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Translational Oncology

Translational Oncology

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Etoposide, an anticancer drug involved in therapy-related secondary leukemia: Enzymes at play

Published:1 October 2021 DOI: 10.1016/j.tranon.2021.101169 PMID: 34243013
Wenchao Zhang , Panhong Gou , Jean-Marie Dupret , Christine Chomienne , Fernando Rodrigues-Lima

Abstract

Etoposide is a semi-synthetic glycoside derivative of podophyllotoxin, also known as VP-16. It is a widely used anticancer medicine in clinics. Unfortunately, high doses or long-term etoposide treatment can induce therapy-related leukemia. The mechanism by which etoposide induces secondary hematopoietic malignancies is still unclear. In this article, we review the potential mechanisms of etoposide induced therapy-related leukemia. Etoposide related leukemogenesis is known to depend on reactive oxidative metabolites of etoposide, notably etoposide quinone, which interacts with cellular proteins such as topoisomerases II (TOP2), CREB-binding protein (CREBBP), and T-Cell Protein Tyrosine Phosphatase (TCPTP). CYP3A4 and CYP3A5 metabolize etoposide to etoposide catechol, which readily oxidizes to etoposide quinone. As a poison of TOP2 enzymes, etoposide and its metabolites induce DNA double-stranded breaks (DSB), and the accumulation of DSB triggers cell apoptosis. If the cell survives, the DSB gives rise to the likelihood of faulty DNA repair events. The gene translocation could occur in mixed-lineage leukemia (MLL) gene, which is well-known in leukemogenesis. Recently, studies have revealed that etoposide metabolites, especially etoposide quinone, can covalently bind to cysteines residues of CREBBP and TCPTP enzymes, . This leads to enzyme inhibition and further affects histone acetylation and phosphorylation of the JAK-STAT pathway, thus putatively altering the proliferation and differentiation of hematopoietic stem cells (HSC). In brief, current studies suggest that etoposide and its metabolites contribute to etoposide therapy-related leukemia through TOP2 mediated DSB and impairs specific enzyme activity, such as CREBBP and TCPTP.

Substances (9)

Related products
Procduct Name CAS Molecular Formula Supplier Price
Etoposide 33419-42-0 C29H32O13 693 suppliers $9.00-$17300.00
Podophyllotoxin 518-28-5 C22H22O8 546 suppliers $9.00-$1720.00
P450 3A4 40 suppliers Inquiry
Etoposide 3',4'-Quinone 105016-65-7 C28H28O13 22 suppliers $320.00-$2200.00
3',4'-dihydroxyetoposide 100007-54-3 C28H30O13 16 suppliers $135.00-$1530.00
ANTI-CBP 15 suppliers Inquiry
Cytochrome P450 3A5 (human) 10 suppliers Inquiry
MLL 8 suppliers $503.00-$503.00
TCPTP peptide 8 suppliers Inquiry

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