Short Interfering RNA Directed against the SLUG Gene Increases Cell Death Induction in Human Melanoma Cell Lines Exposed to Cisplatin and Fotemustine

Background: Melanoma remains largely resistant to currently available chemotherapy, and new strategies have been proposed to flank standardized therapeutic protocols in an effort to improve efficacy. Such an approach requires good knowledge of the mechanisms involved in the resistance and survival of melanoma cells. In this context, the SLUG gene has recently been characterized as a major regulator of melanocytes and melanoma cell survival. Methods: We tested the hypothesis that an oligonucleotide-based short interfering RNA (siRNA) directed against the SLUG gene increases the susceptibility of melanoma cells to drugs such as cisplatin and fotemustine, which are frequently used to treat this cancer. Results: It was found that SLUG siRNA increased cisplatin-induced cell death and rendered the drug active in vitro at half its plasmatic peak concentration. Such activity was correlated with an upregulation of the pro-apoptotic gene, PUMA. Furthermore, SLUG siRNA increased the capacity of fotemustine to elicit cell death and induced p21WAF1 upregulation, resulting in cell cycle arrest. Interestingly, this pathway did not require functional p53. Conclusion: These findings suggest that SLUG siRNA enhances the efficacy of two of the most widely used drugs to treat melanoma.

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Synthesis of Novel Cinnamides and a Bis Cinnamate Bearing 1,2,3-Triazole Functionalities with Antiproliferative and Antimetastatic Activities on Melanoma Cells

Journal of the Brazilian Chemical Society ◽

10.21577/0103-5053.20210109 ◽

2021 ◽

Author(s):

Fabíola Santos ◽

Juliana do Vale ◽

Lucas Santos ◽

Talita Gontijo ◽

Graziela Lima ◽

...

Keyword(s):

Melanoma Cell ◽

High Resolution Mass Spectrometry ◽

Melanoma Cells ◽

Chemotherapeutic Agents ◽

Cycle Arrest ◽

13C Nuclear Magnetic Resonance ◽

Metastatic Behavior ◽

Melanoma Treatment ◽

Murine Melanoma Cell Line

The present investigation describes the synthesis of novel cinnamides and a bis cinnamate bearing 1,2,3-triazole functionalities and investigation of their antiproliferative and antimetastatic effects on melanoma cells. The necessity for the development of new chemotherapeutic agents for melanoma treatment motivated this work. Sixteen derivatives were obtained with yields ranging from 23-81% and fully characterized by spectroscopic (1H and 13C nuclear magnetic resonance, infrared) and spectrometric high resolution mass spectrometry (HRMS) techniques. The derivatives were in vitro evaluated against B16-F10 murine melanoma cell line. The most effective compound (a bis cinnamate) (6b) reduced the melanoma cell viability, generated cell cycle arrest, and influenced the metastatic behavior of melanoma cells by decreasing migration, invasion, and colony formation. Based on these findings, it is believed that compound 6b may represent an interesting scaffold to be explored toward the development of new antimelanoma agents.

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SiRNA technology, the gene therapy of the future?

Orvosi Hetilap ◽

10.1556/oh.2008.28289 ◽

2008 ◽

Vol 149 (4) ◽

pp. 153-159 ◽

Cited By ~ 7

Author(s):

Zsuzsanna Rácz ◽

Péter Hamar

Keyword(s):

Gene Therapy ◽

Short Interfering Rna ◽

The Future ◽

Interfering Rna

A genetikában új korszak kezdődött 17 éve, amikor a petúniában felfedezték a koszuppressziót. Később a koszuppressziót azonosították a növényekben és alacsonyabb rendű eukariótákban megfigyelt RNS-interferenciával (RNSi). Bár a növényekben ez ősi vírusellenes gazdaszervezeti védekezőmechanizmus, emlősökben az RNSi élettani szerepe még nincs teljesen tisztázva. Az RNSi-t rövid kettős szálú interferáló RNS-ek (short interfering RNA, siRNS) irányítják. A jelen cikkben összefoglaljuk az RNSi történetét és mechanizmusát, az siRNS-ek szerkezete és hatékonysága közötti összefüggéseket, a célsejtbe való bejuttatás virális és nem virális módjait. Az siRNS-ek klinikai alkalmazásának legfontosabb akadálya az in vivo alkalmazás. Bár a hidrodinamikus kezelés állatokban hatékony, embereknél nem alkalmazható. Lehetőséget jelent viszont a szervspecifikus katéterezés. A szintetizált siRNS-ek ismert mellékhatásait szintén tárgyaljuk. Bár a génterápia ezen új területén számos problémával kell szembenézni, a sikeres in vitro és in vivo kísérletek reményt jelentenek emberi betegségek siRNS-sel történő kezelésére.

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Simvastatin Induces Death of Multiple Myeloma Cell Lines

Journal of Investigative Medicine ◽

10.1136/jim-52-05-34 ◽

2004 ◽

Vol 52 (5) ◽

pp. 335-344 ◽

Cited By ~ 11

Author(s):

Naomi Gronich ◽

Liat Drucker ◽

Hava Shapiro ◽

Judith Radnay ◽

Shai Yarkoni ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Cell Death ◽

Cell Lines ◽

Myeloma Cell ◽

Cytoplasmic Calcium ◽

Multiple Myeloma Cell ◽

Cycle Arrest ◽

Rpmi 8226

BackgroundAccumulating reports indicate that statins widely prescribed for hypercholesteromia have antineoplastic activity. We hypothesized that because statins inhibit farnesylation of Ras that is often mutated in multiple myeloma (MM), as well as the production of interleukin (IL)-6, a key cytokine in MM, they may have antiproliferative and/or proapoptotic effects in this malignancy.MethodsU266, RPMI 8226, and ARH77 were treated with simvastatin (0-30 μM) for 5 days. The following aspects were evaluated: viability (IC50), cell cycle, cell death, cytoplasmic calcium ion levels, supernatant IL-6 levels, and tyrosine kinase activity.ResultsExposure of all cell lines to simvastatin resulted in reduced viability with IC50s of 4.5 μM for ARH77, 8 μM for RPMI 8226, and 13 μM for U266. The decreased viability is attributed to cell-cycle arrest (U266, G1; RPMI 8226, G2M) and cell death. ARH77 underwent apoptosis, whereas U266 and RPMI 8226 displayed a more necrotic form of death. Cytoplasmic calcium levels decreased significantly in all treated cell lines. IL-6 secretion from U266 cells was abrogated on treatment with simvastatin, whereas total tyrosine phosphorylation was unaffected.ConclusionsSimvastatin displays significant antimyeloma activity in vitro. Further research is warranted for elucidation of the modulated molecular pathways and clinical relevance.

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Novel Thiadiazoline Spiro Quinoline Analogues Induced Cell death in MCF-7 cells via G2/M Phase Cell Cycle Arrest

10.21203/rs.3.rs-289802/v1 ◽

2021 ◽

Author(s):

Selvaraj Shyamsivappan ◽

Raju Vivek ◽

Thangaraj Suresh ◽

Adhigaman Kaviyarasu ◽

Sundarasamy Amsaveni ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Cycle Arrest ◽

Spectroscopic Studies ◽

Phase Cell ◽

Quinoline Derivatives ◽

Cycle Arrest ◽

M Phase ◽

Mcf 7

Abstract A progression of novel thiadiazoline spiro quinoline derivatives were synthesized from potent thiadiazoline spiro quinoline derivatives . The synthesized compounds portrayed by different spectroscopic studies and single X-ray crystallographic studies. The compounds were assessed for in vitro anticancer properties towards MCF-7 and HeLa cells. The compounds showed superior inhibition action MCF-7 malignant growth cells. Amongst, the compound 4a showed significant inhibition activity, the cell death mechanism was evaluated by fluorescent staining, and flow cytometry, RT-PCR, and western blot analyses. The in vitro anticancer results revealed that the compound 4a induced apoptosis by inhibition of estrogen receptor alpha (ERα) and G2/M phase cell cycle arrest. The binding affinity of the compounds with ERα and pharmacokinetic properties were confirmed by molecular docking studies.

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The BRG1- and hBRM-Associated Factor BAF57 Induces Apoptosis by Stimulating Expression of the Cylindromatosis Tumor Suppressor Gene

Molecular and Cellular Biology ◽

10.1128/mcb.25.18.7953-7965.2005 ◽

2005 ◽

Vol 25 (18) ◽

pp. 7953-7965 ◽

Cited By ~ 55

Author(s):

Li Wang ◽

Robert A. Baiocchi ◽

Sharmistha Pal ◽

George Mosialos ◽

Michael Caligiuri ◽

...

Keyword(s):

Cell Death ◽

Tumor Suppressor ◽

Growth Regulation ◽

Suppressor Gene ◽

Breast Carcinoma Cell Line ◽

Chromatin Remodelers ◽

Cycle Arrest ◽

Induced Apoptosis ◽

Familial Cylindromatosis ◽

Interfering Rna

ABSTRACT Mutation of BRG1, hBRM, and their associated factors, INI1 and BAF57, in primary human tumors has suggested that inactivation of human SWI/SNF (hSWI/SNF) complexes may be involved in neoplastic transformation. BT549 is an invasive human breast carcinoma cell line that lacks expression of BAF57, a key hSWI/SNF subunit that mediates interaction with transcriptional activators and corepressors. In this study we investigated the role of BAF57 in suppressing tumorigenesis by establishing BT549 stable cell lines that expresses full-length BAF57 protein. BT549 clones expressing BAF57 demonstrated marked phenotypic changes, slow growth kinetics, and restoration of contact inhibition. Altered growth was found to be due in part to cell cycle arrest and induction of apoptosis. Furthermore, microarray analysis revealed that BAF57-mediated cell death was associated with up-regulation of proapoptotic genes including the tumor suppressor familial cylindromatosis (CYLD), which was found to be a direct target of BAF57 as determined by chromatin immunoprecipitation analysis. Increased expression of CYLD in BT549 cells induced apoptosis, while its suppression by small interfering RNA inhibited cell death in BAF57 expressing BT549 cells. These findings demonstrate the importance of BAF57 in cell growth regulation and provide a novel link between hSWI/SNF chromatin remodelers and apoptosis.

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Treatment of melanoma cells with the synthetic retinoid CD437 induces apoptosis via activation of AP-1 in vitro, and causes growth inhibition in xenografts in vivo.

The Journal of Cell Biology ◽

10.1083/jcb.135.6.1889 ◽

1996 ◽

Vol 135 (6) ◽

pp. 1889-1898 ◽

Cited By ~ 75

Author(s):

D Schadendorf ◽

M A Kern ◽

M Artuc ◽

H L Pahl ◽

T Rosenbach ◽

...

Keyword(s):

Cell Death ◽

Malignant Melanoma ◽

Programmed Cell Death ◽

Melanoma Cells ◽

Human Melanoma ◽

Mrna Levels ◽

Synthetic Retinoid ◽

Human Melanoma Cells

Human malignant melanoma is notoriously resistant to pharmacological modulation. We describe here for the first time that the synthetic retinoid CD437 has a strong dose-dependent antiproliferative effect on human melanoma cells (IC50: 5 x 10(-6) M) via the induction of programmed cell death, as judged by analysis of cell morphology, electron microscopical features, and DNA fragmentation. Programmed cell death was preceded by a strong activation of the AP-1 complex in CD437-treated cells as demonstrated by gel retardation and chloramphenicol transferase (CAT) assays. Northern blot analysis showed a time-dependent increase in the expression of c-fos and c-jun encoding components of AP-1, whereas bcl-2 and p53 mRNA levels remained constant. CD437 also exhibited a strong growth inhibitory effect on MeWo melanoma cells in a xenograft model. In tissue sections of CD437-treated MeWo tumors from these animals, apoptotic melanoma cells and c-fos overexpressing cells were colocalized by TdT-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) staining and in situ hybridization. Taken together, this report identifies CD437 as a retinoid that activates and upregulates the transcription factor AP-1, leading eventually to programmed cell death of exposed human melanoma cells in vitro and in vivo. Further studies are needed to evaluate whether synthetic retinoids such as CD437 represent a new class of retinoids, which may open up new ways to a more effective therapy of malignant melanoma.

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Secretion of Cytokines by Human Choroidal Melanoma Cells and Skin Melanoma Cell Lines in vitro

Ophthalmic Research ◽

10.1159/000055473 ◽

1998 ◽

Vol 30 (3) ◽

pp. 189-194 ◽

Cited By ~ 1

Author(s):

Volker Enzmann ◽

Frank Faude ◽

Leon Kohen ◽

Peter Wiedemann

Keyword(s):

Cell Lines ◽

Melanoma Cell ◽

Choroidal Melanoma ◽

Melanoma Cells ◽

Skin Melanoma ◽

Melanoma Cell Lines

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Effect of Tryptophan-Derived AhR Ligands, Kynurenine, Kynurenic Acid and FICZ, on Proliferation, Cell Cycle Regulation and Cell Death of Melanoma Cells—In Vitro Studies

International Journal of Molecular Sciences ◽

10.3390/ijms21217946 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7946

Author(s):

Katarzyna Walczak ◽

Ewa Langner ◽

Anna Makuch-Kocka ◽

Monika Szelest ◽

Karolina Szalast ◽

...

Keyword(s):

Cell Death ◽

Protein Level ◽

Kynurenic Acid ◽

Melanoma Cells ◽

Aryl Hydrocarbon ◽

Tryptophan Metabolites ◽

Rb Phosphorylation ◽

Retinoblastoma Tumor ◽

Barrier Tissues

Tryptophan metabolites: kynurenine (KYN), kynurenic acid (KYNA) and 6-formylindolo[3,2-b]carbazole (FICZ) are considered aryl hydrocarbon receptor (AhR) ligands. AhR is mainly expressed in barrier tissues, including skin, and is involved in various physiological and pathological processes in skin. We studied the effect of KYN, KYNA and FICZ on melanocyte and melanoma A375 and RPMI7951 cell toxicity, proliferation and cell death. KYN and FICZ inhibited DNA synthesis in both melanoma cell lines, but RPMI7951 cells were more resistant to pharmacological treatment. Tested compounds were toxic to melanoma cells but not to normal human adult melanocytes. Changes in the protein level of cyclin D1, CDK4 and retinoblastoma tumor suppressor protein (Rb) phosphorylation revealed different mechanisms of action of individual AhR ligands. Importantly, all tryptophan metabolites induced necrosis, but only KYNA and FICZ promoted apoptosis in melanoma A375 cells. This effect was not observed in RPMI7951 cells. KYN, KYNA and FICZ in higher concentrations inhibited the protein level of AhR but did not affect the gene expression. To conclude, despite belonging to the group of AhR ligands, KYN, KYNA and FICZ exerted different effects on proliferation, toxicity and induction of cell death in melanoma cells in vitro.

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