Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, 40225 Duesseldorf, Germany.
Int J Mol Sci. 2022 Nov 2;23(21):13398. doi: 10.3390/ijms232113398.
The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance of leukemia. Histone deacetylase (HDAC) inhibitors (HDACIs) can normalize epigenetic disbalance by affecting gene expression. In order to decrease side effects of so far mainly used pan-HDACIs, this paper introduces the novel highly selective class IIa HDACI YAK540. A synergistic cytotoxic effect was observed between YAK540 and the proteasome inhibitor bortezomib (BTZ) as analyzed by the Chou-Talalay method. The combination of YAK540 and BTZ showed generally increased proapoptotic gene expression, increased expression, and synergistic, caspase 3/7-mediated apoptosis. Notably, the cytotoxicity of YAK540 is much lower than that of pan-HDACIs. Further, combinations of YAK540 and BTZ are clearly less toxic in non-cancer HEK293 compared to HL-60 leukemia cells. Thus, the synergistic combination of class IIa selective HDACIs such as YAK540 and proteasome inhibitors represents a promising approach against leukemias to increase the anticancer effect and to reduce the general toxicity of HDACIs.
白血病的治疗，尤其是急性髓系白血病（AML），仍然是一个挑战，因为 AML 的 5 年生存率较差。因此，需要新的治疗方法来提高治疗成功率。表观遗传异常在白血病的发病机制和耐药性中起作用。组蛋白去乙酰化酶（HDAC）抑制剂（HDACIs）可以通过影响基因表达来纠正表观遗传失衡。为了降低目前主要使用的 pan-HDACIs 的副作用，本文介绍了新型高选择性 IIa 类 HDACI YAK540。通过 Chou-Talalay 方法分析，观察到 YAK540 与蛋白酶体抑制剂硼替佐米（BTZ）之间存在协同细胞毒性作用。组合 YAK540 和 BTZ 通常表现出促凋亡基因表达增加、 表达增加和协同 caspase 3/7 介导的细胞凋亡。值得注意的是，YAK540 的细胞毒性远低于 pan-HDACIs。此外，与 HL-60 白血病细胞相比，YAK540 和 BTZ 的组合在非癌细胞 HEK293 中明显毒性较低。因此，IIa 类选择性 HDACIs（如 YAK540）与蛋白酶体抑制剂的协同组合代表了一种有前途的治疗白血病的方法，可以提高抗癌效果并降低 HDACIs 的总体毒性。
