Possible Molecular Mechanisms and Pathways Involved in Bh3 Mimetic Activity of Alpha-Lipoic Acid on Human Colon Cancer Cell Line

Abstract

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. RezumatAcidul alfa-lipoic (ALA), un antioxidant natural, inhibă proliferarea și induce apoptoza la nivelul diferitelor linii celulare canceroase, fără efect asupra celulelor normale netransformate. Scopul acestui studiu a fost de a evalua efectele acidului alfalipoic (ALA), singur și combinat cu 5-fluorouracil (5-FU), asupra exprimării Bcl-2 / Bax în linia celulară Caco-2, de origine din colonul uman, ca să investigheze posibilele mecanisme moleculare și căile implicate în efectele mediate de ALA.În studiul de față ALA și 5-FU au arătat o tendință de scădere a Bcl-2 și creșterea expresiei Bax. ALA a exercitat un efect inhibitor mai mare asupra exprimării Bcl-2, în timp ce creșterea semnificativă a expresiei Bax a fost demonstrată după tratamentul combinat ALA și 5-FU. Modelele de legare a ALA și 5-FU de ambele ținte moleculare s-au dovedit a fi foarte apropiate, iar unele interacțiuni sunt identice cu cele cunoscute pentru mimeticele BH3. Astfel, ALA poate fi considerat ca potențial mimetic BH3. În plus, proprietățile fizico-chimice evaluate in silico au confirmat că ALA are un tropism deosebit pentru țintele intracelulare și membranare ale acțiunii sale.

Efficacy of Cetuximab/Panitumumab After Previous Bevacizumab in Metastatic Colorectal Cancer

“…More than 50% of all CRC patients will develop metastases during the course of the disease, either synchronous or metachronous [14]. Metastatic disease has a poor prognosis, with 5-year relative survival rates only reaching 13.1% [6]. The clinical outcomes have greatly improved in stage IV patients, with a median overall survival (OS) reaching 30 months, due to better management that uses a "treatment continuum".…”

Bioinformatics and Cheminformatics Study of Carbazole Derivatives – P3c7, P3c7-A20 P3c7-S243, and De Novo 2,5-Disubstituted 1,3,4-Oxadiazole Derivatives

“…To evaluate the pharmacological character of compounds, the Lipinski rules and the Veber rules (bioavailability) were applied [17,18]. The Lipinski's rule of five refers to the possibility of drug-like features of small molecules if the following criteria are respected: (i) no more than 5 hydrogen bond donors in the structure; (ii) no more than 10 hydrogen bond acceptors in the structure; (iii) molecular mass less than 500 Daltons; (iv) octanol-water partition coefficient (MlogP) does not exceed 5.…”

“…The Lipinski's rule of five refers to the possibility of drug-like features of small molecules if the following criteria are respected: (i) no more than 5 hydrogen bond donors in the structure; (ii) no more than 10 hydrogen bond acceptors in the structure; (iii) molecular mass less than 500 Daltons; (iv) octanol-water partition coefficient (MlogP) does not exceed 5. Veber rule imposed for a good bioavailability as (i) 10 or fewer rotatable bonds in structure, (ii) less than 12 hydrogen bond donors or acceptors in total in the structure; (iii) topological polar surface area (TPSA) less than 140 Å 2 [17]. To calculate the Lipinski and Veber rules, the SMILES file of the molecules (Table I) was loaded into the ExPASy Bioinformatics Resource Portal and the cheminformatics database Molinspiration [19,20].…”

Alpha‐Lipoic Acid, Auraptene, and Particularly Their Combination Prevent the Metastasis of U87 Human Glioblastoma Cells

“…Previous studies have collectively suggested ALA as a potent inhibitor of MMP-2 and MMP-9 activities, which reduces the invasion of various cancer cells [24][25][26]. ALA also successfully induces cancer cell death by increasing the expression of proapoptotic genes such as Bcl-2-associated X protein (Bax) and decreasing the expression of the primary antiapoptotic gene, B-cell lymphoma 2 (Bcl2) [27,28].…”