Pai Padmini, Reddy Yashaswini, Das Ipshita, Venkidesh Babu Santhi, Bhandari Poonam, Rao Pallavi, Oruganti Srinivas, Prasad Keshava, Shetty Manasa Gangadhar, Satyamoorthy Kapaettu, Sundara Babitha Kampa
Department of Biophysics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
Department of Radiation Biology & Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India.
Invest New Drugs. 2025 Jul 10. doi: 10.1007/s10637-025-01559-y.
Histone deacetylases (HDACs) serve a crucial function in transcription regulation, and their dysregulation is linked to numerous diseases, including cancer. Among them, HDAC1 and HDAC2 are particularly significant in neural progenitors and are frequently overexpressed in neural-derived cancers. HDAC inhibitors (HDACis) have shown promise in overcoming chemoresistance by restoring tumor suppressor function in neuroblastoma cells. However, the lack of selectivity in existing HDACis presents challenges, highlighting the need for isoform-selective inhibitors to reduce side effects. This research investigated the anticancer properties of a newly synthesized hydroxamic acid derivative, emphasizing its selective HDAC1 and HDAC2 inhibition and strong antitumor activity. Our findings demonstrated that the newly developed hydroxamic acid analogues, 3A and 3B, effectively inhibited neuroblastoma cells (SH-SY5Y) proliferation, with IC values of 8.49 µM and 4.44 µM, respectively, comparable to suberoylanilide hydroxamic acid (SAHA) with IC of 0.91 µM. Additionally, compounds 3A and 3B exhibited potent HDAC inhibition. Compound 3A selectively inhibited HDAC2 with an IC value of 0.89 μM, while compound 3B showed dual inhibition of HDAC1 and HDAC2, with IC values of 0.44 μM and 1.94 μM, respectively. Compound 3B triggered cell cycle arrest in the G2/M phase, reduced colony formation efficiency, and altered cellular architecture upon treatment, further highlighting its anticancer potential. In an in vivo xenograft model, compound 3B significantly decreased tumor growth and tumor weight, highlighting its potential as an effective anticancer agent for neuroblastoma, offering both isoform-selective HDAC inhibition and potent anticancer effects.
组蛋白去乙酰化酶（HDACs）在转录调控中发挥着关键作用，其失调与包括癌症在内的多种疾病相关。其中，HDAC1和HDAC2在神经祖细胞中尤为重要，并且在神经源性癌症中经常过度表达。HDAC抑制剂（HDACis）已显示出通过恢复神经母细胞瘤细胞中的肿瘤抑制功能来克服化疗耐药性的潜力。然而，现有HDACis缺乏选择性带来了挑战，凸显了需要异构体选择性抑制剂以减少副作用。本研究调查了一种新合成的异羟肟酸衍生物的抗癌特性，强调其对HDAC1和HDAC2的选择性抑制以及强大的抗肿瘤活性。我们的研究结果表明，新开发的异羟肟酸类似物3A和3B有效抑制神经母细胞瘤细胞（SH-SY5Y）的增殖，IC值分别为8.49 μM和4.44 μM，与IC值为0.91 μM的伏立诺他（SAHA）相当。此外，化合物3A和3B表现出强大的HDAC抑制作用。化合物3A以0.89 μM的IC值选择性抑制HDAC2，而化合物3B对HDAC1和HDAC2表现出双重抑制作用，IC值分别为0.44 μM和1.94 μM。化合物3B在处理后引发细胞周期停滞在G2/M期，降低集落形成效率并改变细胞结构，进一步突出了其抗癌潜力。在体内异种移植模型中，化合物3B显著降低肿瘤生长和肿瘤重量，突出了其作为神经母细胞瘤有效抗癌剂的潜力，兼具异构体选择性HDAC抑制和强大的抗癌效果。
