Background: Newer targeted agents are increasingly used in combination chemotherapy regimens with enhanced survival and improved toxicity profile. Taxols, such as paclitaxel, independently potentiate tumor destruction via apoptosis and are used as first line therapy in patients with advanced nonesmall cell lung cancer (NSCLC). Procaspase-3-activating compound-1 (PAC-1) is a novel proapoptotic agent that directly activates procaspase-3 (PC-3) to caspase-3, leading to apoptosis in human lung adenocarcinoma cells. Hence, we sought to evaluate the antitumor effects of paclitaxel in combination with PAC-1.Methods: Human NSCLC cell lines (A-549 and H-322m) were incubated in the presence of PAC-1 and paclitaxel. Tumor cell viability was determined by a tetrazolium-based colorimetric assay (MTT assay). Western blot and flow cytometric analysis were performed to evaluate expression of PC-3 and the proportion of apoptotic cells, respectively. A xenograft murine model of NSCLC was used to study the in vivo antitumor effects of PAC-1.Results: PAC-1 significantly reduced the inhibitory concentration 50% of paclitaxel from 35.3 to 0.33 nM in A-549 and 8.2 to 1.16 nM in H-322m cell lines. Similarly, the apoptotic activity significantly increased to 85.38% and 70.36% in A-549 and H322m, respectively. Significantly enhanced conversion of PC-3 to caspase-3 was observed with PAC-1 paclitaxel combination (P < 0.05). Mice treated with a drug combination demonstrated 60% reduced tumor growth rate compared with those of controls (P < 0.05).Conclusions: PAC-1 significantly enhances the antitumor activity of paclitaxel against NSCLC. The activation of PC-3 and thus the apoptotic pathway is a potential strategy in the treatment of human lung cancer. (C) 2015 Elsevier Inc. All rights reserved.

Background. The hallmark of lung ischemia-reperfusion injury (IRI) is the production of reactive oxygen species (ROS), and the resultant oxidant stress has been implicated in apoptotic cell death as well as subsequent development of inflammation. Dietary flaxseed (FS) is a rich source of naturally occurring antioxidants and has been shown to reduce lung IRI in mice. However, the mechanisms underlying the protective effects of FS in IRI remain to be determined.Methods. We used a mouse model of IRI with 60 min of ischemia followed by 180 min of reperfusion and evaluated the anti-apoptotic and anti-inflammatory effects of 10% FS dietary supplementation.Results. Mice fed 10% FS undergoing lung IRI had significantly lower levels of caspases and decreased apoptotic activity compared with mice fed 0% FS. Lung homogenates and bronchoalveolar lavage fluid analysis demonstrated significantly reduced inflammatory infiltrate in mice fed with 10% FS diet. Additionally, 10% FS treated mice showed significantly increased expression of antioxidant enzymes and decreased markers of lung injury.Conclusions. We conclude that dietary FS is protective against lung IRI in a clinically relevant murine model, and this protective effect may in part be mediated by the inhibition of apoptosis and inflammation. (C) 2011 Elsevier Inc. All rights reserved.

Razi, Syed Shahzad MD; Schwartz, Gary MD; Li, Xiaogui PhD; Boone, Deva MD; Belsley, Scott MD, FACS; Todd, George MD, FACS; Connery, Cliff P. MD, FACS; Bhora, Faiz Y. MD, FACS Author Information

PURPOSE: Reperfusion injury is an important pathologic feature of several clinically significant lung conditions such as sepsis, shock, pulmonary embolism and lung transplantation. We have recently reported anti-apoptotic properties of dietary flaxseed against lung ischemia/reperfusion (I/R) injury. Our aim was to further investigate if this inhibitory effect is the result of attenuation of caspase enzymes known to be involved in apoptosis.