Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Key Laboratory of Hematology of Nanjing Medical University, Nanjing 210029, China.
Aging (Albany NY). 2020 Aug 27;12(16):16083-16098. doi: 10.18632/aging.103536.
Novel agents have made the management of chronic lymphocytic leukemia (CLL) more promising and personalized. However, long-term treatment is still warranted which may result in toxicity and resistance. Thus, new combination therapy may help achieve deeper remission and limited-duration therapy. Histone deacetylase inhibitors (HDACi) can affect many tumors by modulating key biological functions including autophagy. Studies have shown that some novel targeted agents including ibrutinib induce autophagy. This study aimed to explore the effect of oral HDAC inhibitor, chidamide, on CLL cells as well as the role of autophagy in this process. Here, we showed that autophagy flux in CLL cells was inhibited by chidamide via post-transcriptional modulation and chidamide had cytostatic and cytotoxic effects on CLL cells. Besides, the pro-survival role of autophagy in CLL cells was validated by using autophagy inhibitor and knocking down critical autophagy gene. Notably, a combination of chidamide and ibrutinib showed significant synergism and downregulated ibrutinib-induced autophagy. This work highlights the therapeutic potential of chidamide via its effect on autophagy, especially in combination with ibrutinib.
新型药物使慢性淋巴细胞白血病（CLL）的治疗更有前景和更具个性化。然而，仍需要长期治疗，这可能导致毒性和耐药性。因此，新的联合治疗可能有助于实现更深层次的缓解和有限疗程的治疗。组蛋白去乙酰化酶抑制剂（HDACi）可以通过调节包括自噬在内的关键生物学功能来影响许多肿瘤。研究表明，一些新型靶向药物，包括伊布替尼，可诱导自噬。本研究旨在探讨口服 HDAC 抑制剂西达本胺对 CLL 细胞的影响，以及自噬在这一过程中的作用。在这里，我们发现西达本胺通过转录后调节抑制 CLL 细胞的自噬流，并且对 CLL 细胞具有细胞抑制和细胞毒性作用。此外，通过使用自噬抑制剂和敲低关键自噬基因来验证自噬在 CLL 细胞中的生存作用。值得注意的是，西达本胺与伊布替尼联合具有显著的协同作用，并下调了伊布替尼诱导的自噬。这项工作突出了西达本胺通过其对自噬的影响的治疗潜力，特别是与伊布替尼联合使用时。
