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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
p300/CBP dependent hyperacetylation of histone potentiates anticancer activity of gefitinib nanoparticles
Jasmine Kaur1, Kulbhushan Tikoo
1Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Punjab, India.
Abstract:
Gefitinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, approved for patients with non-small cell lung cancer (NSCLC). In this report we demonstrate that gefitinib loaded PLGA nanoparticles (GNPs), in comparison to gefitinib, exhibited higher anti-cancer activity on A549 lung carcinoma cells and A431 skin carcinoma cells. Increased inhibition of pEGFR in both the cell types explains its higher anti-cancer activity. Interestingly, gefitinib resistant, H1975 (T790M EGFR mutant) lung carcinoma cells was also found to be sensitive to GNPs. Our data shows that GNPs hyperacetylate histone H3 in these cells, either directly or indirectly, which may account for the augmented cell death. GNPs were proficient in activating histone acetyltransferases (p300/CBP), which in turn induces the expression of p21 and cell cycle arrest. Furthermore, inhibition of histone acetyltransferases by garcinol results in alleviation of cell death caused by GNPs. In addition to this, nuclear intrusion of GNPs results in the inhibition of NO production in nucleus, possibly through nuclear EGFR, which might be responsible for preventing cell proliferation in resistant cells. To best of our knowledge, we provide first evidence that GNPs potentiate cell death by activating p300/CBP histone acetyltransferases.
Insights
Gefitinib-loaded nanoparticles show enhanced anti-cancer effects against lung and skin cancer cells. These nanoparticles overcome gefitinib resistance by activating histone acetyltransferases, leading to cell death.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Gefitinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor used for non-small cell lung cancer (NSCLC).
- Drug resistance remains a significant challenge in cancer therapy, necessitating novel drug delivery systems.
Purpose of the Study:
- To evaluate the anti-cancer activity of gefitinib loaded PLGA nanoparticles (GNPs) compared to gefitinib alone.
- To investigate the underlying mechanisms of GNPs' enhanced efficacy, particularly in gefitinib-resistant cancer cells.
Main Methods:
- In vitro assessment of anti-cancer activity on A549, A431, and H1975 lung carcinoma cells.
- Analysis of pEGFR inhibition, histone H3 acetylation, and histone acetyltransferase (p300/CBP) activation.
- Evaluation of cell cycle arrest, NO production, and the effect of histone acetyltransferase inhibition.
Main Results:
- GNPs demonstrated higher anti-cancer activity and increased pEGFR inhibition than gefitinib in A549 and A431 cells.
- GNPs were effective against gefitinib-resistant H1975 cells, inducing hyperacetylation of histone H3.
- GNPs activated p300/CBP, leading to p21 expression, cell cycle arrest, and inhibition of nuclear NO production.
Conclusions:
- Gefitinib-loaded nanoparticles offer superior anti-cancer efficacy and overcome resistance mechanisms.
- GNPs potentiate cancer cell death by activating p300/CBP histone acetyltransferases and inhibiting nuclear NO production.
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