rottlerin has been researched along with Melanoma* in 4 studies
1 review(s) available for rottlerin and Melanoma
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Non-conventional rottlerin anticancer properties.
In the past few years, we focused the interest on rottlerin, an old/new natural substance that, over the time, has revealed a number of cellular and molecular targets, all potentially implicated in the fight against cancer. Past and recent literature well demonstrated that rottlerin is an inhibitor of enzymes, transcription factors and signaling molecules that control cancer cell life and death. Although the rottlerin anticancer activity has been mainly ascribed to apoptosis and/or autophagy induction, recent findings unveiled the existence of additional mechanisms of toxicity. The major novelties highlighted in this mini review are the ability to bind and inhibit key molecules, such as ERK and mTOR, directly, thus independently of upstream signaling cascades, and to cause a profound dysregulation of cap-dependent protein translation through the mTORC1/4EBP1/eIF4E axis and by inhibition of eIF2, an initiation factor of translation that is negatively regulated by endoplasmic reticulum (ER) stress. These last mechanisms, proved to be lethal in cancer cell lines derived from breast and skin, strongly enforce the potential of rottlerin as a promising natural lead compound for the development of novel therapeutic approaches. Topics: Acetophenones; Antineoplastic Agents; Benzopyrans; Breast Neoplasms; Humans; Melanoma | 2018 |
3 other study(ies) available for rottlerin and Melanoma
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Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells.
Rottlerin is a cytostatic and cytotoxic drug in a variety of cancer cells. Our previous experience demonstrated that depending upon the genetic/biochemical background of cancer cells, rottlerin is able to induce both apoptotic and autophagic cell death, or dramatically disturb protein homeostasis leading to lethal cellular atrophy. In the current study, we investigated the cytotoxic effects and mechanisms of rottlerin against human amelanotic A375 melanoma cells. In this cell line, rottlerin exhibits its main and newest cytotoxic properties, that is, growth arrest, apoptosis induction, and translation shutoff. In fact, the drug, time-, and dose-dependently, markedly inhibited cell proliferation through cyclin D1 downregulation and induced apoptotic cell death as early as after 18 h treatment. Mechanistically, rottlerin triggered apoptosis by both intrinsic and extrinsic pathways. Both pathways are likely activated by the downregulation of the antiapoptotic B-cell lymphoma 2 (Bcl-2) protein, which simultaneously affects mitochondrial and endoplasmic reticulum (ER) membranes stability. Concomitantly to extrinsic apoptosis induction, the rottlerin-activated ER stress/eukaryotic initiation factor 2 (eIF2) α axis blocked the translational apparatus. The altered proteostasis precluded the complete cells' rescue from death in the presence of apoptosis inhibitors. Topics: Acetophenones; Antineoplastic Agents; Apoptosis; Benzopyrans; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mitochondria; Reactive Oxygen Species; Signal Transduction | 2019 |
Inhibitions of mTORC1 and 4EBP-1 are key events orchestrated by Rottlerin in SK-Mel-28 cell killing.
Earlier studies demonstrated that Rottlerin exerts a time- and dose-dependent antiproliferative effect on SK-Mel-28 melanoma cells during 24 h of treatment, but cytotoxicity due to cell death began only after a 48 h exposure. In the current study, in order to identify the type of cell death in this cell line, which is notoriously refractory to most anticancer therapies, and to clarify the underlying mechanisms of this delayed outcome, we searched for apoptotic, necrotic/necroptotic and autophagic traits in Rottlerin-exposed cells. Although SK-Mel-28 cells are both apoptosis and autophagy competent, Western blotting analysis, caspase activity assay, nuclear imaging and the effects of autophagy, apoptosis and necroptosis inhibitors, indicated that Rottlerin cytotoxicity was due to none of the aforementioned death mechanisms. Nevertheless, in growth arrested cells, the death did occur after a prolonged treatment and most likely ensued from the observed blockage of protein synthesis that reached levels expected to be incompatible with cell survival. From a mechanistic point of view, we ascribed this effect to the documented inhibition of mTORC1 activity; mTORC1 inhibition on the one hand led to a not deadly, rather protective autophagic response but, on the other hand caused a near complete arrest of protein synthesis. Interestingly, no cytotoxicity was found towards normal skin fibroblasts, which only resulted mildly growth arrested by the drug. Topics: Acetophenones; Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Autophagy; Benzopyrans; Cell Cycle Proteins; Cell Line; Dose-Response Relationship, Drug; Humans; Mechanistic Target of Rapamycin Complex 1; Melanoma; Multiprotein Complexes; Phosphoproteins; Protein Biosynthesis; Protein Kinase Inhibitors; Protein Synthesis Inhibitors; Signal Transduction; Skin Neoplasms; Time Factors; TOR Serine-Threonine Kinases | 2016 |
Establishment of a melanogenesis regulation assay system using a fluorescent protein reporter combined with the promoters for the melanogenesis-related genes in human melanoma cells.
There are two established depigmenting agent assays currently in use. However, these methods are unreliable and time-consuming. Therefore, it will be valuable to establish a better assay system for depigmenting agent analysis. In this study, we established a melanogenesis regulation assay system using a fluorescent protein reporter combined with the promoters for the microphthalmia-associated transcription factor (MITF), tyrosinase (Tyr) and dopachrome tautomerase (Dct) genes in MeWo human melanoma cells. We used several melanogenesis regulators, including theophylline, hesperetin, arbutin and rottlerin, to confirm the function of this assay system. The established MeWo/pMITF-EGFP, MeWo/pTyr-EGFP and MeWo/pDct-EGFP stable cells integrated the pMITF-EGFP, pTyr-EGFP and pDct-EGFP plasmids into their genomic DNA. These stably transfected cells were used to examine alterations in the expression of the MITF, Tyr and Dct genes. All of the tested compounds, including theophylline, hesperetin, arbutin and rottlerin, could be analyzed in the stable cells, producing reliable results. Therefore, we believe that this melanogenesis regulation assay system can be used as a rapid and reliable assay system to analyze the regulation of melanogenesis by many known or unknown compounds. Topics: Acetophenones; Arbutin; Benzopyrans; Cell Line, Tumor; Drug Evaluation, Preclinical; Enzyme Induction; Gene Expression Regulation, Neoplastic; Genes, Reporter; Genes, Synthetic; Green Fluorescent Proteins; Hesperidin; Humans; Intramolecular Oxidoreductases; Melanins; Melanoma; Melanoma, Experimental; Microphthalmia-Associated Transcription Factor; Microscopy, Fluorescence; Monophenol Monooxygenase; Neoplasm Proteins; Promoter Regions, Genetic; Recombinant Fusion Proteins; RNA, Messenger; Skin Lightening Preparations; Theophylline; Transfection | 2015 |