A Novel cytarabine analog evokes synthetic lethality by targeting MK2 in p53-deficient cancer cells.

Abstract

Most nucleoside anticancer drugs show a primary resistance to p53-deficient or p53-mutated cancer cells and are limited in the clinic to the treatment of hematological malignancies. However, 2'-fluoro-4'-seleno-ara-C (F-Se-Ara-C), a new generation of cytarabine (Ara-C) analogs, exhibited potent antitumor activity against the p53-deficient prostate cancer cell line PC-3. The distinct activity of F-Se-Ara-C was achieved by targeting the synthetic lethal interaction between p53 and mitogen-activated protein kinase-activated protein kinase-2 (MK2). MK2 is a checkpoint effector for DNA damage responses to drive cell cycle arrest and DNA repair in p53-deficient cancer cells. Therefore, targeting MK2 may be an effective therapeutic strategy that induces apoptosis for cancers deficient in p53. F-Se-Ara-C effectively induced anti-prostate cancer activity in vitro and in vivo by inhibition of MK2 activation in p53-deficient prostate cancer cells. Moreover, combining F-Se-Ara-C with cabozantinib, an anticancer drug currently in clinical use, induced synergistic antitumor activity in p53-deficient prostate cancer cells. Taken together, these data show that F-Se-Ara-C may become great anticancer drug candidate with its unique mechanism of action for overcoming the apoptotic resistance of p53-deficient cells by targeting the synthetic lethal interaction.

• Authors: Jayoung Song, Jinha Yu, Lak Shin Jeong, Sang Kook Lee
• Journal: Cancer letters (Cancer Lett) Vol. 497 Pg. 54-65 (01 28 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33075425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antimetabolites, Antineoplastic
• Biomarkers, Tumor
• Intracellular Signaling Peptides and Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Cytarabine
• MAP-kinase-activated kinase 2
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antimetabolites, Antineoplastic (chemistry, pharmacology)
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Cycle Checkpoints
• Cell Movement
• Cell Proliferation
• Cytarabine (analogs & derivatives, pharmacology)
• DNA Damage
• DNA Repair
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Synthetic Lethal Mutations
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays