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

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.

Structure–Activity Relationship of Cytotoxic Natural Products from Indonesian Marine Sponges

“…The isolation campaign was conducted on four primary Indo-Pacific Zone, including Indonesia, resulting in the isolation of two known compounds, makaluvamine A ( 25 ; PANC-1: IC 50 0.45 μM) and damirone D ( 26 ; PANC-1: IC 50 3.4 μM) (Lin et al 2017 ). The cytotoxicity of 25 is found to be comparable to etoposide (PANC-1: IC 50 0.39 μM), a semisynthetic glycoside derivative of podophyllotoxin used in combination chemotherapies for treating lung cancer, lymphoma, and leukemia (Zhang et al 2021b ). Despite of the different location, the comparison between compound 25 – 26 and makaluvamine J ( 27 ) provides the essentials moiety to cytotoxicity against PANC-1 cell lines, which are possibly related with the following structural features: 1) the substituent at B-ring, 2) the presence of iminium ion on C-ring, and 3) the conjugation of fused ABC-ring (Lin et al 2017 ).…”

Reduction of H3K27cr Modification During DNA Damage in Colon Cancer

“…Ionizing radiation (IR) can directly disrupt atomic structures, leading to chemical and biological changes (30). Etoposide (VP16) is a drug that induces DNA double-strand breaks by poisoning topoisomerases II as covalent adduct (31). IR and VP16 are frequently utilized to induce DNA damage in living cells.…”

Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment

“…While there have been no recent trials examining the efficacy of oral etoposide in rMB alone, its use is still commonplace [ 163 ]. However, prolonged oral etoposide therapy with high cumulative doses poses the risk of secondary leukaemia [ 164 , 165 ].…”