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7-Epiclusianone, a Benzophenone Extracted from Garcinia brasiliensis (Clusiaceae), Induces Cell Cycle Arrest in G1/S Transition in A549 Cells.
Ionta M
,
Ferreira-Silva GA
,
Niero EL
,
Costa ÉD
,
Martens AA
,
Rosa W
,
Soares MG
,
Machado-Santelli GM
,
Lago JH
,
Santos MH
.
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Lung cancer is the leading cause of cancer deaths in the world. Disease stage is the most relevant factor influencing mortality. Unfortunately, most patients are still diagnosed at an advanced stage and their five-year survival rate is only 4%. Thus, it is relevant to identify novel drugs that can improve the treatment options for lung cancer. Natural products have been an important source for the discovery of new compounds with pharmacological potential including antineoplastic agents. We have previously isolated a prenylated benzophenone (7-epiclusianone) from Garcinia brasiliensis (Clusiaceae) that has several biological properties including antiproliferative activity against cancer cell lines. In continuation with our studies, the present work aimed to investigate the mechanisms involved with antiproliferative activity of 7-epiclusianone in A549 cells. Our data showed that 7-epiclusianone reduced the viability of A549 cells in a concentration-dependent manner (IC50 of 16.13 ± 1.12 μM). Cells were arrested in G1/S transition and apoptosis was induced. In addition, we observed morphological changes with cytoskeleton disorganization in consequence of the treatment. Taken together, the results showed that cell cycle arrest in G1/S transition is the main mechanism involved with antiproliferative activity of 7-epiclusianone. Our results are promising and open up the prospect of using this compound in further anticancer in vivo studies.
Figure 1. (A) Cell viability profile of A549 and CCD-1059Sk cells after treatment with 7-epiclusianone for 48 h; (B) Phase contrast microscopy images showing morphological aspect of A549 cells. 7-epiclusianone treatment clearly affected cell density in a concentration-dependent manner and induced cell morphology changes. Scale bars: 200 µm.
Figure 2. (A) Histograms showing the EdU incorporation rate after treatment with different concentrations of 7-epiclusianone for 48 h; (B) Mitotic indices determined from cytological preparations that were immunostained for tubulin, with propidium iodide-stained nuclei. Significant differences to control results were determined using ANOVA followed by Tukey’s post-test. ** p < 0.01 and *** p < 0.001.
Figure 3. (A) Cell death evaluated by Annexin V assay; doxorubicin was used as a positive control; (B) Immunoblot for cleaved caspase 3; β-actin was used as loading control. Significant differences compared to control results are indicated. *** p < 0.001.
Figure 4. Images obtained by laser-scanning confocal microscopy evidencing microtubule network (A–C) and microfilament distribution pattern (A1–C1) in A549 cells in presence or absence of 7-epiclusianone. Nuclei were stained with propidium iodide (red).
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