Effect of zoledronic acid treatment on cell adhesion molecules in prostate cancer stem cells

Prostat kanserinin tanı ve tedavisine yönelik birçok alanda ilerleme sağlanabilmesine rağmen hastalık bazı vakalar için ölümcül olma niteliğini sürdürmektedir. Hastaların ölümden kurtulması için atılan her adım hedefe yaklaşılmasına yardım etse de halen sonuca ulaşmak için araştırılması gereken pek çok konu bulunmaktadır. Kök hücrenin keşfi ile bu hücrelerin insan sağlığı için önemi anlaşılmış ve tedavide nasıl kullanılacağının belirlenmesine yönelik çalışmalar büyük hız kazanmıştır. İlerleyen yıllarda Kanser Kök Hücresi kavramı ortaya çıkmış ve bu hücrelerin, kök hücre özelliklerini taşıyan ancak tümör dokusu içinde metastazı yapan, tedavi sonrası nükse yol açabilen veya tedaviye direnç̧ geliştiren hücreler oldukları belirlenmiştir. Köklülük özelliğine sahip bu hücreler dışında kalan hücre gurubu kanser kök hücresi olmayan hücre gurubudur ve konvansiyonel kanser tedavisine cevap veren kanser hücrelerdir. Kanserin metastaz yapması ve çevre dokuya invazyonunda adezyon moleküllerinin önemi büyüktür. Yapılan çalışmalar özellikle çoklu ilaç direnci ve epitelial mezenşimal geçişte adezyon moleküllerinin büyük önem kazandığını göstermiştir. Bu çalışmanın amacı prostat kanseri kök hücreleri üzerine zoledronik asit uygulaması sonrası, metastaz geliştirme sürecinde önemli rolü olan adezyon molekülleri üzerine etkisinin incelenmesidir. Bu amaçla DU145 insan prostat kanseri hücre hattından akım sitometri cihazı ile CD133/CD44 yüzey belirteçleri kullanılarak izole edilen kanser kök hücreleri üzerine zoledronik asit tedavisi uygulanmıştır. Kanser kök hücresinde oluşan değişiklikler adezyon molekülleri yönü ile araştırılmıştır. Elde edilen sonuçlar zoledronik asit tedavisi sonrası kanser kök hücresi sayısında önemli bir düşüş olduğunu ve bu uygulamanın CD44, ITGB1, CD29, LAMB1, LAMB3, LAMC1, SPP1, TGFB1, TGFB1, TIMP2, ADAMTS1, ITGB5’de önemli değişimlere yol açtığını göstermiştir. Bu çalışmada in-vitro ortamda zoledronik asit uygulamasının kanser kök hücresi adezyon molekülleri üzerine baskılayıcı etki oluşturduğu ve ilerleyen çalışmalarda bu ilacın klinik kullanımda prostat kanseri tedavisinde uygulanabilme olasılığının olduğunu göstermiştir.Although the diagnosis and treatment of prostate cancer has made a progress, the disease remains fatal for some cases. Every step taken to save patients from death helps to approach the goal but there are still many issues that need to be investigated to reach a result. With the discovery of stem cells, the importance of these cells for human health has been understood and studies on how to use them in treatment have gained great momentum. In the following years, the concept of Cancer Stem Cell has emerged. It has been shown that these cells have stem cell characteristics but metastasize within the tumor tissue. They can cause recurrence after treatment or develop resistance to treatment. The other group of cells with rootedness is the non-cancer stem cell group and are cancer cells that respond to conventional cancer treatment. Adhesion molecules are of great importance in the cancer metastasis and invasion into the surrounding tissue. Studies have shown that adhesion molecules has great importance spesifically in multi-drug resistance and epithelial-mesenchymal transition. The aim of this study is to examine the effect of zoledronic acid application on prostate cancer stem cells on adhesion molecules, which have an important role in the metastasis development process. For this purpose, zoledronic acid treatment was applied to cancer stem cells isolated from DU145 human prostate cancer cell line using a flow cytometry device and CD133/CD44 surface markers. Changes in cancer stem cells have been investigated in terms of adhesion molecules. The results showed that there was a significant decrease in the number of cancer stem cells after zoledronic acid treatment and this application led to significant changes in CD44, ITGB1, CD29, LAMB1, LAMB3, LAMC1, SPP1, TGFB1, TGFB1, TIMP2, ADAMTS1, ITGB5. In this study, it has been shown that zoledronic acid administration in-vitro has a suppressive effect on cancer stem cell adhesion molecules and that this drug may be used in the treatment of prostate cancer in clinical use in further studies

CD133+/CD44+prostate cancer stem cells exhibit embryo-like behavior patterns

Cancer stem cells (CSCs), which act as an important bridge between cancer formation and embryonic development, represent a small population associated with tumor initiation, drug resistance, metastasis and recurrence. CSCs have the ability to form spheroids in three-dimensional culture systems. Tumor spheroids derived from CSCs with symmetric and asymmetric division patterns were found to contain highly heterogeneous cell groups. The biological behavior patterns which some CSCs display serve as an important bridge between cancer formation and embryonic development. The cell population in the DU-145 prostate cancer cell line with surface markers CD133+/CD44+ was isolated by FACS. Prostate spheroids were formed by using agarose-coated plates. The morphological characteristics of the cell population within spheroid structure and the expression of Ki-67 and Caspase-3 were investigated by histochemical methods. In this study, we observed that CD133+/CD44+ prostate CSCs form different spheroid structures as well as normal spheroid structures: i) some spheroid structures formed with a highly transparent zone on the outer part of the spheroid, in addition to the normal spheroidal zones and ii) spheroidal structures obtained from prostate CD1334+/CD44+ CSCs that share the same microenvironment are hollow spheres similar to the blastula-like structure in the embryo. These spheroidal structures exhibiting embryo-like properties indicate that the expression of embryonic factors might be reiterated in CSCs. Further investigation of the formation mechanism of the transparent zone and the hollow sphere will shed light on the embryonic origin of prostate cancer and the design of new therapeutic strategies

Protective effects of Hawthorn (Crataegus oxyacantha) extract against digoxin-induced arrhythmias in rats

Objective: Digitalis preparations are commonly used by children and adults with heart diseases worldwide, although excessive doses may cause cardiac effects. The aim of the study is to evaluate the antiarrhythmic effect of Crataegus oxyacantha extract on digoxin-induced arrhythmias in anesthetized Wistar rats. Methods: Control and experimental groups were evaluated for arrhythmias induced by digoxin. Fifteen rats (7 as controls and 8 as the experimental group) were included in the study. The dry fruits of 100 mg Crataegus oxyacantha were extracted by percolation method. Digoxin, at a dose of 40 ?g/kg/min, was infused to form the arrhythmias in all rats. Simultaneously, the extract was infused into the experimental group, while 0.9% NaCl was infused into control group. Electrocardiographic QRS prolongation and arterial blood pressure changes were analyzed.Results: The experimental group lived longer (62.13 2.20 min) than the controls (p0.002). On the other hand, the time to beginning of QRS prolongation did not differ between the two groups (p0.812). Bradycardia was significant in the control group (288.01 10.54 beat/min and p0.01). The maximum QRS duration was observed in the control group during the digoxin and 0.9% NaCl infusion period (53.29 3.99 ms and p0.001). Also, the durations of atrial and ventricular arrhythmias were shorter in the experimental group. However, arterial blood pressure dipping was significant in the experimental group (23.67 10.89 mm Hg and p0.001).Conclusion: Crataegus oxyacantha alcoholic extract produced an antiarrhythmic effect that was induced by digoxin in Wistar rats. However, in the clinical use of this extract, the hypotensive effect should be considered. Also, the alcoholic extract of Crataegus oxyacantha may be an alternative treatment medication for arrhythmias induced by digoxin toxicity in humans

Pharmacogenetic Dependent Interindividual Pharmacokinetic Variations

Farmakogenetik (PGx), genetik varyasyonlar ve bunların bireyler arasında oluşturduğu ilaç yanıtı farklılıkları ile ilgilenir. İlaç metabolizmasından sorumlu enzimlerin keşfi ve bu enzimleri kodlayan DNA dizilimlerinin araştırılması bireysel tedavi stratejilerinin oluşturulmasını sağlar. İlaç metabolizmasından sorumlu sitokrom 2B6, sitokrom 2C9, sitokrom 2C19, sitokrom 2D6, sitokrom 3A4, N-asetil transferaz, dihidropirimidin dehidrogenaz, tiopurin metiltransferaz, 5’-difosfat (UDP)-glukuronoziltransferaz ve katekol-O-metil transferaz enzim polimorfizleri ilacın farmokokinetik özelliğini etkileyerek bireyler arası ilaç yanıtı farklılıklarına neden olabilirler. PGx çalışmaların temelini oluşturan ilk örnekler N- asetil transferaz ve sitokrom 2D6 polimorfizmleridir. İlaç seçiminde ciddi farmakokinetik farklılıklara neden olan enzim polimorfizmlerinin göz önünde bulundurulması tedavi başarısını artırmak ve advers/toksik reaksiyon riskini önlemek açısından önemlidir. Yaklaşık 50 yıl önce temelleri atılan farmakogenetik ile ilgili çalışmalar gen teknolojisinin gelişmesi ile günümüzde daha önemli bir hale gelmiştir. Teknolojik gelişmeler sayesinde hızlanan farmakogenetik çalışmalar ile bireye özgü ilaç seçimi farmakogenetiğin ikinci 50 yılı içerisinde daha fazla gelişme kaydederek önemli bir parametre olacaktır.Pharmacogenetics deals with genetic variations and individual response differences of drugs . The discovery of enzymes responsible for drug metabolism and the research to DNA sequences encoding these enzymes enable the creation of individual treatment strategies. Cytochrome 2B6, cytochrome 2C9, cytochrome C19, cytochrome 2D6, cytochrome 3A4, N-acetyltransferase, dihydropyrimidine dehydrogenase, thiopurine methyltransferase, UDP-glucuronyl transferase and catechol-O-methyltransferase enzymes are mainlyresponsible from drug metabolism and polymorphisms in enzyme activities affect the pharmacokinetic properties of the drug which leads to differences in drug response between individuals. First examples that form of the basis of pharmacogenetic studies are N-acetyltransferase and cytochrome 2D6 polymorphisms. Consideration of enzyme polymorphisms that may result with pharmacokinetic differences during drug choice is important to increase the success of treatment and to prevent adverse/toxic reaction risk. The studies about pharmacogenetics, which was studied about 50 years ago, has become more important nowadays with the development of gene technology. Individual drug choice will be an important parameter by further development of pharmacogenetics in the second 50 years through pharmacogenetic studies that is accelerated due to technological developments

Neuroprotective effect of intrastriatal caffeic acid phenethyl ester treatment in 6-oh dopamine model of parkinson's disease in rats

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the main cause of PD is still not known. Until now, no cure for Parkinson's disease is yet in sight. Caffeic acid phenethyl ester (CAPE) is a polyphenolic component of the propolis, which can be derived from honeybee hive propolis. We aimed to determine the effect of intrastriatal CAPE administration as a neuroprotective agent on 6-hydroxydopamine (6-OHDA)-induced PD model. Adult male Wistar rats weighing 280-320 g were used. The PD model was induced with unilateral intrastriatal 6-OHDA injection. Treatment groups received 20 mu mol/5 mu L/4 day and 80 mu mol/5 mu L/4 day CAPE 24 h after 6-OHDA injection. Eight days after 6-OHDA application, behavioral studies (adhesive tape removal test, open-field test, cylinder test, and apomorphine-induced asymmetric rotational behavior) were performed once more to compare the effects of CAPE on behavior tests. Striatal histological verifications, immunohistochemistry, and stereological quantitation were performed. Our results for the first time showed that, besides improving the motor performance, CAPE treatment also prevents 6-OHDA-induced loss of TH-positive neurons. From our results, CAPE may be a promising clinical agent in the treatment of PD.Scientific Research Projects Coordination Unit of the University of N