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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Thea Kristin Våtsveen, Marit Renée Myhre, Chloé Beate Steen, Sébastien Wälchli, Ole Christian Lingjærde, Baoyan Bai, Pierre Dillard, Theodossis A Theodossiou, Toril Holien, Anders Sundan, Else Marit Inderberg, Erlend B Smeland, June Helen Myklebust, Morten P Oksvold
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 11 Issue 1 Pg. 23 (02 20 2018) ISSN: 1756-8722 [Electronic] England
• PMID: 29458389 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Artesunate

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Artesunate (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Glycolysis (drug effects)
• Humans
• Lymphoma, B-Cell (drug therapy, genetics, metabolism, pathology)
• Mice
• Transcriptome (drug effects)
• Unfolded Protein Response (drug effects)
• Xenograft Model Antitumor Assays