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Trichostatin A Promotes Cytotoxicity of Cisplatin, as Evidenced by Enhanced Apoptosis/Cell Death Markers

Yang Zhou1,2, Qun Luo1,2, Fangang Zeng3

  • 1Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

Molecules (Basel, Switzerland)
|June 19, 2024
PubMed

Insights

Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, enhances cisplatin

Area of Science:

  • Cancer Research
  • Molecular Biology
  • Pharmacology

Background:

  • Histone deacetylase (HDAC) inhibitors like Trichostatin A (TSA) can modulate cancer cell responses.
  • The combination of HDAC inhibitors with genotoxic chemotherapy drugs like cisplatin is a potential therapeutic strategy.
  • The precise mechanisms by which TSA enhances cisplatin cytotoxicity are not fully elucidated.

Purpose of the Study:

  • To investigate the underlying mechanisms of Trichostatin A (TSA) in enhancing cisplatin-induced cytotoxicity in A549 cancer cells.
  • To elucidate the molecular pathways involved in the synergistic effect of TSA and cisplatin.

Main Methods:

  • Utilized A549 cancer cells treated with TSA and cisplatin.
  • Assessed apoptosis and cell cycle arrest using caspase-3/6 activation, cleaved PARP1, and lamin A&C degradation.
  • Quantified DNA-bound platinum using ICP-MS and ToF-SIMS.
  • Performed global quantitative proteomics to analyze signaling pathway alterations.
  • Investigated ferroptosis and post-translational modifications, specifically H4K8 acetylation.

Main Results:

  • TSA (1 μM) promoted cisplatin-induced apoptosis and G2/M phase arrest by activating caspase-3/6, increasing cleaved PARP1, and degrading lamin A&C.
  • TSA increased DNA-bound platinum levels, enhancing genomic DNA accessibility to cisplatin.
  • Proteomics revealed TSA-cisplatin activated INF signaling (STAT1, SAMHD1), downregulated ICAM1 and CD44, and reduced TFAM and SLC3A2, promoting apoptosis and ferroptosis.
  • Acetylation at H4K8 was identified as a key post-translational modification promoting cisplatin cytotoxicity.

Conclusions:

  • TSA synergistically enhances cisplatin cytotoxicity through multiple mechanisms, including increased DNA damage, apoptosis, cell cycle arrest, and ferroptosis.
  • The findings highlight the crucial role of H4K8 acetylation in this combined therapy.
  • This study provides a deeper understanding of combining HDAC inhibitors with genotoxic drugs for cancer treatment.
Keywords:
cisplatincytotoxicityhistone acetylationquantitative proteomicstrichostatin A

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