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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an active lead, the lack of solubility of SQ1 in both organic and aqueous media has complicated its preclinical evaluation. In response, our team turned its effort to explore analogues with the goal of returning synthetically accessible materials with comparable selectivity and activity. The analogue SQ2 showed improved solubility and reached a 30–40-fold greater selectivity for melanoma cells. Here, we report a detailed comparison of the activity of SQ1 and SQ2 in SK-MEL-28 and SK-MEL-147 cell lines, carrying the top melanoma-associated mutations, BRAFV600E and NRASQ61R, respectively. These studies provide a definitive report on the activity, viability, clonogenicity, dermcidin expression, autophagy, and apoptosis induction following exposure to SQ1 or SQ2. Overall, these studies showed that SQ1 and SQ2 demonstrated comparable activity and modulation of dermcidin expression. These studies are further supported through the evaluation of a panel of basal expression of key-genes related to autophagy and apoptosis, providing further insight into the role of these mutations. To explore this rather as a survival or death mechanism, autophagy inhibition sensibilized BRAF mutants to SQ1 and SQ2, whereas the opposite happened to NRAS mutants. These data suggest that the seriniquinones remain active, independently of the melanoma mutation, and suggest the future combination of their application with inhibitors of autophagy to treat BRAF-mutated tumors.

Details

Title
Seriniquinones as Therapeutic Leads for Treatment of BRAF and NRAS Mutant Melanomas
Author
Hirata, Amanda S 1   VIAFID ORCID Logo  ; Rezende-Teixeira, Paula 1   VIAFID ORCID Logo  ; João Agostinho Machado-Neto 1 ; Jimenez, Paula C 2   VIAFID ORCID Logo  ; La Clair, James J 3 ; Fenical, William 4 ; Costa-Lotufo, Leticia V 1   VIAFID ORCID Logo 

 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, SP, Brazil; [email protected] (A.S.H.); [email protected] (P.R.-T.); [email protected] (J.A.M.-N.) 
 Institute of Marine Science, Federal University of São Paulo, Santos 11070-100, SP, Brazil; [email protected] 
 Department of Chemistry and Biochemistry, University of California, La Jolla, San Diego, CA 92093-0358, USA; [email protected] 
 Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, La Jolla, San Diego, CA 92093-0204, USA; [email protected] 
First page
7362
Publication year
2021
Publication date
2021
Publisher
MDPI AG
e-ISSN
14203049
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2608135747
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.