Momordica cochinchinensis (Gac) Seed Extracts Induce Apoptosis and Necrosis in Melanoma Cells.

Momordica cochinchinensis is a herbal medicine used throughout Asia and this study investigated the antimelanoma potentials and molecular mechanisms of M. cochinchinensis seed with emphasis on extraction to optimise bioactivity. Overall, the aqueous extract was superior, with a wider diversity and higher concentration of proteins and peptides that was more cytotoxic to the melanoma cells than other extraction solvents. The IC50 of the aqueous extract on melanoma cells were similar to treatment with current anticancer drugs, vemurafenib and cisplatin. This cytotoxicity was cancer-specific with lower cytotoxic effects on HaCaT epidermal keratinocytes. Cytotoxicity correlated with MAPK signalling pathways leading to apoptosis and necrosis induced by triggering tumour necrosis factor receptor-1 (TNFR1), reducing the expression of nuclear factor kappa B (NF-kB), and suppression of BRAF/MEK. This efficacy of M. cochinchinensis seed extracts on melanoma cells provides a platform for future clinical trials as potent adjunctive therapy for metastatic melanoma.

Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation.

Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combination, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic for thoracic cancers.

Targeting the epigenome for the treatment of thoracic malignancies.

Despite considerable efforts to improve the diagnosis and treatment of lung cancer, this disease remains the leading cause of cancer-related mortality worldwide. Recent elucidation of epigenetic regulation of gene expression during malignant transformation, together with the identification of agents that modulate DNA methylation and histone acetylation, provide new opportunities for the treatment and prevention of lung cancer via chromatin remodeling mechanisms. Further analysis of molecular response in tumor tissues following exposure to chromatin remodeling agents may enable us to identify novel mechanisms pertaining to lung cancer epigenetics, and design more efficacious regimens.

Autotransfusion of shed mediastinal blood: a risk factor for mediastinitis after cardiac surgery? Results of a cluster investigation.

RATIONALE: After the introduction of autotransfusion of shed mediastinal blood following cardiac surgery, the incidence of mediastinitis increased. The role of autotransfusion in the increased occurrence of this serious complication was examined. METHODS: Using a case-control design, the preoperative, intraoperative, and postoperative characteristics of 11 patients with mediastinitis were compared to those of 33 randomly selected patients undergoing cardiac surgery between September 1, 2000, and April 15, 2001 (control subjects). RESULTS: Patients with mediastinitis were significantly more likely to have a body mass index > 30 (unadjusted odds ratio [OR], 9.9; 95% confidence interval [CI], 2.3 to 42.5), to have received antibiotic therapy during the 2 weeks prior to cardiac surgery (OR, 12.0; 95% CI, 1.1 to 131), or to have required re-exploration within 24 h of the original operation (OR, 8.3; 95% CI, 1.8 to 39). Patients with mediastinitis had 3.4 known risk factors for mediastinitis, compared to only 1.4 risk factors per control subject (p = 0.0001), and longer duration of autotransfusion. After adjustment for other risk factors, autotransfusion for > 6 h was significantly associated with the development of mediastinitis (adjusted OR, 11.9; 95% CI, 1.4 to 97.2). CONCLUSION: Retransfusion of shed mediastinal blood for > 6 h after cardiac surgery was an independent risk factor for mediastinitis.

Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques.

OBJECTIVE: Although paclitaxel is widely used as a systemic agent for the treatment of solid tumors, limited information is available concerning administration of this taxane by regional techniques. The present study was undertaken to evaluate the pharmacokinetics and acute toxicity of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques to ascertain its potential for the regional therapy of unresectable pulmonary neoplasms. METHODS: Adult sheep underwent 90 minutes of retrograde isolated lung perfusion with escalating doses of paclitaxel and moderate hyperthermia using a protein-free, oxygenated extracorporeal circuit and a steady perfusion pressure of 14 to 16 mm Hg. An additional animal received paclitaxel by means of 1-hour central venous infusion. Paclitaxel concentrations in lung tissues, perfusates, and systemic circulation were determined by high-performance liquid chromotography techniques. Cytotoxicity of paclitaxel in cancer cells and in normal human bronchial epithelial cells was evaluated in vitro using 4, 5-dimethylthiazo-2-yl-25-dipagnyl tetrazolium bromide assays. Lung tissues were examined by hematoxylin-and-eosin techniques. RESULTS: Paclitaxel concentrations (maximum concentration and area under the plasma concentration time curve) in perfused tissues increased with escalating perfusate doses. Uptake of drug into lung parenchyma appeared saturable at high paclitaxel exposure; a substantial pharmacokinetic advantage was observed. Paclitaxel concentrations in systemic circulation were undetectable or exceedingly low after perfusion. Histopathologic examination of lung tissues harvested 3 hours after completion of isolated lung perfusion revealed no immediate toxicity, even at a paclitaxel exposure 20-fold higher than that achievable after 1 hour of intravenous administration at the maximum tolerable dose in human subjects. Moderate hyperthermia enhanced paclitaxel-mediated cytotoxicity 5- to 100-fold in cultured cancer lines. No paclitaxel toxicity was observed in cultured normal human bronchial epithelial cells after exposure to paclitaxel under normothermic or hyperthermic conditions. CONCLUSIONS: These data support further evaluation of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques for the treatment of unresectable malignant pulmonary tumors.