ABSTRACT
Vorinostat [suberoylanilide hydroxamic acid (SAHA)], a histone deacetylase inhibitor, shows limited clinical activity against solid tumors when used alone. The methyl xanthine drug, pentoxifylline (PENT), has been described to have antitumor properties. The aim of this study was to look for the enhanced anticancer activities of both agents when used in combination at doses lower than their respective efficacy dose when used alone. We investigated the antitumor potential of this novel combination in vitro and in vivo. The combination index was assessed for these two drugs to look for synergistic antiproliferative activity against a broad spectrum of human cancer cell lines. Consistent additive to synergistic interactions were observed in HCT116 cells when PENT was combined with SAHA at all drug tested concentrations. The combination of SAHA and PENT induces chromatin condensation and apoptosis downstream of the pan histone deacetylase inhibition and phosphodiesterase regulation, leading to subsequent cell cycle arrest at their lower tested concentrations. Further, the ability of this combination to inhibit angiogenesis, both in vitro and in vivo, was examined and a significant inhibition in tube formation in HUVEC cells and neovascularization of Matrigel plug was observed. A significant inhibition in tumor growth was observed in severe combined immunodeficient mice bearing HCT116 (colon) and PC3 (prostate) human xenografts treated with SAHA (30 mg/kg, intraperitoneal) in combination with PENT (60 mg/kg, intraperitoneal), with no loss in body weight and 100% survival. In conclusion, these findings indicate the enhanced anticancer activity of SAHA in combination with PENT both in vitro and in vivo.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Neoplasms/drug therapy , Pentoxifylline/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Growth Processes/drug effects , Cell Line, Tumor , Drug Synergism , HCT116 Cells , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/pharmacokinetics , Human Umbilical Vein Endothelial Cells , Humans , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/pharmacokinetics , MCF-7 Cells , Male , Mice , Mice, SCID , Neoplasms/blood supply , Neoplasms/metabolism , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Pentoxifylline/administration & dosage , Pentoxifylline/pharmacokinetics , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/pharmacokinetics , Random Allocation , Vorinostat , Xenograft Model Antitumor AssaysABSTRACT
N-methyl-D-aspartate (NMDA) antagonists and γ-aminobutyric acid (GABA) agonists are proven protective in various animal models of ischemic brain damage. Tramadol, a centrally acting opioid analgesic reportedly possesses NMDA antagonistic and GABA agonistic properties, with additional ion channel blocking activity. The aim of the present study was to evaluate the possible neuroprotective effect of tramadol hydrochloride in a rat model of transient forebrain ischemia. Male Wistar rats were pretreated with tramadol hydrochloride at doses of 10 and 20 mg/kg b.w. intraperitoneally for 4 days and were subjected to 30 min occlusion of bilateral common carotid arteries followed by reperfusion for 24 h. Impairment in sensorimotor functions was evaluated by beam walking task, spontaneous locomotor activity and hanging wire test. Animals were sacrificed and the brain homogenates were used for estimating the levels of lipid peroxidation, a marker for extent of oxidative stress. Ischemic rats exhibited a significant decrease in locomotion, grip strength and increase in beam walking latency. Tramadol attenuated the post ischemic motor impairment evidenced by improvement in the performance in sensorimotor tests. The extent of lipid peroxidation was significantly (p < 0.001) reduced by tramadol pretreatment which was higher in ischemic control. This study demonstrates the neuroprotective effect of tramadol against transient forebrain ischemia in rats.
Subject(s)
Behavior, Animal/drug effects , Ischemic Attack, Transient/drug therapy , Lipid Peroxidation/drug effects , Neuroprotective Agents/therapeutic use , Prosencephalon/drug effects , Tramadol/therapeutic use , Animals , Dose-Response Relationship, Drug , Ischemic Attack, Transient/complications , Ischemic Attack, Transient/metabolism , Ischemic Attack, Transient/physiopathology , Male , Malondialdehyde/metabolism , Motor Activity/drug effects , Neuroprotective Agents/administration & dosage , Prosencephalon/blood supply , Prosencephalon/metabolism , Rats , Rats, Wistar , Reperfusion Injury/etiology , Reperfusion Injury/metabolism , Reperfusion Injury/physiopathology , Reperfusion Injury/prevention & control , Tramadol/administration & dosageABSTRACT
OBJECTIVE: The aim of the present study was to evaluate the sedative and antiepileptic activities of ethanolic extract of Anthocephalus cadamba (ACE) bark in various experimental animal models. MATERIALS AND METHODS: ACE was tested at three doses viz. 100, 200 and 400 mg/kg p.o. We used ketamine-induced sleeping time model to test the sedative property of the extract where, onset and duration of sleep were observed. A paradigm of anticonvulsant models (pentylenetetrazole, isoniazid and maximal electroshock-induced seizures) were used to evaluate its protective effect against absence and generalized types of seizures. Onset of clonic convulsions, tonic extension and time of death were observed in PTZ and INH-induced seizure models. In MES model, duration of tonic hind leg extension and onset of stupor were observed. RESULTS: ACE showed significant increase in ketamine induced sleeping time. It also exhibited significant increase (P<0.05, 0.01 and 0.001) in latency to clonic convulsion, tonic extension and time of death in PTZ and INH models at all tested doses, whereas in the MES model, the lower dose was found to be effective when compared with the higher doses (200 and 400 mg/kg, p.o.). CONCLUSION: The results of the present investigation demonstrated that ACE possesses sedative and antiepileptic activities.
