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Toxicol Lett. 2017 Aug 15;278:9-17. doi: 10.1016/j.toxlet.2017.06.010. Epub 2017 Jun 27.

Triptonide acts as a novel potent anti-lymphoma agent with low toxicity mainly through inhibition of proto-oncogene Lyn transcription and suppression of Lyn signal pathway.

Author information

1
Department of Pathophysiology, Medical College, Nantong University, Nantong, Jiangsu, 226000, PR China.
2
Laboratory of Nuclear Receptors and Cancer Research, Center for Basic Medical Research, Medical College, Nantong University, Nantong, Jiangsu, 226000, PR China.
3
Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: zhouqs@suda.edu.cn.

Abstract

Lyn is a proto-oncogene overexpressed and constitutively activated in lymphoma, and plays an important role in lymphoma initiation and malignant progression. Hence, the oncogenic Lyn has recently been targeted for novel anti-lymphoma drug discovery; however, the effective Lyn-targeted drug for lymphoma treatment with low toxicity is absent in the clinical setting. The goal of this study is to explore powerful and low toxic Lyn-targeted anti-lymphoma agent. Here we show that triptonide, a small molecule purified from the herb Tripterygium wilfordii Hook F, potently inhibits the proliferation of human B-lymphoma Raji and T-lymphoma Jurkat cells with IC50 of 5.7nM and 4.8nM, respectively. Strikingly, triptonide at a dose of 5mg/kg/day almost completely inhibited the lymphoma growth in human lymphoma cells-xenografted mice without obvious side effects, particularly; the tumors in 6 mice among the 8 xenografted mice were completely eradicated in vivo. Cell biological studies showed that triptonide at the doses of 2.5-10nM notably suppressed B-lymphoma cell colony-forming capability, and that triptonide at the dose of 20nM promoted apoptosis through activation of PARP and caspase 3, but reduction of BCL2 protein levels in the lymphoma cells. Molecular studies revealed that triptonide markedly inhibited oncogenic Lyn transcription through suppressing the promoter activity of the gene, and that it remarkably reduced both total and phosphorylated Lyn proteins, and diminished Lyn downstream ERK and ATK signal pathways. Additionally, triptonide significantly enhanced p38 phosphorylation. Together, triptonide exerts potent anti-lymphoma effect with low toxicity mainly through inhibition of proto-oncogene Lyn transcription and suppression of Lyn downstream ERK and ATK signal pathways, providing an attractive drug candidate for development of novel anti-lymphoma therapeutics.

KEYWORDS:

Anti-cancer; ERK; Lymphoma; Lyn; Triptonide

PMID:
28666825
DOI:
10.1016/j.toxlet.2017.06.010
[Indexed for MEDLINE]

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