5-carboxy-8-hydroxyquinoline and Neoplasms

The histone lysine demethylase 4 (KDM4) family plays an important role in regulating gene transcription, DNA repair, and metabolism. The dysregulation of KDM4 functions is associated with many human disorders, including cancer, obesity, and cardiovascular diseases. Selective and potent KDM4 inhibitors may help not only to understand the role of KDM4 in these disorders but also to provide potential therapeutic opportunities. Here, we provide an overview of the field and discuss current status, challenges, and opportunities lying ahead in the development of KDM4-based anticancer therapeutics.

Topics: Enzyme Inhibitors; Histone Demethylases; Humans; Jumonji Domain-Containing Histone Demethylases; Neoplasms

Increasing studies show that methylation of histone lysine residues is implicated in the development and progression of varying disease states such as schizophrenia, diabetes, and multiple human cancers. Targeting the specific enzymes responsible for these processes has fueled global investigation into the understanding and correction of epigenetic pathology. This review aims to assemble a timely account of the current progress against chromatin-modifying histone lysine methyltransferases (KMTs) and demethylases (KDMs) to inform ongoing and future efforts into this promising field. In particular, we report on their role in tumor growth and progression and the development of small molecules that modulate these enzymes.

Topics: Animals; Epigenomics; Histone Demethylases; Histone-Lysine N-Methyltransferase; Histones; Humans; Lysine; Methylation; Neoplasms

Anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells' P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

Topics: Animals; Antibodies; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Cell Line, Tumor; Cell Survival; Doxorubicin; HCT116 Cells; Humans; Hydroxyquinolines; Immunotherapy; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neoplasms, Experimental; NIH 3T3 Cells; Programmed Cell Death 1 Receptor; T-Lymphocytes; Tumor Burden