Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibrates and thiazolidinediones are agonists of peroxisome proliferator-activated receptors (PPAR) alpha and gamma, pharmacologically designed to control dyslipidemia and insulin resistance, respectively. Several works have reported the toxicity of some agonists in a number of tissues. In this work we have analyzed the toxicity of two PPARalpha (WY14643 and clofibrate) and two PPARgamma (pioglitazone and ciglitazone) agonists, using three different renal proximal tubular cell lines: Opossum OK, pig LLC-PK1, and murine MCT. Cell death was determined by the activity of intracellular lactate dehydrogenase. WY14643 and ciglitazone increased cell death with LC50 values of 92-124 microM and 8.6-14.8 microM, respectively, depending on the cell line. Clofibrate and pioglitazone were, however, non-cytotoxic even at concentrations of 10 and 100 higher than the corresponding EC50, which suggests that cell death is independent of PPAR activation. Discrimination between apoptosis or necrosis was analyzed by light microscopy and stress fiber morphology, double staining with acridine orange and ethidium bromide, binding of annexin V, caspase-3 activity, and DNA laddering. With these methods, no signs of apoptosis were observed, which suggests a direct necrosis of the compounds on these renal proximal tubular cell lines.
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PMID:Cytotoxicity of peroxisome proliferator-activated receptor alpha and gamma agonists in renal proximal tubular cell lines. 1752 63

Chemical libraries constitute a reservoir of pharmacophoric molecules to identify potent anti-cancer agents. Virtual screening of heterocyclic compound library in conjugation with the agonist-competition assay, toxicity-carcinogenicity analysis, and string-based structural searches enabled us to identify several drugs as potential anti-cancer agents targeting protein kinase C (PKC) as a target. Molecular modeling study indicates that Cinnarizine fits well within the PKC C2 domain and exhibits extensive interaction with the protein residues. Molecular dynamics simulation of PKC-Cinnarizine complex at different temperatures (300, 325, 350, 375, and 400[Formula: see text]K) confirms that Cinnarizine fits nicely into the C2 domain and forms a stable complex. The drug Cinnarizine was found to bind PKC with a dissociation constant Kd of [Formula: see text]M. The breast cancer cells stimulated with Cinnarizine causes translocation of PKC-[Formula: see text] to the plasma membrane as revealed by immunoblotting and immunofluorescence studies. Cinnarizine also dose dependently reduced the viability of MDAMB-231 and MCF-7 breast cancer cells with an IC[Formula: see text] of [Formula: see text] and [Formula: see text]g/mL, respectively. It is due to the disturbance of cell cycle of breast cancer cells with reduction of S-phase and accumulation of cells in G1-phase. It disturbs mitochondrial membrane potentials to release cytochrome C into the cytosol and activates caspase-3 to induce apoptosis in cancer cells. The cell death was due to induction of apoptosis involving mitochondrial pathway. Hence, the current study has assigned an additional role to Cinnarizine as an activator of PKC and potentials of the approach to identify new molecules for anti-cancer therapy. Thus, in silico screening along with biochemical experimentation is a robust approach to assign additional roles to the drugs present in the databank for anti-cancer therapy.
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PMID:Integrating virtual screening and biochemical experimental approach to identify potential anti-cancer agents from drug databank. 2956 37