Mechanisms of resistance to histone deacetylase inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents.
• HDAC inhibitors induce protein acetylation, impacting gene expression and cellular pathways like apoptosis and cell cycle arrest.
• Two HDAC inhibitors, vorinostat and romidepsin, are FDA-approved for cutaneous T-cell lymphoma, with over 20 others in clinical trials.

Purpose of the Study:

• To review identified mechanisms of resistance to HDAC inhibitors in cancer treatment.
• To explain the selective induction of cancer cell death versus normal cell death by HDAC inhibitors.
• To identify specific molecular pathways that may confer resistance to HDAC inhibitors.

Main Methods:

• Literature review of studies on HDAC inhibitors and cancer.
• Analysis of mechanisms underlying differential effects of HDAC inhibitors on cancer versus normal cells.
• Identification of specific proteins and pathways associated with resistance.

Main Results:

• Several mechanisms contribute to resistance, including functional Chk1, elevated thioredoxin levels, and the presence of prosurvival BCL-2.
• These resistance mechanisms may explain why cancer cells, but not normal cells, are selectively targeted by HDAC inhibitors.
• Understanding these pathways is crucial for overcoming treatment limitations.

Conclusions:

• Resistance to HDAC inhibitors in cancer is mediated by specific cellular mechanisms.
• Targeting pathways like Chk1, thioredoxin, and BCL-2 could enhance the efficacy of HDAC inhibitors.
• Further research into resistance mechanisms is vital for improving cancer therapy outcomes.