CPI-455 is a KDM5 inhibitor. KDM5 (Kissinger Demethylase 5) is a lysine-specific demethylase that plays a crucial role in chromatin modification and is involved in various biological processes, including tumor development and immune response[1, 2]. CPI-455 pretreatment of cancer cells can lead to the ablation of cancer cell subpopulations and reduce the survival rate of drug-resistant cancer cells[3]. CPI-455 can induce neural stem cells (NSC) to differentiate into astrocytes[4].
In vitro, CPI-455 (15µM) treatment of esophageal squamous cell carcinoma Eca-109 cells for 24h reduced the decrease in mitochondrial membrane potential, significantly upregulated intracellular ROS content, expression of P53, Bax, Caspase-9 and Caspase-3 proteins, and downregulated KDM5C protein expression[5]. CPI-455 (50µM) treatment of prostate cancer cell lines (C4-2B and PC-3 cells) for 24-96h significantly reduced cell proliferation[6].
In vivo, CPI-455 (20mg/kg) was injected subcutaneously into mice bearing liver cancer cell xenografts, significantly inhibiting the growth of subcutaneous tumors in mice and reducing the volume and weight of tumor tissue, and CPI-455 combination with cisplatin enhanced the anti-tumor effect of cisplatin[7].
References:
[1] Das N D, Niwa H, Umehara T. Chemical inhibitors targeting the histone lysine demethylase families with potential for drug discovery[J]. Epigenomes, 2023, 7(1): 7.
[2] Metzler V M, de Brot S, Haigh D B, et al. The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer[J]. Frontiers in Cell and Developmental Biology, 2023, 11: 1116424.
[3] Vinogradova M, Gehling V S, Gustafson A, et al. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells[J]. Nature chemical biology, 2016, 12(7): 531-538.
[4] San T T, Kim J, Kim H J. Histone lysine demethylase KDM5 inhibitor CPI-455 induces astrocytogenesis in neural stem cells[J]. ACS Chemical Neuroscience, 2024, 15(7): 1570-1580.
[5] Xue X J, Li F R, Yu J. Mitochondrial pathway of the lysine demethylase 5C inhibitor CPI-455 in the Eca-109 esophageal squamous cell carcinoma cell line[J]. World Journal of Gastroenterology, 2021, 27(16): 1805.
[6] Smith T, White T, Chen Z, et al. The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancer cells via cell cycle arrest and the induction of senescence[J]. Experimental cell research, 2024, 437(1): 113991.
[7] Fang S, Zheng L, Shen L, et al. Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway[J]. European Journal of Pharmacology, 2023, 940: 175465.
CPI-455是一种KDM5抑制剂，KDM5（Kissinger Demethylase 5）是一种赖氨酸特异性脱甲基酶，在染色质修饰中起着至关重要的作用，并参与各种生物学过程，包括肿瘤发展和免疫反应[1, 2]。CPI-455预处理癌细胞能够导致癌细胞亚群的消融，降低耐药癌细胞的存活率[3]。CPI-455能够诱导神经干细胞（NSC）分化生成星形胶质细胞[4]。
在体外，CPI-455（15µM）处理食管鳞癌细胞Eca-109细胞24h，降低了细胞线粒体膜电位降低，显著上调了细胞内ROS含量、P53、Bax、Caspase-9和 Caspase-3蛋白的表达，下调了KDM5C蛋白的表达[5]。CPI-455（50µM）处理前列腺癌细胞系（C4-2B和PC-3细胞）24-96h，显著降低了细胞的增殖[6]。
在体内，CPI-455（20mg/kg）通过皮下注射治疗肝癌细胞异种移植小鼠，显著抑制了小鼠皮下肿瘤的生长，减小了肿瘤组织的体积和重量，CPI-455与顺铂联用增强了顺铂的抗肿瘤效果[7]。