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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Toxicogenomic and bioinformatics platforms to identify key molecular mechanisms of a curcumin-analogue DM-1 toxicity in melanoma cells

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de Oliveira, Erica Aparecida [1] ; de Lima, Diogenes Saulo [2] ; Cardozo, Lucas Esteves [2] ; de Souza, Garcia Ferreira [3] ; de Souza, Nayane [1] ; Alves-Fernandes, Debora Kristina [1] ; Faiao-Flores, Fernanda [1] ; Pablo Quincoces, Jose Agustin [3] ; de Moraes Barros, Silvia Berlanga [1] ; Nakaya, Helder I. [2] ; Monteiro, Gisele [4] ; Maria-Engler, Silvya Stuchi [1]
Total Authors: 12
[1] Univ Sao Paulo, Sch Pharmaceut Sci, Skin Biol Grp, Clin Chem & Toxicol Dept, FCF USP, Sao Paulo - Brazil
[2] Univ Sao Paulo, Sch Pharmaceut Sci, Computat Syst Biol Lab, FCF USP, Sao Paulo - Brazil
[3] Anhanguera Univ Sao Paulo, Lab Organ Synth, UNIAN, Sao Paulo - Brazil
[4] Univ Sao Paulo, Sch Pharmaceut Sci, Biochem Pharmaceut Technol Dept, FCF USP, Sao Paulo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: PHARMACOLOGICAL RESEARCH; v. 125, n. B, p. 178-187, NOV 2017.
Web of Science Citations: 5

Melanoma is a highly invasive and metastatic cancer with high mortality rates and chemoresistance. Around 50% of melanomas are driven by activating mutations in BRAF that has led to the development of potent anti-BRAF inhibitors. However resistance to anti-BRAF therapy usually develops within a few months and consequently there is a need to identify alternative therapies that will bypass BRAF inhibitor resistance. The curcumin analogue DM-1 (sodium 4-{[}5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-penta-1,4-dieny1]-2-methoxy-ph enolate) has substantial anti-tumor activity in melanoma, but its mechanism of action remains unclear. Here we use a synthetic lethal genetic screen in Saccharomyces cerevisiae to identify 211 genes implicated in sensitivity to DM-1 toxicity. From these 211 genes, 74 had close human orthologues implicated in oxidative phosphorylation, insulin signaling and iron and RNA metabolism. Further analysis identified 7 target genes (ADIC, ATP6V0B, PEMT, TOP1, ZFP36, ZFP36L1, ZFP36L2) with differential expression during melanoma progression implicated in regulation of tumor progression, cell differentiation, and epithelial-mesenchymal transition. Of these TOP1 and ADK were regulated by DM-1 in treatment-naive and vemurafenib-resistant melanoma cells respectively. These data reveal that the anticancer effect of curcumin analogues is likely to be mediated via multiple targets and identify several genes that represent candidates for combinatorial targeting in melanoma. (C) 2017 Elsevier Ltd. All rights reserved. (AU)

FAPESP's process: 14/24400-0 - In vitro models for pre clinical studies of melanoma Chemoresistant
Grantee:Silvya Stuchi Maria-Engler
Support type: Regular Research Grants