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The Combined Use of Phenothiazines and Statins Strongly Affects Doxorubicin-Resistance, Apoptosis, and Cox-2 Activity in Colon Cancer Cells.
Sroda-Pomianek, Kamila; Michalak, Krystyna; Palko-Labuz, Anna; Uryga, Anna; Swiatek, Piotr; Majkowski, Michal; Wesolowska, Olga.
Afiliación
  • Sroda-Pomianek K; Department of Biophysics, Wroclaw Medical University, ul. Chalubinskiego 10, 50-368 Wroclaw, Poland. kamila.sroda-pomianek@umed.wroc.pl.
  • Michalak K; Department of Biophysics, Wroclaw Medical University, ul. Chalubinskiego 10, 50-368 Wroclaw, Poland. krystyna.michalak@umed.wroc.pl.
  • Palko-Labuz A; Department of Biophysics, Wroclaw Medical University, ul. Chalubinskiego 10, 50-368 Wroclaw, Poland. anna.palko-labuz@umed.wroc.pl.
  • Uryga A; Department of Biophysics, Wroclaw Medical University, ul. Chalubinskiego 10, 50-368 Wroclaw, Poland. anna.uryga@umed.wroc.pl.
  • Swiatek P; Department of Chemistry of Drugs, Wroclaw Medical University, ul. Borowska 211, 50-556 Wroclaw, Poland. piotr.swiatek@umed.wroc.pl.
  • Majkowski M; Confocal Microscopy Laboratory, Polish Center for Technology Development, ul. Stablowicka 147, 54-066 Wroclaw, Poland. michaljozefmajkowski@gmail.com.
  • Wesolowska O; Department of Biophysics, Wroclaw Medical University, ul. Chalubinskiego 10, 50-368 Wroclaw, Poland. olga.wesolowska@umed.wroc.pl.
Int J Mol Sci ; 20(4)2019 Feb 22.
Article en En | MEDLINE | ID: mdl-30813251
Since none of the multidrug resistance (MDR) modulators tested so far found their way into clinic, a novel approach to overcome the MDR of cancer cells has been proposed. The combined use of two MDR modulators of dissimilar mechanisms of action was suggested to benefit from the synergy between them. The effect of three phenothiazine derivatives that were used as single agents and in combination with simvastatin on cell growth, apoptosis induction, activity, and expression of cyclooxygenase-2 (COX-2) in doxorubicin-resistant colon cancer cells (LoVo/Dx) was investigated. Treatment of LoVo/Dx cells by phenothiazine derivatives combined with simvastatin resulted in an increase of doxorubicin cytotoxicity and its intracellular accumulation as compared to the treatment with phenothiazine derivatives that were used as single agents. Similarly, LoVo/Dx cells treated with two-component mixture of modulators showed the reduced expression of ABCB1 (P-glycoprotein) transporter and COX-2 enzyme, both on mRNA and protein level. Reduced expression of anti-apoptotic Bcl-2 protein and increased expression of pro-apoptotic Bax were also detected. Additionally, COX-2 activity was diminished, and caspase-3 activity was increased to a higher extent by phenothiazine derivative:simvastatin mixtures than by phenothiazine derivatives themselves. Therefore, the introduction of simvastatin strengthened the anti-MDR, anti-inflammatory, and pro-apoptotic properties of phenothiazines in LoVo/Dx cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotiazinas / Doxorrubicina / Apoptosis / Neoplasias del Colon / Resistencia a Antineoplásicos / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Ciclooxigenasa 2 Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2019 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotiazinas / Doxorrubicina / Apoptosis / Neoplasias del Colon / Resistencia a Antineoplásicos / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Ciclooxigenasa 2 Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2019 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Suiza