[Abstract unavailable

The lung is a highly specialized organ that facilitates uptake of oxygen and release of carbon dioxide. Due to its unique structure providing enormous surface area to outside ambient air, it is vulnerable to numerous pathogens, pollutants, oxidants, gases, and toxicants that are inhaled continuously from air, which makes the lung susceptible to varying degrees of oxidative injury. To combat these unrelenting physical, chemical, and biological insults, the respiratory epithelium is covered with a thin layer of lining fluid containing several antioxidants and surfactants. Inhaled toxic agents stimulate the generation of reactive oxygen/nitrogen species (ROS/RNS), which in turn provoke inflammatory responses resulting in the release of proinflammatory cytokines and chemokines. These subsequently stimulate the influx of polymorphonuclear leukocytes (PMNs) and monocytes into the lung so as to combat the invading pathogens or toxic agents. In addition to the beneficial effects, persistent inhalation of the invading pathogens or toxic agents may result in overwhelming production of ROS/RNS, producing chronic inflammation and lung injury. During inflammation, enhanced ROS/RNS production may induce recurring DNA damage, inhibition of apoptosis, and activation of proto-oncogenes by initiating signal transduction pathways. Therefore, it is conceivable that chronic inflammation-induced production of ROS/RNS in the lung may predispose individuals to lung cancer. This review describes the complex relationship between lung inflammation and carcinogenesis, and highlights the role of ROS/RNS in cancer development.

Breast cancer is the most frequently diagnosed cancer in women, and one of the leading causes of cancer-related deaths worldwide. Recent evidences indicate that dietary agents such as resveratrol may inhibit cancer progression through modulation of microRNAs (miRNAs). We demonstrate that resveratrol regulates apoptotic and cell cycle machinery in breast cancer cells by modulating key tumor-suppressive miRNAs including miR-125b-5p, miR-200c-3p, miR-409-3p, miR-122-5p and miR-542-3p. Resveratrol-mediated miRNA modulation regulates key anti-apoptotic and cell cycle proteins including Bcl-2, X-linked inhibitor of apoptosis protein and CDKs, which are critical for its activity. Modulating miRNAs with mimics or inhibitors further validated a key role for miR-542-3p in MCF-7 and miR-122-5p in MDA-MB-231 breast cancer cell death in response to resveratrol. In conclusion, this study reveals novel miRNAs modulated by resveratrol that have a key role in breast cancer cell death.

The antioxidant ␣-lipoic acid (LA) is a naturally occurring compound that has been shown to possess promising anticancer activity because of its ability to preferentially induce apoptosis and inhibit proliferation of cancer cells relative to normal cells. However, the molecular mechanisms underlying the apoptotic effect of LA are not well understood. We report here that LA induced reactive oxygen species (ROS) generation and a concomitant increase in apoptosis of human lung epithelial cancer H460 cells. Inhibition of ROS generation by ROS scavengers or by overexpression of antioxidant enzymes glutathione peroxidase and superoxide dismutase effectively inhibited LA-induced apoptosis, indicating the role of ROS, especially hydroperoxide and superoxide anion, in the apoptotic process. Apoptosis induced by LA was found to be mediated through the mitochondrial death pathway, which requires caspase-9 activation. Inhibition of caspase activity by the pan-caspase inhibitor (z-VAD-FMK) or caspase-9-specific inhibitor (z-LEHD-FMK) completely inhibited the apoptotic effect of LA. Likewise, the mitochondrial respiratory chain inhibitor rotenone potently inhibited the apoptotic and ROS-inducing effects of LA, supporting the role of mitochondrial ROS in LA-induced cell death. LA induced down-regulation of mitochondrial Bcl-2 protein through peroxide-dependent proteasomal degradation, and overexpression of the Bcl-2 protein prevented the apoptotic effect of LA. Together, our findings indicate a novel pro-oxidant role of LA in apoptosis induction and its regulation by Bcl-2, which may be exploited for the treatment of cancer and related apoptosis disorders.