Alkylating antitumor agents reduce histone acetyl-transferase activity

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Histone acetylation regulates gene expression and is crucial for cellular processes.
• Alkylating agents like N-Mustard are used in cancer chemotherapy.
• The precise mechanisms by which N-Mustard affects cellular processes, including histone modification, are not fully understood.

Purpose of the Study:

• To investigate the effect of N-Mustard on histone acetylation in cancer cells.
• To determine whether N-Mustard inhibits histone acetylation through altered deacetylation or impaired acetyl-transferase activity.
• To explore the relationship between histone acetylation inhibition and drug resistance.

Main Methods:

• Treatment of Ehrlich ascites and Walker carcinoma cells with N-Mustard and 4-sulphonatoethylthio-cyclophosphamide.
• Assay of histone acetylation and deacetylation rates.
• Analysis of chromatin fractions.
• Comparison of drug-sensitive and drug-resistant cell lines.

Main Results:

• N-Mustard inhibits the acetyl-transferase reaction, leading to reduced histone acetylation.
• The drug primarily affects the acetylation of a specific chromatin fraction.
• Recovery of histone acetylation after drug removal shows a significant lag period.
• N-Mustard-induced reduction in histone acetylation is less pronounced in resistant cell lines compared to sensitive lines.
• This contrasts with DNA cross-linking, which shows similar inhibition and repair in both sensitive and resistant cells.

Conclusions:

• N-Mustard's inhibition of histone acetylation is primarily due to reduced acetyl-transferase activity.
• The differential effect on histone acetylation in resistant vs. sensitive cells suggests its importance in drug efficacy.
• Inhibition of histone acetylation may be a key mechanism underlying the anti-tumor effects of alkylating agents.