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)

Ketoconazole (KTZ) has been used as a second-line agent in hormone-refractory cancer therapy. Since transition metal complexes including those of Ru(III), show important anticancer activity with limited toxicity, we investigated the potential antitumor efficacy of Ru(II) complexed to KTZ or clotrimazole (CTZ) compared to Ru(II) alone or uncomplexed azoles. RuCl2(KTZ)2 exerted greater apoptosis- associated caspase-3 activation than RuCl2(CTZ)2, KTZ, CTZ or RuCl2(MeCN)4 against several human tumor cell monolayers. PARP cleavage and a decrease in S+G2 cells were evident after RuCl2(KTZ)2 treatment in genetically matched C8161 melanoma monolayers with unequal p53 functional status. Release of mitochondrial cytochrome c and Mn-SOD suggest mitochondria as a target of RuCl2(KTZ)2. Treatment of WM164 melanoma monolayers with 25 microM of cisplatin or RuCl2(KTZ)2 showed that the latter is more effective than cisplatin at inducing PARP fragmentation and proapoptotic Bak expression. Such results suggest that these Ru(II) and Pt(II) metal complexes are unequally effective and act through alternative signaling pathways. In studies with multicellular spheroids, which frequently are more resistant to cytotoxic anticancer drugs than monolayers, those from wt p53 C8161 melanoma underwent PARP fragmentation in response to RuCl2(KTZ)2. In contrast, spheroids of mut p53 A431 carcinoma overexpressing EGF receptor were resistant to either RuCl2(KTZ)2 or anti-EGF receptor C225 MAb. However, joint treatment with both agents restored growth arrest and apoptosis in these spheroids. In contrast to the antitumor action of cisplatin, which is known to be hampered by p53 dysfunction, we show that RuCl2(KTZ)2 is active irrespective of p53 functional status against several adherent tumor cells and synergizes with anti-EGF receptor C225 MAb to kill tumor spheroids resistant to either agent.
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PMID:Tumor apoptosis induced by ruthenium(II)-ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor. 1538 61

This study examined the effect of ketoconazole on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca(2+) levels in MG63 osteosarcoma cells. Ketoconazole at 20-200 microM decreased cell viability via apoptosis as demonstrated by propidium iodide staining and activation of caspase-3. Immunoblotting suggested that ketoconazole induced phosphorylation of ERK and JNK, but not p38, MAPKs. Ketoconazole-induced cell death and apoptosis were partially reversed by the selective JNK inhibitor SP600125, but not by the selective ERK inhibitor PD98059, suggesting that ketoconazole's cytotoxic action was via JNK, but not via ERK and p38 MAPKs. Ketoconazole at a concentration of 100 microM induced [Ca(2+)](i) increases. Chelation of intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) totally inhibited ketoconazole-induced [Ca(2+)](i) increases without reversing ketoconazole-induced cell death. Collectively, in MG63 cells, ketoconazole induced cell death and apoptosis via evoking JNK phosphorylation in a Ca(2+)-independent manner.
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PMID:Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. 1963 32

Ketoconazole (KCZ) is the most commonly used systemic antifungal drug. However, long-term treatment of KCZ induces hepatic injury. Oxidative stress is involved in KCZ-induced hepatic injury. Oxidative stress plays an important role in apoptosis-associated hepatic damage. Sesame oil is rich in potent antioxidants and antifungal constituents. It attenuates hepatic injury by inhibiting oxidative stress. Thus, sesame oil may protect against KCZ-induced oxidative stress, apoptosis and hepatic damage. The aim of the present study was to investigate the protective effect of sesame oil as a nutritional supplement on KCZ-induced hepatic injury in mice. KCZ (300 mg/kg/day) was administered by gastric intubation; 30 min later, sesame oil (0, 0.0625, 0.125, 0.25 or 0.5 ml/kg/day; p.o.) was administered to mice for 14 days. Blood and liver tissue were collected. Hepatic injury was evaluated by serum biochemistry and histology. Oxidative stress was evaluated by myeloperoxidase activity, p47-phox, reactive oxygen species generation, lipid peroxidation and glutathione level. Apoptosis was evaluated by p53, caspase-3, Bcl-2, Bax and Cyto-C expression. Osteopontin was measured to assess liver healing. Sesame oil attenuated hepatic injury; it also decreased oxidative stress and apoptosis in KCZ-treated mice. Sesame oil may be used as a nutritional supplement with existing antifungal therapies to neutralize the adverse hepatotoxic nature of antifungal drugs by attenuating hepatic apoptosis through redox system to protect and heal liver injury in KCZ-treated mice.
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PMID:Daily sesame oil supplementation mitigates ketoconazole-induced oxidative stress-mediated apoptosis and hepatic injury. 2761 44