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      Differences of statin activity in 2D and 3D pancreatic cancer cell cultures

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          Abstract

          Purpose

          To evaluate the anticancer activity of lovastatin (LOVA), mevastatin (MEVA), pitavastatin (PITA), and simvastatin (SIMVA) in 2D and 3D models of three human pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and PANC-1).

          Methods

          The effect of statins on cell viability was estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. The activity of statins in 3D pancreatic cancer cell cultures was examined by measuring the size change of spheroids. The type of cell death was identified by cell staining with Hoechst 33342 and propidium iodide. The activity of statins on the clonogenicity of cancer cells was tested by evaluating the effect on the colony-forming ability of cells.

          Results

          The rank order of the activity of tested statins on cell viability was as follows: PITA > SIMVA > LOVA > MEVA. Among the tested statins, PITA had the greatest effect on cell viability (half maximal effective concentration values after 72 h on BxPC-3, MIA PaCa-2, and PANC-1 cells were 1.4±0.4 μM, 1.0±0.2 μM, and 1.0±0.5 μM, respectively). PITA also showed the strongest effect on tumor spheroid growth. Statins suppressed the colony formation of cancer cells. PITA demonstrated the greatest reduction in colony size and number. Apoptosis and necrosis assay results showed that at lower concentrations statins mostly induced cell death through apoptosis, whereas higher concentrations of compounds activated also necrotic processes.

          Conclusion

          Statins, especially PITA, demonstrate an anticancer activity against pancreatic cancer cell lines BxPC-3, MIA PaCa-2, and PANC-1 in both 2D and 3D models.

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          Most cited references 20

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          Structural mechanism for statin inhibition of HMG-CoA reductase.

          HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.
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            Tumor microenvironment: the role of the tumor stroma in cancer.

            The tumor microenvironment, composed of non-cancer cells and their stroma, has become recognized as a major factor influencing the growth of cancer. The microenvironment has been implicated in the regulation of cell growth, determining metastatic potential and possibly determining location of metastatic disease, and impacting the outcome of therapy. While the stromal cells are not malignant per se, their role in supporting cancer growth is so vital to the survival of the tumor that they have become an attractive target for chemotherapeutic agents. In this review, we will discuss the various cellular and molecular components of the stromal environment, their effects on cancer cell dynamics, and the rationale and implications of targeting this environment for control of cancer. Additionally, we will emphasize the role of the bone marrow-derived cell in providing cells for the stroma.
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              Targeting protein prenylation for cancer therapy.

              Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming activity of many oncogenic proteins, including some RAS family members. This observation prompted the development of inhibitors of farnesyltransferase (FT) and geranylgeranyl-transferase 1 (GGT1) as potential anticancer drugs. In this Review, we discuss the mechanisms by which FT and GGT1 inhibitors (FTIs and GGTIs, respectively) affect signal transduction pathways, cell cycle progression, proliferation and cell survival. In contrast to their preclinical efficacy, only a small subset of patients responds to FTIs. Identifying tumours that depend on farnesylation for survival remains a challenge, and strategies to overcome this are discussed. One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                16 November 2017
                : 11
                : 3273-3280
                Affiliations
                [1 ]Department of Drug Chemistry, Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania
                [2 ]Department of Biothermodynamics and Drug Design, Vilnius University Institute of Biotechnology, Vilnius, Lithuania
                Author notes
                Correspondence: Vilma Petrikaitė, Department of Drug Chemistry, Faculty of Pharmacy, Lithuanian University of Health Sciences, Sukilėlių Street 13, LT-50162, Kaunas, Lithuania, Tel +370 686 293 83, Email vilmapetrikaite@ 123456gmail.com
                Article
                dddt-11-3273
                10.2147/DDDT.S149411
                5695256
                © 2017 Paškevičiūtė and Petrikaitė. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                apoptosis, spheroid, cell viability, hmg-coa reductase

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