کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5509110 | 1538397 | 2017 | 36 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells
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کلمات کلیدی
XTTTBSTADRleflunomideEC50BCABHKORODHODHNHDFPVDF2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilideLFMEthylenediaminetetraaceticacidNCIDHOPBSDihydroorotateDMSO - DMSOH2DCFDA - H2DCFD بهROS - ROSTris-buffered saline and Tween 20 - Tris-buffered saline و Tween 20Adenosine Triphosphate - آدنوزین تری فسفاتATP - آدنوزین تری فسفات یا ATPRheumatoid arthritis - آرتریتروماتوئیدEDTA - اتیلن دی آمین تترا استیک اسید sodium dodecyl sulphate-polyacrylamide gel electrophoresis - الکتروفورز ژل دوده سولفات سدیم پلی آکریل آمیدSDS-PAGE - الکتروفورز ژل پلی آکریل آمیدOrotate - اورتوتbaby hamster kidney - بچه هامستر کلیهbicinchoninic acid - بیسینکنینیک اسیدAbsorbance - جذبdihydroorotate dehydrogenase - دی هیدرووراتا د هیدروژنازDimethyl sulfoxide - دیمتیل سولفواکسیدDoubling time - زمان دو برابر شدنBreast cancer - سرطان پستانAdverse drug reaction - عارضه ناخواسته داروییphosphate buffer saline - فسفات بافر شورNormal human dermal fibroblast - فیبروبلاست طبیعی پوستی انسانNational Cancer Institute - موسسه ملی سرطانhalf maximal effective concentration - نیمه حداکثر غلظت موثرpolyvinylidenedifluoride - پی ویوییدیلدین فلوئوریدReactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Dihydroorotate dehydrogenase (DHODH) is the key enzyme in de novo biosynthesis of pyrimidine in both prokaryotes and eukaryotes. The de novo pathway of pyrimidine biosynthesis is essential in cancer cells proliferation. Leflunomide is an approved DHODH inhibitor that has been widely used for the treatment of arthritis. Similarly, brequinar sodium is another DHODH inhibitor that showed anti-tumour effect in MC38 colon carcinoma cells when used in combination with fluorouracil. Despite the potential role of DHODH inhibitors in cancer therapy, their mechanisms of action remain obscure and await further elucidation. Here, we evaluated the effect of DHODH inhibitors on the production of ATP and ROS in sensitive and non-sensitive breast cancer cells. Subsequently, the effects of DHODH inhibitors on cell cycle as well as on signalling molecules such as p53, p65 and STAT6 were evaluated in sensitive T-47D and non-sensitive MDAMB-436Â cells. The correlations between DHODH protein expression, proliferation speed and sensitivity to DHODH inhibitors were also investigated in a panel of cancer cell lines. DHODH inhibitors-sensitive T-47D and MDAMB-231Â cells appeared to preserve ROS production closely to endogenous ROS level whereas the opposite was observed in non-sensitive MDAMB-436 and W3.006Â cells. In addition, we observed approximately 90% of intracellular ATP depletion in highly sensitive T-47D and MDAMB-231Â cells compared to non-sensitive MDAMB-436Â cells. There was significant over-expression of p53, p65 and STAT6 signalling molecules in sensitive cells which may be involved in mediating the S-phase arrest in cell cycle progression. The current study suggests that DHODH inhibitors are most effective in cells that express high levels of DHODH enzyme. The inhibition of cell proliferation by these inhibitors appears to be accompanied by ROS production as well as ATP depletion. The increase in expression of signalling molecules observed may be due to pyrimidine depletion which subsequently leads to cell cycle arrest at S-phase.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimie - Volume 135, April 2017, Pages 154-163
Journal: Biochimie - Volume 135, April 2017, Pages 154-163
نویسندگان
A.K. Mohamad Fairus, B. Choudhary, S. Hosahalli, N. Kavitha, O. Shatrah,