Int J Med Sci 2020; 17(10):1375-1384. doi:10.7150/ijms.41793

Research Paper

Cladribine Induces ATF4 Mediated Apoptosis and Synergizes with SAHA in Diffuse Large B-Cell Lymphoma Cells

Linyan Xu1,2,3#, Jun Jiao1,3#, Xiaoshen Sun1,3#, Wei Sang1,2,3, Xiang Gao1,3, Pu Yang4, Dongmei Yan2, Xuguang Song2, Cai Sun2, Mengdi Liu1,3, Yuanyuan Qin1,3, Yu Tian2, Feng Zhu1,2,3, Lingyu Zeng1,2,3, Zhenyu Li1,2,3, Kailin Xu1,2,3✉

1. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
2. Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
3. Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China.
4. Department of Hematology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan, China.
#These authors contributed equally to this work.

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Citation:
Xu L, Jiao J, Sun X, Sang W, Gao X, Yang P, Yan D, Song X, Sun C, Liu M, Qin Y, Tian Y, Zhu F, Zeng L, Li Z, Xu K. Cladribine Induces ATF4 Mediated Apoptosis and Synergizes with SAHA in Diffuse Large B-Cell Lymphoma Cells. Int J Med Sci 2020; 17(10):1375-1384. doi:10.7150/ijms.41793. Available from http://www.medsci.org/v17p1375.htm

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Abstract

Cladribine is a purine nucleoside analog used to treat B-cell chronic lymphocytic leukemia and hairy cell leukemia, also functions as an inhibitor of DNA synthesis to block the repair of the damaged DNA. The therapeutic role of cladribine against diffuse large B-cell lymphoma cells (DLBCL) is still undefined. In the present study, we demonstrated that cladribine inhibited cell proliferation and induced G1 phase arrest in human DLBCL cells. Furthermore, we showed that cladribine induced apoptosis by decreasing the expression of c-FLIPL and increasing the expression of DR4 and the cleaved form of caspase8. Cladribine also upregulated the expression of Bax, and downregulated the expression of Mcl-1 and Bcl-2 in a dose-dependent manner. It also activated endoplasmic reticulum (ER) stress, and ATF4 expression was required for cladribine induced apoptosis. Also, we showed that suberoylanilide hydroxamic acid (SAHA) enhanced the pro-apoptotic role of cladribine. Collectively, cladribine activated extrinsic and intrinsic apoptotic signaling pathways via stimulating ER stress signaling pathway and eliciting synergistic effect with SAHA in DLBCL cells.

Keywords: cladribine, ATF4, SAHA, apoptosis, DLBCL