Oncotarget

Research Papers:

Cell internalization of 7-ketocholesterol-containing nanoemulsion through LDL receptor reduces melanoma growth in vitro and in vivo: a preliminary report

Giovani M. Favero, Jessica L. Paz, Andréia H. Otake, Durvanei A. Maria, Elia G. Caldini, Raphael S.S. de Medeiros, Debora F. Deus, Roger Chammas, Raul C. Maranhão and Sergio P. Bydlowski _

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Oncotarget. 2018; 9:14160-14174. https://doi.org/10.18632/oncotarget.24389

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Abstract

Giovani M. Favero1,2, Jessica L. Paz1, Andréia H. Otake3,4, Durvanei A. Maria5, Elia G. Caldini6, Raphael S.S. de Medeiros3,4, Debora F. Deus7, Roger Chammas3,4, Raul C. Maranhão7,8 and Sergio P. Bydlowski1

1Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

2Department of General Biology, Universidade Estadual de Ponta Grossa, Ponta Grossa, PR, Brazil

3Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

4Instituto do Cancer do Estado de Sao Paulo (ICESP), SP, Brazil

5Biochemistry and Biophysics Laboratories, Instituto Butantan, Sao Paulo, SP, Brazil

6Laboratory for Cell Biology, Department of Pathology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

7Laboratory of Metabolism and Lipids, Heart Institute (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

8Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

Correspondence to:

Sergio P. Bydlowski, email: [email protected]

Keywords: 7-ketocholesterol; nanoemulsion; melanoma; cell death; LDL receptor

Received: October 29, 2017     Accepted: January 25, 2018     Epub: February 04, 2018     Published: March 06, 2018

ABSTRACT

Oxysterols are cholesterol oxygenated derivatives which possess several biological actions. Among oxysterols, 7-ketocholesterol (7KC) is known to induce cell death. Here, we hypothesized that 7KC cytotoxicity could be applied in cancer therapeutics. 7KC was incorporated into a lipid core nanoemulsion. As a cellular model the murine melanoma cell line B16F10 was used. The nanoparticle (7KCLDE) uptake into tumor cells was displaced by increasing amounts of low-density-lipoproteins (LDL) suggesting a LDL-receptor-mediated cell internalization. 7KCLDE was mainly cytostatic, which led to an accumulation of polyploid cells. Nevertheless, a single dose of 7KCLDE killed roughly 10% of melanoma cells. In addition, it was observed dissipation of the transmembrane potential, evidenced with flow cytometry; presence of autophagic vacuoles, visualized and quantified with flow cytometry and acridine orange; and presence of myelin figures, observed with ultrastructural microscopy. 7KCLDE impaired cytokenesis was accompanied by changes in cellular morphology into a fibroblastoid shape which is supported by cytoskeletal rearrangements, as shown by the increased actin polymerization. 7KCLDE was injected into B16 melanoma tumor-bearing mice. 7KCLDE accumulated in the liver and tumor. In melanoma tumor 7KCLDE promoted a >50% size reduction, enlarged the necrotic area, and reduced intratumoral vasculature. 7KCLDE increased the survival rates of animals, without hematologic or liver toxicity. Although more pre-clinical studies should be performed, our preliminary results suggested that 7KCLDE is a promising novel preparation for cancer chemotherapy.


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