Abstract
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.
Highlights
Despite the permanent progress in medical sciences, the effective treatment of many malignant diseases remains out of our reach
We demonstrate that the treatment of Dox-resistant human colon adenocarcinoma cells LoVo/Dx by phenothiazine derivatives combined with simvastatin results in the increase of Dox-induced cytotoxicity as well as its intracellular accumulation as compared to the treatment with phenothiazine derivatives alone
It was concluded that the introduction of simvastatin to LoVo/Dx cells that were treated by phenothiazine-type modulators strengthened their anti-multidrug resistance (MDR), anti-inflammatory, and pro-apoptotic properties
Summary
Despite the permanent progress in medical sciences, the effective treatment of many malignant diseases remains out of our reach. The inhibition of the transport activity of ABCB1 protein was suggested to be responsible for their anti-MDR properties [12,13] Such compounds as trifluoperazine, fluphenazine, and thioridazine turned out to be efficient MDR reversing agents when used in vitro [14,15], no phenothiazine derivative proved to be useful in the in vivo settings [16]. Statins are specific inhibitors of the major enzyme of cholesterol biosynthesis pathway, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase [17] They belong to the most popular drugs that are prescribed to decrease the concentration of cholesterol in plasma and to reduce the risk of the development of cardiovascular diseases. It was concluded that the introduction of simvastatin to LoVo/Dx cells that were treated by phenothiazine-type modulators strengthened their anti-MDR, anti-inflammatory, and pro-apoptotic properties
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