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© 2019 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 (http://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

The identification of signaling pathways that are involved in gliomagenesis is crucial for targeted therapy design. In this study we assessed the biological and therapeutic effect of ingenol-3-dodecanoate (IngC) on glioma. IngC exhibited dose-time-dependent cytotoxic effects on large panel of glioma cell lines (adult, pediatric cancer cells, and primary cultures), as well as, effectively reduced colonies formation. Nevertheless, it was not been able to attenuate cell migration, invasion, and promote apoptotic effects when administered alone. IngC exposure promoted S-phase arrest associated with p21CIP/WAF1 overexpression and regulated a broad range of signaling effectors related to survival and cell cycle regulation. Moreover, IngC led glioma cells to autophagy by LC3B-II accumulation and exhibited increased cytotoxic sensitivity when combined to a specific autophagic inhibitor, bafilomycin A1. In comparison with temozolomide, IngC showed a mean increase of 106-fold in efficacy, with no synergistic effect when they were both combined. When compared with a known compound of the same class, namely ingenol-3-angelate (I3A, Picato®), IngC showed a mean 9.46-fold higher efficacy. Furthermore, IngC acted as a potent inhibitor of protein kinase C (PKC) activity, an emerging therapeutic target in glioma cells, showing differential actions against various PKC isotypes. These findings identify IngC as a promising lead compound for the development of new cancer therapy and they may guide the search for additional PKC inhibitors.

Details

Title
Semi-Synthetic Ingenol Derivative from Euphorbia tirucalli Inhibits Protein Kinase C Isotypes and Promotes Autophagy and S-Phase Arrest on Glioma Cell Lines
Author
Oliveira Silva, Viviane Aline 1   VIAFID ORCID Logo  ; Marcela Nunes Rosa 1   VIAFID ORCID Logo  ; Tansini, Aline 1 ; Martinho, Olga 2   VIAFID ORCID Logo  ; Tanuri, Amilcar 3 ; Evangelista, Adriane Feijó 1   VIAFID ORCID Logo  ; Adriana Cruvinel Carloni 1 ; Lima, João Paulo 4 ; Pianowski, Luiz Francisco 5 ; Reis, Rui Manuel 2   VIAFID ORCID Logo 

 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo 14784-400, Brazil; [email protected] (V.A.O.S.); [email protected] (M.N.R.); [email protected] (A.T.); [email protected] (O.M.); [email protected] (A.F.E.); [email protected] (A.C.C.) 
 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo 14784-400, Brazil; [email protected] (V.A.O.S.); [email protected] (M.N.R.); [email protected] (A.T.); [email protected] (O.M.); [email protected] (A.F.E.); [email protected] (A.C.C.); Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; ICVS/3B’s - PT Government Associate Laboratory, 4806-909 Braga/Guimarães, Portugal 
 Laboratory of Molecular Virology, Departaments of genetics, IB, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; [email protected] 
 Medical Oncology, Barretos Cancer Hospital, Barretos, São Paulo 14784-400, Brazil; [email protected]; Medical Oncology Department, A C Camargo Cancer Center, São Paulo 01509-010, SP, Brazil 
 Kyolab Pesquisas Farmacêuticas, Valinhos, São Paulo 13273-105, Brazil; [email protected] 
First page
4265
Publication year
2019
Publication date
2019
Publisher
MDPI AG
e-ISSN
14203049
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2549038663
Copyright
© 2019 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 (http://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.