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

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 ac...

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Bibliographic Details
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
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Summary: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.
ISSN:1525-7770
1532-2335
DOI:10.1080/15257770.2021.2013500