Meclizine Chloridrate and Methyl-β-Cyclodextrin Associated with Monophosphoester Synthetic Phosphoethanolamine Modulating Proliferative Potential in Triple-Negative Breast Cancer Cells

Abstract

Synthetic phosphoethanolamine (Pho-s) is a monophosphoester ester with anti-inflammatory and pro-apoptotic properties. Meclizine chloridrate (MC) is a histamine H1 receptor blocker that is also able to inhibit cellular respiration. However, MC does not inhibit cellular respiration in isolated mitochondria such as antimycin and rotenone. Methyl-β-cyclodextrin (MβCD) belongs to the β-cyclodextrin family, which is capable of removing cholesterol from the plasma membrane. The aim of this study was to evaluate the proliferative effects of meclizine chloridrate and methyl-β-cyclodextrin compounds associated with synthetic phosphoethanolamine in a triple-negative human breast tumor line, MDA-MB-231 Cell viability of the tumor line and normal cells FN1 was evaluated by MTT colorimetric test; the production of free radicals was determined by lipoperoxidation (LPO) test; and the percentage of cell cycle phases and proliferative index was evaluated by flow cytometry. Cell viability demonstrated a significant decrease with the treatments of MβCD, MC and Pho-s associated with MC. The production of free radicals decreases significantly in all treatments. In addition, a significant increase of DNA fragment and decrease in G0/G1 cell cycle phase were observed in cellular percentage with concentrations of 20 and 30 mM of Pho-s in association with MC and MβCD, respectively.

Antiproliferative Modulation and Pro-Apoptotic Effect of BR2 Tumor-Penetrating Peptide Formulation 2-Aminoethyl Dihydrogen Phosphate in Triple-Negative Breast Cancer

“…Monophosphoester 2-aminoethyl dihydrogen phosphate (2-AEH 2 P) is a molecule involved in phospholipid turnover, acting as a precursor in the synthesis of membrane phospholipids, including phosphatidylcholine and phosphatidylethanolamine, that participate as ligands or intermediary substrates in lipid signaling pathways [8,9]. 2-AEH 2 P interest as an adjuvant to in vitro and in vivo therapy has already been demonstrated by our group for numerous types of cancer [10][11][12][13][14][15][16]. Indeed, 2-AEH 2 P exerts antiproliferative and pro-apoptotic effects in triple-negative human breast adenocarcinoma cells (MDA-MB-231) [13], human breast cancer cell line with estrogen, progesterone, and glucocorticoid receptors (MCF-7) [11], myelogenous leukemia cell line (K562 e K562 Lucena MDR+) 13 , murine hepatoma cell line (Hepa-1c1c7) and melanoma-mouse cell line (B16-F10) [14][15][16].…”

“…2-AEH 2 P interest as an adjuvant to in vitro and in vivo therapy has already been demonstrated by our group for numerous types of cancer [10][11][12][13][14][15][16]. Indeed, 2-AEH 2 P exerts antiproliferative and pro-apoptotic effects in triple-negative human breast adenocarcinoma cells (MDA-MB-231) [13], human breast cancer cell line with estrogen, progesterone, and glucocorticoid receptors (MCF-7) [11], myelogenous leukemia cell line (K562 e K562 Lucena MDR+) 13 , murine hepatoma cell line (Hepa-1c1c7) and melanoma-mouse cell line (B16-F10) [14][15][16].…”

Potencial antiproliferativo do monofosfoester 2-aminoetil dihidrogeno fosfato associado ao peptídeo penetrante de tumor BR2 em células tumorais de mama triplo-negativo

“…Em trabalhos recentes o 2-AEH 2 F apresentou caráter citotóxico para as células de adenocarcinoma de mama humano triplo-negativo (MDA-MB-231) quando comparado com células de fibroblasto humano normal (FN1) o valor da IC 50% obtido foi 30 vezes maior, houve diminuição significativa dos lipoperoxidos, aumento do DNA fragmentado e diminuição das fases G0/G1 46 . O 2-AEH 2 F também apresentou uma significância terapêutica para a leucemia mielóide crônica (K562), promovendo apoptose independente do perfil de resistência molecular (MDR+) 47 .…”

“…(adenocarcinoma de mama humano); células MDA MB-231 (câncer de mama triplo negativo humano); células H292 (carcinoma de pulmão humano); células Skmel-28, Mewo (melanoma humano); células Hepa1c1c7 (hepatocarcinoma); K562 e K562-Lucena (Leucemia mieliode crônica -MDR + ) [42][43][44][45][46][47][76][77][78] .…”

“…Estes resultados indicam que o 2-AEH 2 F promoveu seus efeitos antitumorais por meio de um mecanismo que, provavelmente, é comum em todas as linhagens, sem promover efeitos citotóxicos significativos nas células endoteliais HUVEC e fibroblasto FN1. Os nossos dados comportam a hipótese de que a sensibilidade e os valores inibitórios de 50% obtidos para as células tumorais independem do perfil molecular destas, tais como, resistência e agressividade[42][43][44][45][46][47][76][77][78] .Para o tratamento com o peptídeo BR2, as concentrações testadas apresentaram citotoxicidade para as células tumorais, com efeito menor nas células normais, corroborando com dados já descritos na literatura54,[71][72][73] . A associação farmacêutica dessas duas moléculas em concentrações mais baixas tiveram também resultados positivos, apresentando citotoxicidade para as células tumorais.…”