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

Springer Science and Business Media LLC - Tập 11 - Trang 1-12 - 2018
Thea Kristin Våtsveen1,2, Marit Renée Myhre3, Chloé Beate Steen1,2,4, Sébastien Wälchli1,2,3, Ole Christian Lingjærde2,4, Baoyan Bai1,2, Pierre Dillard3, Theodossis A. Theodossiou5, Toril Holien6,7, Anders Sundan6,7, Else Marit Inderberg3, Erlend B. Smeland1,2, June Helen Myklebust1,2, Morten P. Oksvold1,2
1Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
2Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
3Department of Cellular Therapy, Department of Oncology, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
4Department of Computer Science, University of Oslo, Oslo, Norway
5Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
6Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
7Department of Hematology, St. Olav’s Hospital HF, Trondheim, Norway

Tóm tắt

Although chemo-immunotherapy has led to an improved overall survival for most B-cell lymphoma types, relapsed and refractory disease remains a challenge. The malaria drug artesunate has previously been identified as a growth suppressor in some cancer types and was tested as a new treatment option in B-cell lymphoma. We included artesunate in a cancer sensitivity drug screen in B lymphoma cell lines. The preclinical properties of artesunate was tested as single agent in vitro in 18 B-cell lymphoma cell lines representing different histologies and in vivo in an aggressive B-cell lymphoma xenograft model, using NSG mice. Artesunate-treated B lymphoma cell lines were analyzed by functional assays, gene expression profiling, and protein expression to identify the mechanism of action. Drug screening identified artesunate as a highly potent anti-lymphoma drug. Artesunate induced potent growth suppression in most B lymphoma cells with an IC50 comparable to concentrations measured in serum from artesunate-treated malaria patients, while leaving normal B-cells unaffected. Artesunate markedly inhibited highly aggressive tumor growth in a xenograft model. Gene expression analysis identified endoplasmic reticulum (ER) stress and the unfolded protein response as the most affected pathways and artesunate-induced expression of the ER stress markers ATF-4 and DDIT3 was specifically upregulated in malignant B-cells, but not in normal B-cells. In addition, artesunate significantly suppressed the overall cell metabolism, affecting both respiration and glycolysis. Artesunate demonstrated potent apoptosis-inducing effects across a broad range of B-cell lymphoma cell lines in vitro, and a prominent anti-lymphoma activity in vivo, suggesting it to be a relevant drug for treatment of B-cell lymphoma.

Tài liệu tham khảo

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