Fludarabine nucleoside induces major changes in the p53 interactome in human B-lymphoid cancer cell lines

• Published in: Nucleosides, nucleotides & nucleic acids nucleotides & nucleic acids, 2022, Vol.41 (3), p.314-320
• Main Authors: Almazi, Juhura G., Alomari, Munther, Belov, Larissa, Best, O. Giles, Shen, Yandong, Graham, Mark E., Mulligan, Stephen P., Christopherson, Richard I.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols; Cell Line; CHK1 protein; Chronic lymphocytic leukemia; Cyclophosphamide; Cytotoxicity; DNA damage; drug mechanism; Fludarabine; Humans; interactome; Isoforms; leukemia; Lymphatic leukemia; Lymphoma; Multiple myeloma; Neoplasms - drug therapy; Non-Hodgkin's lymphoma; Nucleosides; p53 Protein; Protein folding; Protein kinase; Proteins; Rituximab; Tumor cell lines; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Vidarabine - analogs & derivatives; Vidarabine - pharmacology
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1080/15257770.2021.2013500

Triple combination FCR (fludarabine, cyclophosphamide and rituximab) is often used as front-line treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma. Results from our laboratory indicate that 2-FaraAMP (fludarabine) has multiple mechanisms of cytotoxicity that include accumulation of isoforms and phosphorylated derivatives of p53, and induction of the unfolded protein response (UPR). Using protein pull-downs with Dynabeads coated with p53 antibody, we have found that 2-FaraA (fludarabine nucleoside) induces major changes in the p53 interactome in human Raji lymphoma and IM9 multiple myeloma cells. These changes are likely driven by DNA strand breaks induced by 2-FaraA that activate protein kinases such as ATM, ATR and Chk1.