MDR reversal and pro-apoptotic effects of statins and statins combined with flavonoids in colon cancer cells

Palko-Łabuz, Anna; Środa-Pomianek, Kamila; Wesołowska, Olga; Kostrzewa-Susłow, Edyta; Uryga, Anna; Michalak, Krystyna

doi:10.1016/j.biopha.2018.10.169

Cited by 42 publications

(49 citation statements)

References 69 publications

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“…It has been shown previously that MAE-TPR, APh-FLU, and FLU induced apoptosis in LoVo and LoVo/Dx cells [24]. Similarly, pro-apoptotic properties of simvastatin in these cell lines were demonstrated [22]. Here, we have investigated whether phenothiazine derivatives alone or in combination with simvastatin influenced the level of expression of Bax and Bcl-2, the proteins engaged in regulation of apoptosis.…”

Section: Resultsmentioning

confidence: 78%

“…Each of the modulators was first applied alone, and then phenothiazine derivatives were applied in combination with simvastatin (Figure 2). All of the modulators were used at the concentration of 2.5 μM, at which their cytotoxicity to LoVo/Dx cells was previously shown to be less than 10% [22,24]. Simvastatin and MAE-TPR used alone significantly increased Dox cytotoxicity (Figure 2A).…”

Section: Resultsmentioning

confidence: 95%

“…The model that was used in the present work was doxorubicin-resistant subline LoVo/Dx (IC 50 Dox = 30.0 ± 3.7 μM) derived from human adenocarcinoma cell line LoVo (IC 50 Dox = 4.0 ± 0.9 μM). Simvastatin applied both at the concentration of 2.5 μM [22] and 10-[3-( N -2-hydroxyethyl- N -methylamino)-2-hydroxypropyl]-2-trifluoromethylphenothiazine (MAE-TPR) at 5 μM [23] was previously demonstrated to increase the cytotoxic effect of Dox on LoVo/Dx cells (for structures of the modulators used, see Figure 1). Here, the influence of simvastatin, fluphenazine (FLU), and its two derivatives MAE-TPR and 10-{3-[4-(4-acetylphenyl)piperazin-1-yl]-2-hydroxypropyl}-2-trifluoromethylphenothiazine dihydrochloride (APh-FLU) on the cytotoxicity of Dox on LoVo/Dx cells was tested.…”

Section: Resultsmentioning

confidence: 99%

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The Combined Use of Phenothiazines and Statins Strongly Affects Doxorubicin-Resistance, Apoptosis, and Cox-2 Activity in Colon Cancer Cells

Środa-Pomianek

Michalak

Palko-Łabuz

et al. 2019

IJMS

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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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Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

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The Combined Use of Phenothiazines and Statins Strongly Affects Doxorubicin-Resistance, Apoptosis, and Cox-2 Activity in Colon Cancer Cells

Środa-Pomianek

Michalak

Palko-Łabuz

et al. 2019

IJMS

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“…The cytotoxicity of doxorubicin was greatly enhanced in doxorubicin-resistant LoVo cancer cells, but there was little change in sensitive LoVo cells. Both statins promoted the accumulation of doxorubicin in LoVo cells, possibly through the induction of MDR1 gene expression which codes for P-glycoprotein[ 35 ]. Furthermore, simvastatin and atorvastatin, at a concentration of 12.5 µmol/L, which did not induce significant cytotoxicity, enhanced the effect of bortezomib in multiple myeloma U266 cells.…”

Section: Preclinical Studies Evaluating the Anticancer Effects Of Stamentioning

confidence: 99%

Statins in risk-reduction and treatment of cancer

Barbălată

Tefas

Achim

et al. 2020

WJCO

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Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer ( i.e ., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.

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“…The combination index (CI) values were determined by IC 50 and calculated by the median-effect equation as described by Chou and Talaly 39,40 and Palko-Łabuz et al The value of CI<1 represents drug synergy, CI>1 indicates drug antagonism, while an additive effect is observed when CI=1.…”

Section: Mtt Assay and Combination Index Calculationmentioning

confidence: 99%

<p>Synergistic Effect of Tangeretin and Atorvastatin for Colon Cancer Combination Therapy: Targeted Delivery of These Dual Drugs Using RGD Peptide Decorated Nanocarriers</p>

He¹,

Zheng

Li³

et al. 2020

DDDT

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Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the fourth leading cause of cancer death over the world. Nano-sized drug delivery systems are used for the treatment of cancers. The aim of this study was to develop a tangeretin (TAGE) and atorvastatin (ATST) combined nano-system decorated with RGD (RGD-ATST/TAGE CNPs) for colon cancer combination therapy. Materials and Methods: In this study, cyclized arginine-glycine-aspartic acid sequences (RGD) contained ligand was synthesized by conjugating cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) with D-α-tocopheryl succinate dichloromethane (TOSD) using polyethylene glycol (PEG) as a linker to obtain cRGDfK-PEG-TOSD. ATST and TAGE combined nanosystems: RGD-ATST/TAGE CNPs were prepared. The combination effects as well as antitumor effects of these two agents were evaluated on colon cancer cells and mice bearing cancer models. Results: Drug entrapment efficiencies of nano-systems were high (around 90%), suggesting the good loading capacity. The release profiles of ATST or TAGE from RGD-ATST/TAGE CNPs followed Higuchi model. The RGD-decorated nano-system showed more obvious cytotoxicity on HT-29 cells than the undecorated nano-system, but no obvious difference was found on normal CCD-18 cells. The strongest synergism was observed when the weight ratio of ATST to TAGE was 1:1. In vivo biodistribution of RGD-ATST/TAGE CNPs in the tumor site is high and prominently inhibited the in vivo tumor growth. Conclusion: The results demonstrated that RGD-ATST/TAGE CNPs showed the most significant synergistic therapeutic efficacy, exhibited no significant toxicity to major organs and tissues, and body weight of the treated mice was stable. Therefore, the combination nano-system is a promising platform for colon cancer therapy.

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MDR reversal and pro-apoptotic effects of statins and statins combined with flavonoids in colon cancer cells

Cited by 42 publications

References 69 publications

The Combined Use of Phenothiazines and Statins Strongly Affects Doxorubicin-Resistance, Apoptosis, and Cox-2 Activity in Colon Cancer Cells

The Combined Use of Phenothiazines and Statins Strongly Affects Doxorubicin-Resistance, Apoptosis, and Cox-2 Activity in Colon Cancer Cells

Statins in risk-reduction and treatment of cancer

<p>Synergistic Effect of Tangeretin and Atorvastatin for Colon Cancer Combination Therapy: Targeted Delivery of These Dual Drugs Using RGD Peptide Decorated Nanocarriers</p>

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