Phase Separation in Phosphatidylcholine Membrane Caused by the Presence of a Pyrimidine Analogue of Fluphenazine with High Anti-Multidrug-Resistance Activity

Abstract

Phenothiazine compounds are known as effective inhibitors of a multidrug resistance (MDR) of tumor cells to chemotherapeutic agents. This group consists of many important substances used in human medicine such as antipsychotic drugs in the case of fluphenazine (FPh) or chlorpromazine (CPZ). Fluphenazine was on the World Health Organization (WHO) list of Essential Medicines of 2009, and its new pyrimidine analog (FPh-prm) presented in this work has been documented to have a high anti-MDR activity. In order to discover the character of alterations of the lipid bilayer structure caused by the presence of FPh-prm inside the lipid membrane, which is responsible for the essential increase of an anti-MDR activity of FPh-prm, microcalorimetric (differential scanning calorimetry), Laurdan fluorescence, (31)P nuclear magnetic resonance spectroscopy (NMR), and attenuated total reflectance Fourier transfer infrared spectroscopy (FTIR-ATR) were used for dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes mixed with a different concentration of amine analogue. It was stated that the formation of domains with different content of FPh-prm/DPPC can be a reason for the membrane-related mechanism of chemoprevention associated with the inhibition of the outward transport of anticancer drugs by the glycoprotein P (Pgp) in cancer cells by the pyrimidine analog of FPh. To our best knowledge, this report is the first to show the bilayer structure of domains formed by incomplete miscibility of fluphenazine-related compounds and phospholipid molecules. Our results provide a sound basis for the design of future modifications of anti-MDR drugs by providing very effective inhibitors of the pump activity of Pgp.

Cinnamic acid derived compounds loaded into liposomes: antileishmanial activity, production standardisation and characterisation

“…By using DSC it is possible to determine the enthalpy variation (DH) between the sample and reference during the cooling and heating processes (Bernal et al, 2002). The thermogram of DPPC liposomes by DSC presented parameters similar to literature data (Huang and Li, 1999;Bolean et al, 2010;Cieślik-Boczula et al, 2014). The presence of the B2 drug made the pre-transition more evident, probably due to the interactions between the drug and the polar lipid head.…”

Highly Halaven-resistant KBV20C Cancer Cells Can Be Sensitized by Co-treatment with Fluphenazine

“…In this study, the effects of co-treatment using FLU and AZA were analyzed for the first time. Since both drugs showed similar sensitization effects in cancer screening and in the literature (13,28,29), we tested them and compared their effects to those of THIO and MEF. The cancer-sensitizing ability of FLU has been demonstrated in various cancer models (9-12, 28, 29), suggesting that it has potential as a chemotherapeutic agent.…”

Reconstituição da Anexina V em sistemas de lipossomos: associação com a fosfatase alcalina e correlação com estudos de biomineralização

“…O DPPC apresenta temperatura de transição de fase de 41,5 °C (Koynova et al, 1996;Cieślik-Boczula et al, 2014), o qual foi determinado por DSC e será descrito nos itens de discussão a seguir.…”

“…(Koynova et al, 1996;Cieślik-Boczula et al, 2014) para verificar se a membrana na fase líquido-cristalina (mais fluida) proporciona uma melhor eficiência na incorporação da TNAP quando comparado com os dados de incorporação obtidos em temperatura ambiente, ou seja, com a membrana lipídica na fase gel. Obteve-se apenas em torno de 30% de incorporação da atividade fosfomonohidrolase nos proteolipossomos, mostrando um aumento, porém não expressivo, em relação aos dados anteriores com a membrana na fase gel, mas sendo ainda um baixo valor de incorporação da enzima.…”

“…Além do pico de transição principal, detectou-se um pico menor e largo referente à sua pré-transição com T C em torno de 33 °C. Estes resultados são condizentes com os valores descritos na literatura (Koynova et al, 1996;Tristam-Nagle e Nagle, 2004;Bolean et al, 2010;Cieślik-Boczula et al, 2014). A pré-transição de fase é uma transição de baixa entalpia, abaixo da transição principal, a qual é dependente do grupo cabeça-polar do lipídio.…”