Biochemical and Biophysical Research Communications
Regular ArticleResveratrol Arrests the Cell Division Cycle at S/G2 Phase Transition☆
Abstract
Resveratrol (3,5,4′-trihydroxystilbene) is a naturally occurring phytoalexin, found in grapes and wine, which has been reported to exert a variety of important pharmacological effects. We have investigated the activity of resveratrol on proliferation and differentiation of the promyelocitic cell line HL-60. A concentration as low as 30 μM causes a complete arrest of proliferation and a rapid induction of differentiation towards a myelo-monocytic phenotype. Analyses by flow cytometry showed the absence of the G2/M peak and the accumulation of cells in G1 and S phases. Moreover, at the concentrations employed, a very low amount of apoptotic cells was evidenced. A detailed biochemical analysis demonstrated that the G1 phase of the cell division cycle engine was completely unmodified by resveratrol addition, thus indicating that the G1 → S transition occurs normally. Conversely, after only 24 h treatment, a significant increase of cyclins A and E could be observed along with the accumulation of cdc2 in the inactive phosphorylated form. These data demonstrate that resveratrol causes a complete and reversible cell cycle arrest at the S phase checkpoint.
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Phytostilbenes in lymphoma: Focuses on the mechanistic and clinical prospects of resveratrol, pterostilbene, piceatannol, and pinosylvin
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Unveiling the potential effects of resveratrol in lung cancer treatment: Mechanisms and nanoparticle-based drug delivery strategies
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2022, Biomedicine and PharmacotherapyWith the development in tumor immunology, people are gradually understanding the complexity and diversity of the tumor microenvironment immune status and its important effect on tumors. Tumor-associated macrophages (TAMs), an important part of the tumor immune microenvironment, have a double effect on tumor growth and metastasis. Many studies have focused on lung cancer, especially non-small cell lung cancer and other "hot tumors" with typical inflammatory characteristics. The polarization and infiltration of TAMs is an important mechanism in the occurrence and development of malignant tumors, such as lung cancer, and in the tumor immune microenvironment. Therapeutic drugs designed for these reasons are key to targeting TAMs in the treatment of lung cancer. A large number of reports have suggested that natural compounds have a strong potential of affecting immunity by targeting the polarization and infiltration of TAMs to improve the immune microenvironment of lung cancer and exert a natural antitumor effect. This paper discusses the infiltration and polarization effects of natural compounds on lung cancer TAMs, provides a detailed classification and systematic review of natural compounds, and summarizes the bias of different kinds of natural compounds by affecting their antitumor mechanism of TAMs, with the aim of providing new perspectives and potential therapeutic drugs for targeted macrophages in the treatment of lung cancer.
Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells
2020, Molecular CellResveratrol is a natural product associated with wide-ranging effects in animal and cellular models, including lifespan extension. To identify the genetic target of resveratrol in human cells, we conducted genome-wide CRISPR-Cas9 screens to pinpoint genes that confer sensitivity or resistance to resveratrol. An extensive network of DNA damage response and replicative stress genes exhibited genetic interactions with resveratrol and its analog pterostilbene. These genetic profiles showed similarity to the response to hydroxyurea, an inhibitor of ribonucleotide reductase that causes replicative stress. Resveratrol, pterostilbene, and hydroxyurea caused similar depletion of nucleotide pools, inhibition of replication fork progression, and induction of replicative stress. The ability of resveratrol to inhibit cell proliferation and S phase transit was independent of the histone deacetylase sirtuin 1, which has been implicated in lifespan extension by resveratrol. These results establish that a primary impact of resveratrol on human cell proliferation is the induction of low-level replicative stress.
Resveratrol differentially modulates immune responses in human THP-1 monocytes and macrophages
2019, Nutrition ResearchResveratrol (Res), a natural polyphenol compound found in grapes and red wine, has been shown to exhibit anti-inflammatory, antioxidant, and anticarcinogenic effects. However, proinflammatory/tumor-promoting properties of Res have also been reported, rendering the polyphenol's reported therapeutic benefits less convincing and controversial. To evaluate the underlying plausible factors contributing to the differential immunomodulatory effects imparted by Res, herein, we investigated, at both physiological and pharmacological doses, the in vitro effects of Res on cell survival/proliferation, inflammatory genes, and cytokine production in human monocytic cell line (THP-1) and phorbol 12-myristate 13-acetate differentiated human THP-1–derived macrophages. We hypothesized that the differential effects observed in monocytes and macrophages may largely depend on dietary vs pharmacological doses of Res, duration of treatment, and the target cells it acts upon. Our data showed that Res, at physiological concentrations, inhibited proliferation of THP-1 monocytes with S phase arrest. On the other hand, at pharmacological concentrations, Res induced cell apoptosis and caused G0/G1 phase arrest. Additionally, Res showed differential effects on proinflammatory cytokine expression and production measured by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively, in THP-1 monocytes vs macrophages: promoting inflammation in monocytes while exhibiting anti-inflammatory effects in macrophages. Comparative analysis on Res and 2 other phytochemicals, pterostilbene and genistein, revealed that the immunomodulatory effects of Res were consistent with those observed in pterostilbene and not genistein. Our results reveal a pleiotropic immunomodulatory property of Res that is dose-time-target cell–dependent and thus serve as a caution for the use of Res in the treatment of inflammatory diseases.
Pleiotropic molecular effects of dietary polyphenols resveratrol and apigenin in Leukemia
2018, Polyphenols: Prevention and Treatment of Human DiseaseResveratrol and apigenin are commonly found polyphenols in many fruits and vegetables and recognition of these dietary polyphenols for human health owing to their biological and pharmacological features including antiinflammatory and antioxidative functions has increased recently. In addition to direct antioxidative effects, they have impacts on various important signaling pathways dysregulated in cancer, genetic and epigenetic regulators, transcription factors and even on miRNAs as anticarcinogenic compounds. Numerous in vitro and in vivo studies have demonstrated their pleiotropic molecular mechanisms of action in cancer, particularly in solid tumors. However, in recent years, significant progress has been made in studying the antileukemic effects of resveratrol and apigenin at the cellular and molecular levels. Herein, we have critically discussed the main molecular targets of resveratrol and apigenin and their promising potential as chemopreventive agents as well as their limitations, with a special emphasis on leukemias.
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Abbreviations used: araC, arabinoside cytidine; cdk, cyclin-dependent kinase
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