Phosphoethanolamine induces caspase-independent cell death by reducing the expression of C-RAF and inhibits tumor growth in human melanoma model

Author(s)

Mambelli, Lisley I. ^[1] ; Teixeira, Sarah F. ^[2] ; Jorge, Salomao D. ^{[1, 3]} ; Kawamura, Barbara ^{[1, 4]} ; Meneguelo, Renato ^[5] ; Barbuto, Jose A. M. ^[1] ; de Azevedo, Ricardo A. ^{[1, 3]} ; Ferreira, Adilson K. ^{[1, 3, 4]}

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Oncol, CIETEC IPEN, Alchemy Innovat Res & Dev, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Med Sch, Med Sci, Sao Paulo - Brazil

^[5] Inst Tecnol Aeronaut, Sao Jose Dos Campos, SP - Brazil

• Document type: Journal article
• Source: BIOMEDICINE & PHARMACOTHERAPY; v. 103, p. 18-28, JUL 2018.
• Web of Science Citations: 1

Abstract

Phosphoethanolamine (PEA) is a fundamental precursor during the biosynthesis of cell membranes phospholipids. In the past few years, it has been described as a potential antitumor agent. In previous studies, we demonstrated that PEA showed antitumor properties in vitro and in vivo in a wide range of tumor cell lines. Herein, we showed that PEA possesses cytotoxic properties and notably revealed to induce caspase-independent cell death. Of interest, we provided evidence that PEA inhibits melanoma cells proliferation through the reduction of C-RAF. Molecular docking of PEA evidenced that this compound indeed fits satisfactory in the binding site located between the dimers of C-RAF protein with 107,01 A and score of-29,62. Also, PEA arrested A2058 cells at G2/M phase in the cell cycle. Moreover, cell proliferation, migration and adhesion capacities of A2058 cells were also inhibited by PEA. Most importantly, PEA inhibited tumor growth of melanoma tumors and prolonged survival rate of mice. Also, PEA induced a significant immune response in a syngeneic metastatic melanoma model. Taken together, these data indicate that PEA is a promising candidate for future developments in cancer field. (AU)

• FAPESP's process: 15/18528-7 - Development of new drug candidate for the treatment of non-small cell lung cancer: CHY-1 as a novel inhibitor of autophagy and prototype of a novel class of inhibitors of the enzyme CTP: phosphoethanolamine citidililtransferase
• Grantee: Adilson Kleber Ferreira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 16/07519-0 - Development of CHY-1 as a new drug candidate for the treatment of different types of breast cancer
• Grantee: Lisley Inata Mambelli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/01265-9 - Multi-target potentially antitumor agents for malignant melanoma: rational design, synthesis, and biological assays of novel benzofuroxan derivatives
• Grantee: Salomão Dória Jorge
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 16/09392-7 - Validation of CTP:phosphoethanolamine cytidylyltransferase enzyme and ethanolamine transport as new targets for the rational development of new drugs in Non-Small Cell Lung Cancer treatment
• Grantee: Sarah Fernandes Teixeira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/07273-2 - Rational design and development of new prototypes derived of antitumor phospholipids as potential inhibitors of the enzyme CtP: phosphoethanolamine citidililtransferase and antitumor agents in non-small cell lung cancer
• Grantee: Jose Alexandre Marzagão Barbuto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/14267-1 - Multi-target potentially antitumor agents for malignant melanoma: rational design, synthesis, and biological assays of novel benzofuroxan derivatives
• Grantee: Salomão Dória Jorge
• Support Opportunities: Scholarships in Brazil - Post-Doctoral