guttiferone-e and Leukemia

Topics: Apoptosis; bcl-2-Associated X Protein; Benzophenones; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin D1; Cytotoxins; Humans; Leukemia; Magnetic Resonance Spectroscopy; Molecular Structure; Polycyclic Compounds; Proto-Oncogene Proteins c-bcl-2; Resting Phase, Cell Cycle; Spectrometry, Mass, Electrospray Ionization

Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of ε-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for in vivo use that underlies the therapeutic potential for p300/CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Enzyme Inhibitors; Female; Humans; Leukemia; Mice, Nude; Molecular Docking Simulation; p300-CBP Transcription Factors; Thiobarbiturates; Transcriptome

The emergence of drug-resistant cancer cells drastically reduces the efficacy of many antineoplasic agents and, consequently, increases the frequency of therapeutic failure. Benzophenones are known to display many pharmacological properties including cytotoxic activities. The present study was aimed at investigating the cytotoxicity and the modes of action of four naturally occurring benzophenones 2,2',5,6'-tetrahydroxybenzophenone (1), isogarcinol (2), isoxanthochymol (3) and guttiferone E (4) on a panel of eleven cancer cell lines including various sensitive and drug-resistant phenotypes.. The cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 2-4. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS).. The four tested benzophenones inhibited the proliferation of all tested cancer cell lines including sensitive and drug-resistant phenotypes. Collateral sensitivity of cancer cells to compounds 1-4 was generally better than to doxorubicin. Compound 2 showed the best activity with IC50 values below or around 1 μM against HCT116 colon carcinoma cells (p53+/+) (0.86 μM) and leukemia CCRF-CEM (1.38 μM) cell lines. Compounds 2-4 strongly induced apoptosis in CCRF-CEM cells via caspases 3/7, caspase 8 and caspase 9 activation and disruption of MMP.. The studied benzophenones are cytotoxic compounds that deserve more detailed exploration in the future, to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzophenones; Carcinoma; Caspases; Cell Proliferation; Colonic Neoplasms; Doxorubicin; Drug Resistance, Neoplasm; HCT116 Cells; HL-60 Cells; Humans; Inhibitory Concentration 50; Leukemia; Matrix Metalloproteinases; Neoplasms; Phenotype; Phytotherapy; Plant Extracts; Reactive Oxygen Species