Romanian Society of Pharmaceutical Sciences
 

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POSSIBLE MOLECULAR MECHANISMS AND PATHWAYS INVOLVED IN BH3 MIMETIC ACTIVITY OF ALPHA-LIPOIC ACID ON HUMAN COLON CANCER CELL LINE

IVANA DAMNJANOVIC 1*, GORDANA KOCIC 2, STEVO NAJMAN 3, SANJA STOJANOVIC 3, KATARINA TOMOVIC 1, BUDIMIR ILIC 4, ANDREJ VELJKOVIC 2, SRDJAN PESIC 5, ANDRIJA SMELCEROVIC 1,4

1.Department of Pharmacy, Faculty of Medicine, University of Nis, Blvd. Dr Zorana Djindjica 81, 1800 Nis, Serbia
2.Department of Biochemistry, Faculty of Medicine, University of Nis, Blvd. Dr Zorana Djindjica 81, 18000 Nis, Serbia
3.Department for Cell and Tissue Engineering, Institute of Biology and Human Genetics, Faculty of Medicine, University of Nis, Blvd. Dr Zorana Djindjica 81, 18000 Nis, Serbia
4.Department of Chemistry, Faculty of Medicine, University of Nis, Blvd. Dr Zorana Djindjica 81, 18000 Nis, Serbia
5.Department of Pharmacology, Faculty of Medicine, University of Nis, Blvd. Dr Zorana Djindjica 81, 18000 Nis, Serbia

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Alpha-lipoic acid (ALA), a naturally-occurring antioxidant, inhibits proliferation and induces apoptosis in various cancer cell lines without effects on normal non-transformed cells. The aim of this study was to examine the effects of alpha-lipoic acid (ALA), alone and combined with 5-fluorouracil (5-FU), on Bcl-2/Bax expression in human colon cancer Caco-2 cell line as well as to investigate possible molecular mechanisms and pathways involved in ALA-mediated effects. In the present study ALA and 5-FU showed a tendency to decrease Bcl-2 and increase Bax expression. ALA exerted higher inhibitory effects on Bcl-2 expression, while the significant increase of Bax expression was shown after the treatment with the combination of ALA and 5-FU. The binding modes of ALA and 5-FU with both targets were shown to be closely similar, and some interactions the same like those of known BH3 mimetics. Thus, ALA may be considered as potential BH3 mimetic. Additionally, with in silico calculated physico-chemical properties taken into account, it was confirmed that ALA may easily be delivered to its intracellular and membrane targets.