scholarly journals 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

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.

scholarly journals UVB Radiation and Selected Tryptophan-Derived AhR Ligands—Potential Biological Interactions in Melanoma Cells

2021 ◽  
Vol 22 (14) ◽  
pp. 7500
Author(s):  
Katarzyna Walczak ◽  
Paulina Kazimierczak ◽  
Karolina Szalast ◽  
Tomasz Plech
Keyword(s):  
Cell Cycle Regulation ◽  
Kynurenic Acid ◽  
Melanoma Cells ◽  
Biological Interactions ◽  
Uvb Radiation ◽  
Aryl Hydrocarbon ◽  
Crucial Effect ◽  
Tryptophan Metabolites ◽  
Cycle Regulation

Excessive UV exposure is considered the major environmental factor in melanoma progression. Human skin is constantly exposed to selected tryptophan-derived aryl hydrocarbon receptor (AhR) ligands, including kynurenine (KYN) and kynurenic acid (KYNA), as they are endogenously produced and present in various tissues and body fluids. Importantly, recent studies confirmed the biological activity of KYN and KYNA toward melanoma cells in vitro. Thus, in this study, the potential biological interactions between UVB and tryptophan metabolites KYN and KYNA were studied in melanoma A375, SK-MEL-3, and RPMI-7951 cells. It was shown that UVB enhanced the antiproliferative activity of KYN and KYNA in melanoma cells. Importantly, selected tryptophan-derived AhR ligands did not affect the invasiveness of A375 and RPMI-7951 cells; however, the stimulatory effect was observed in SK-MEL-3 cells exposed to UVB. Thus, the effect of tryptophan metabolites on metabolic activity, cell cycle regulation, and cell death in SK-MEL-3 cells exposed to UVB was assessed. In conclusion, taking into account that both UVB radiation and tryptophan-derived AhR ligands may have a crucial effect on skin cancer formation and progression, these results may have a significant impact, revealing the potential biological interactions in melanoma cells in vitro.

scholarly journals How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function

2020 ◽  
Vol 21 (24) ◽  
pp. 9614
Author(s):  
Iain A. Murray ◽  
Gary H. Perdew
Keyword(s):  
Physiological Function ◽  
Innate Immune ◽  
Ah Receptor ◽  
Ligand Specificity ◽  
Aryl Hydrocarbon ◽  
Innate Immune Signaling ◽  
Tryptophan Metabolites ◽  
Barrier Tissues ◽  
Endogenous Metabolites

Increasingly, the aryl hydrocarbon receptor (AHR) is being recognized as a sensor for endogenous and pseudo-endogenous metabolites, and in particular microbiota and host generated tryptophan metabolites. One proposed explanation for this is the role of the AHR in innate immune signaling within barrier tissues in response to the presence of microorganisms. A number of cytokine/chemokine genes exhibit a combinatorial increase in transcription upon toll-like receptors and AHR activation, supporting this concept. The AHR also plays a role in the enhanced differentiation of intestinal and dermal epithelium leading to improved barrier function. Importantly, from an evolutionary perspective many of these tryptophan metabolites exhibit greater activation potential for the human AHR when compared to the rodent AHR. These observations underscore the importance of the AHR in barrier tissues and may lead to pharmacologic therapeutic intervention.

scholarly journals 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.

1996 ◽  
Vol 135 (6) ◽  
pp. 1889-1898 ◽  
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.

scholarly journals Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms

2015 ◽  
Vol 26 (6) ◽  
pp. 1044-1057 ◽  
Author(s):  
Chen Wei ◽  
Ma Lin ◽  
Bian Jinjun ◽  
Feng Su ◽  
Cao Dan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Protein Level ◽  
Cell Apoptosis ◽  
General Control ◽  
Screening Assay ◽  
Cancer Cell Apoptosis ◽  
Cancer Cell Death

General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na+,K+-ATPase ligand–induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na+,K+-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2–β-arrestin–NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na+,K+-ATPase ligand–induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na+,K+-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.

scholarly journals Polyphenols and Tryptophan Metabolites Activate the Aryl Hydrocarbon Receptor in an in vitro Model of Colonic Fermentation

2018 ◽  
Vol 63 (3) ◽  
pp. 1800722 ◽  
Author(s):  
Jonna E. B. Koper ◽  
Linda M. P. Loonen ◽  
Jerry M. Wells ◽  
Antonio Dario Troise ◽  
Edoardo Capuano ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
In Vitro Model ◽  
Colonic Fermentation ◽  
Aryl Hydrocarbon ◽  
Tryptophan Metabolites ◽  
Vitro Model

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

2007 ◽  
Vol 29 (4) ◽  
pp. 279-287
Author(s):  
Ivan Vannini ◽  
Massimiliano Bonafe ◽  
Anna Tesei ◽  
Marco Rosetti ◽  
Francesco Fabbri ◽  
...  
Keyword(s):  
Cell Death ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Short Interfering Rna ◽  
Apoptotic Gene ◽  
Cycle Arrest ◽  
Therapeutic Protocols ◽  
Interfering Rna ◽  
New Strategies

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.

scholarly journals The In Vitro and In Vivo Anticancer Properties of Chalcone Flavokawain B through Induction of ROS-Mediated Apoptotic and Autophagic Cell Death in Human Melanoma Cells

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2936
Author(s):  
You-Cheng Hseu ◽  
Yu-Chi Chiang ◽  
Yugandhar Vudhya Gowrisankar ◽  
Kai-Yuan Lin ◽  
Sheng-Teng Huang ◽  
...  
Keyword(s):  
Cell Death ◽  
Nude Mice ◽  
Melanoma Cell Line ◽  
Caspase 3 ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Autophagic Cell Death ◽  
Anticancer Properties

Melanoma is the most prevalent type of skin cancer with high mortality rates. This study demonstrates the in vitro and in vivo anticancer properties of chalcone flavokawain B (FKB) induced ROS-mediated apoptosis and autophagy in human melanoma (human epithelial melanoma cell line A375 and/or human skin lymph node derived melanoma cell line A2058) cells. Cell viability was calculated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the expression patterns of various apoptosis, autophagy-associated proteins were determined by Western blot methods. Annexin V was detected by flow cytometry, whereas acidic vesicular organelles (AVOs) and intracellular ROS levels were measured by fluorescence microscopy. The in vivo anticancer properties of FKB were evaluated by xenografting the A375 cells into nude mice. The results convey that FKB inhibited cell viability, B-Raf proto-oncogene, serine/threonine kinase (BRAF)/extracellular signal-regulated kinase (ERK) expression in human melanoma cells. Caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage pathway, and Bcl2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2) dysregulation were involved in the execution of apoptosis. Moreover, FKB-induced autophagy was observed through increased microtubule-associated protein 1A/1B-light chain 3B (LC3-II) accumulation and AVOs formation, which was also associated with an increase in sequestosome 1 (SQSTM1/p62), decreased protein kinase B (AKT)/mammalian target of rapamycin (mTOR) expressions, and dysregulated Beclin-1/Bcl-2 levels. Autophagy inhibitors [3-methyladenine (3-MA)/chloroquine (CQ)] and LC3 silencing suppressed FKB-induced apoptosis by decreasing caspase-3 in melanoma cells. The antioxidant N-acetylcysteine (NAC) diminished FKB-induced apoptotic and autophagic cell death. However, the inhibition of apoptosis decreased FKB-induced autophagy (LC3-I/II). The in vivo study confirmed that FKB inhibited melanoma growth in A375-xenografted nude mice. This study concluded that FKB is critically associated with the execution and generation of ROS-modulated apoptotic and autophagic cell death of melanoma cells. FKB also repressed tumor growth in xenografted nude mice. Therefore, flavokawain B might be a potential anti-tumor agent in human melanoma treatment.

scholarly journals Evaluation of In Vitro Antioxidant and Anticancer Properties of the Aqueous Extract from the Stem Bark of Stryphnodendron adstringens

2018 ◽  
Vol 19 (8) ◽  
pp. 2432 ◽  
Author(s):  
Débora Baldivia ◽  
Daniel Leite ◽  
David Castro ◽  
Jaqueline Campos ◽  
Uilson Santos ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Cell Death ◽  
Chemical Constituents ◽  
Radical Scavenging ◽  
Stem Bark ◽  
Melanoma Cells ◽  
In Vivo Models ◽  
Anticancer Effects

Stryphnodendron adstringens (Mart.) Coville (Fabaceae) is a tree species native to the Brazilian Cerrado commonly known as barbatimão. In traditional medicine, decoctions or infusions of the stem bark of this plant are used in the treatment of several diseases. The objective of this study was to analyze the chemical composition of Stryphnodendron adstringens aqueous extracts (SAAE) prepared from the stem bark to assess their antioxidant activity and anticancer effects as well as characterize cell death mechanisms against murine B16F10Nex-2 melanoma cells. From the SAAE, gallic acid, gallocatechin, epigallocatechin, dimeric and trimeric proanthocyanidins mainly composed of prodelphinidin units and the isomeric chromones C-hexosyl- and O-pentosyl-5,7-dihydroxychromone were identified. The SAAE showed antioxidant activity through direct free-radical scavenging as well as through oxidative hemolysis and lipid peroxidation inhibition in human erythrocytes. Furthermore, SAAE promoted apoptosis-induced cell death in melanoma cells by increasing intracellular reactive oxygen species (ROS) levels, inducing mitochondrial membrane potential dysfunction and activating caspase-3. Together, these data show the antioxidant and anticancer effects of Stryphnodendron adstringens. These results open new perspectives for studies against other tumor cell lines and in vivo models as well as for the identification and isolation of the chemical constituents responsible for these effects.

scholarly journals Susceptibility of In Vitro Melanoma Skin Cancer to Photoactivated Hypericin versus Aluminium(III) Phthalocyanine Chloride Tetrasulphonate

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
I. M. Ndhundhuma ◽  
H. Abrahamse
Keyword(s):  
Cell Death ◽  
Laser Irradiation ◽  
Membrane Integrity ◽  
Annexin V ◽  
Melanoma Cells ◽  
Cancer Cell Death ◽  
Blue Cell ◽  
Late Apoptosis ◽  
A375 Cell Line

The sensitivity of human melanoma cells to photoactivated Hypericin (Hyp) compared to aluminium(III) phthalocyanine chloride tetrasulphonate (AlPcS4Cl) is reported in this study. Melanoma cells (A375 cell line) were treated with various concentrations of Hyp or AlPcS4Cl alone, for 1, 4, and 24 hrs; varying doses of laser irradiation alone (594 or 682 nm); or optimal concentrations of PSs combined with laser irradiation. Changes in cell morphology, viability, membrane integrity, and proliferation after treatment of cells were determined using inverted microscopy, Trypan blue cell exclusion, Lactate Dehydrogenase (LDH) membrane integrity, and adenosine triphosphate (ATP) cell proliferation assay, respectively. More than 60% of cell survival was observed when cells were treated with 2.5 μM of Hyp or AlPcS4Cl alone at all incubation times or with 5 J/cm2 of 594 or 682 nm laser alone. Combination of PSs and respective lasers leads to a statistically significant incubation time-dependent decrease in survival of cells. Flow cytometry using the FITC Annexin V/PI apoptosis kit demonstrated that cell death induced after Hyp-PDT is via early and late apoptosis whereas early apoptosis was the main mechanism observed with AlPcS4Cl-PDT. Hyp-PDT compared to AlPcS4Cl-PDT is indicated to be a more effective cancer cell death inducer in melanoma cells.

Sign in / Sign up

Export Citation Format

Share Document