2.2-3.9 mg/kg per day is well tolerated [701]. Another phase I study is assessed in patients with advanced solid tumor malignancies, and the maximum tolerated dose of intravenous artesunate is 18 mg/kg [698]. The tolerability and anti-proliferative properties of oral artesunate are also shown in patients with colorectal cancer [699].…”

Section: Artesunatementioning

confidence: 99%

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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%

Section: Artesunatementioning

confidence: 99%

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

et al. 2019

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“…In this respect, several phase 1 and phase two studies (colorectal cancer, hepatocellular carcinoma, breast cancer and several intraepithelial neoplasias) are ongoing (www.clinicaltrials.gov), and for a few trials results have already been published. These reports highlighted the favorable tolerability of artesunate [69][70][71][72], and some even found first hints for clinical activity [69,70]. It may be interesting to see how artesunate, maybe even in combination with immune checkpoint inhibitors, performs in cancer trials in the future.…”

Section: Discussionmentioning

confidence: 97%

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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“…It is therefore unsurprising that artemisinin has become the subject of increasing scrutiny for its possible application in cancer. Accumulating evidence demonstrates that artemisinin induces cytotoxicity in a wide range of cancers in vitro and in vivo . Known examples include liver, gastric, colorectal, lung, breast, cervical, ovarian, and esophageal cancers among others .…”

Section: Introductionmentioning

confidence: 99%

“…Accumulating evidence demonstrates that artemisinin induces cytotoxicity in a wide range of cancers in vitro and in vivo. [13][14][15][16][17] Known examples include liver, gastric, colorectal, lung, breast, cervical, ovarian, and esophageal cancers among others. 18 In vivo, many human tumor xenograft models also show the anticancer effect of artemisinin in both subcutaneously and orthotopically transplanted tumors.…”

mentioning

confidence: 99%

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

Sun

Yan

Zou

et al. 2019

Medicinal Research Reviews

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Artemisinin and its derivatives, with their outstanding clinical efficacy and safety, represent the most effective and impactful antimalarial drugs. Apart from its antimalarial effect, artemisinin has also been shown to exhibit selective anticancer properties against multiple cancer types both in vitro and in vivo. Specifically, our previous studies highlighted the therapeutic effects of artemisinin on autophagy regulation. Autophagy is a well‐conserved degradative process that recycles cytoplasmic contents and organelles in lysosomes to maintain cellular homeostasis. The deregulation of autophagy is often observed in cancer cells, where it contributes to tumor adaptation to nutrient‐deficient tumor microenvironments. This review discusses recent advances in the anticancer properties of artemisinin and its derivatives via their regulation of autophagy, mitophagy, and ferritinophagy. In particular, we will discuss the mechanisms of artemisinin activation in cancer and novel findings regarding the role of artemisinin in regulating autophagy, which involves changes in multiple signaling pathways. More importantly, with increasing failure rates and the high cost of the development of novel anticancer drugs, the strategy of repurposing traditional therapeutic Chinese medicinal agents such as artemisinin to treat cancer provides a more attractive alternative. We believe that the topics covered here will be important in demonstrating the potential of artemisinin and its derivatives as safe and potent anticancer agents.

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A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies

Abstract: NCT02353026.

Cited by 72 publications

References 39 publications

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

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

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

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

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