Cr(VI)-containing compounds are well established environmental carcinogens. Although the mechanisms of Cr(VI) carcinogenesis remain to be investigated, various studies indicate that Cr(VI)-induced generation of reactive oxygen species (ROS) plays a key role. Many naturally occurring substances present in the human diet have been identified as potential chemopreventive agents. Investigations using animal models and epidemiological studies indicate that consumption of phytochemicals might reduce the incidence of cancers and other chronic diseases. These plant-derived phytochemicals are rich sources of naturally occurring antioxidants. Our preliminary studies have shown that oral administration of apple peel extract decreased the number of nonmalignant and malignant skin tumors induced by 12-O-tetradecanolyphorbol-13-acetate (TPA) in 7, 12-dimethyl Benz (a) anthracene-initiated mouse skin. Apple peel extract is able to directly scavenge hydroxyl radial (?OH) and superoxide radical (O2?-). Our preliminary studies have also shown that apple peel extract inhibited Cr(VI)-induced """"""""OH radical generation in cellular system. The mechanisms involve direct scavenging of ?OH radical and chelation of Cr(V) by apple peel extract to make this chromium intermediate less reactive toward hydrogen peroxide(H2O2) for ?OH radical generation. Our preliminary data have shown that apple peel extract inhibited Cr(VI)-induced expressions of inflammatory proteins including NF-?B and TNF-?. We hypothesize that apple peel extract may function as an antioxidant and as a chemopreventive agent against Cr(VI)-induced lung cancer via inhibition of Cr(VI)-induced oxidative stress.
Aim 1 will use in vivo electron spin resonance (ESR) to investigate inhibition of Cr(VI)-generated free radicals by apple peel extract in living animals (BALB/c mice). Two approaches will be used: (a) to investigate the chelation of Cr(V)-NADPH complex or change of its structure by apple peel extract;and (b) to investigate the inhibition of apple peel extract on Cr(VI)-induced free radical generation.
Aim 2 will investigate the protection of apple peel extract against Cr(VI)-induced lung inflammation, chronic oxidative lung tissue injury, and cell proliferation using BALB/c mice. There are increasing studies supporting the association among oxidative stress, chronic inflammation, and cancer development. Because oxidative stress plays an important role in inflammation, cell proliferation, and tissue injury, itis likely that inhibition of oxidative stress will protect Cr(VI)-induced chronic lung injury and an inflammatory microenvironment, leading to the protection in Cr(VI)-induced lung cancer. In this aim we will Investigate the protection of apple peel extract against Cr(VI)-induced inflammation, chronic oxidative lung injury, and cell proliferation using female BALB/c mice.
The Cr(VI)-containing compounds are well established environmental carcinogens. Oxidative stress is considered to play an important role in the mechanism of Cr(VI)-induced carcinogenesis. The goal of this proposal is to develop apple peel extract as an antioxidant and a protective agent against Cr(VI)-induced oxidative stress and lung cancer.
|Kim, Donghern; Dai, Jin; Park, Youn-Hee et al. (2016) Activation of Epidermal Growth Factor Receptor/p38/Hypoxia-inducible Factor-1? Is Pivotal for Angiogenesis and Tumorigenesis of Malignantly Transformed Cells Induced by Hexavalent Chromium. J Biol Chem 291:16271-81|
|Kim, Donghern; Dai, Jin; Fai, Leonard Yenwong et al. (2015) Constitutive activation of epidermal growth factor receptor promotes tumorigenesis of Cr(VI)-transformed cells through decreased reactive oxygen species and apoptosis resistance development. J Biol Chem 290:2213-24|