Abstract
Chlorambucil is a nitrogen mustard-based DNA alkylating drug, which is widely used as a front-line treatment of chronic lymphocytic leukaemia (CLL). Despite its widespread application and success for the initial treatment of leukaemia, a majority of patients eventually develop acquired resistance to chlorambucil. In this regard, we have designed and synthesised a novel hybrid molecule, chloram-HDi that simultaneously impairs DNA and HDAC enzymes. Chloram-HDi efficiently inhibits the proliferation of HL-60 and U937 leukaemia cells with GI50 values of 1.24 µM and 1.75 µM, whereas chlorambucil exhibits GI50 values of 21.1 µM and 37.7 µM against HL-60 and U937 leukaemia cells, respectively. The mechanism behind its remarkably enhanced cytotoxicity is that chloram-HDi not only causes a significant DNA damage of leukaemia cells but also downregulates DNA repair protein, Rad52, resulting in the escalation of its DNA-damaging effect. Furthermore, chloram-HDi inhibits HDAC enzymes to induce the acetylation of α-tubulin and histone H3.
Keywords:
DNA damage; cancer; histone deacetylases; leukaemia.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Cycle Checkpoints / drug effects
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Cell Proliferation / drug effects
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Chlorambucil / chemical synthesis
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Chlorambucil / chemistry
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Chlorambucil / pharmacology*
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DNA Damage
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DNA, Neoplasm / chemistry
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DNA, Neoplasm / drug effects*
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Dose-Response Relationship, Drug
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Drug Design
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Drug Screening Assays, Antitumor
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Histone Deacetylase Inhibitors / chemical synthesis
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / metabolism*
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Molecular Structure
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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DNA, Neoplasm
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Histone Deacetylase Inhibitors
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Chlorambucil
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Histone Deacetylases
Grants and funding
This research was supported by Basic Science Research Programme through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1A6A1A03011325 and 2016R1D1A1B01009559).