The Role of Manganese Superoxide Dismutase in Skin Cancer

Recent studies have shown that antioxidant enzyme expression and activity are drastically reduced in most human skin diseases, leading to propagation of oxidative stress and continuous disease progression. However, antioxidants, an endogenous defense system against reactive oxygen species (ROS), can be induced by exogenous sources, resulting in protective effects against associated oxidative injury. Many studies have shown that the induction of antioxidants is an effective strategy to combat various disease states. In one approach, a SOD mimetic was applied topically to mouse skin in the two-stage skin carcinogenesis model. This method effectively reduced oxidative injury and proliferation without interfering with apoptosis. In another approach, Protandim, a combination of 5 well-studied medicinal plants, was given via dietary administration and significantly decreased tumor incidence and multiplicity by 33% and 57%, respectively. These studies suggest that alterations in antioxidant response may be a novel approach to chemoprevention. This paper focuses on how regulation of antioxidant expression and activity can be modulated in skin disease and the potential clinical implications of antioxidant-based therapies

New Aspects of Mitochondrial Uncoupling Proteins (UCPs) and Their Roles in Tumorigenesis

Uncoupling proteins (UCPs) belong to a family of mitochondrial carrier proteins that are present in the mitochondrial inner membrane. UCP1 was first identified followed by its two homologs, UCP2 and UCP3. The physiological functions of UCP include lowering mitochondrial membrane potential and dissipating metabolic energy as heat. However, UCP can be dysregulated and may contribute to the pathogenesis of metabolic disorders and obesity. Recent studies suggest that UCP also plays a role in neurodegenerative diseases and atherosclerosis. In addition, the widely expressed UCP, UCP2, has been shown to be upregulated in a number of aggressive human cancers. One mechanism of UCP2 upregulation in these cancers is due to oxidative stress, and elevated UCP2 in turn reduces oxidative stress, which provides a growth advantage for these cancers. Nevertheless, new studies suggest UCP2 may interact with oncogenes and tumor suppressor genes, providing a potential new mechanism of how UCP2 contributes to cancer development. In this review, the evidence supporting the role of UCPs in diseases other than diabetes and obesity, the reports on how UCP is regulated in cancer cells, and how UCP may regulate p53 will be discussed

The Chemopreventive Effects of Protandim: Modulation of p53 Mitochondrial Translocation and Apoptosis during Skin Carcinogenesis

Protandim, a well defined dietary combination of 5 well-established medicinal plants, is known to induce endogenous antioxidant enzymes, such as manganese superoxide dismutase (MnSOD). Our previous studies have shown through the induction of various antioxidant enzymes, products of oxidative damage can be decreased. In addition, we have shown that tumor multiplicity and incidence can be decreased through the dietary administration of Protandim in the two-stage skin carcinogenesis mouse model. It has been demonstrated that cell proliferation is accommodated by cell death during DMBA/TPA treatment in the two-stage skin carcinogenesis model. Therefore, we investigated the effects of the Protandim diet on apoptosis; and proposed a novel mechanism of chemoprevention utilized by the Protandim dietary combination. Interestingly, Protandim suppressed DMBA/TPA induced cutaneous apoptosis. Recently, more attention has been focused on transcription-independent mechanisms of the tumor suppressor, p53, that mediate apoptosis. It is known that cytoplasmic p53 rapidly translocates to the mitochondria in response to pro-apoptotic stress. Our results showed that Protandim suppressed the mitochondrial translocation of p53 and mitochondrial outer membrane proteins such as Bax. We examined the levels of p53 and MnSOD expression/activity in murine skin JB6 promotion sensitive (P+) and promotion-resistant (P-) epidermal cells. Interestingly, p53 was induced only in P+ cells, not P- cells; whereas MnSOD is highly expressed in P- cells when compared to P+ cells. In addition, wild-type p53 was transfected into JB6 P- cells. We found that the introduction of wild-type p53 promoted transformation in JB6 P- cells. Our results suggest that suppression of p53 and induction of MnSOD may play an important role in the tumor suppressive activity of Protandim

Effects of ATRA combined with citrus and ginger-derived compounds in human SCC xenografts

<p>Abstract</p> <p>Background</p> <p>NF-κB is a survival signaling transcription factor complex involved in the malignant phenotype of many cancers, including squamous cell carcinomas (SCC). The citrus coumarin, auraptene (AUR), and the ethno-medicinal ginger (Alpinia galanga) phenylpropanoid, 1'-acetoxychavicol acetate (ACA), were previously shown to suppress 12-<it>O</it>-tetradecanoylphorbol-13-acetate (TPA) induced mouse skin tumor promotion. The goal of the present study was to determine whether AUR and ACA are effective either alone or in combination with all-<it>trans </it>retinoic acid (ATRA) for suppressing SCC tumor growth.</p> <p>Methods</p> <p>We first determined the effects of orally administered ACA (100 mg/kg bw) and AUR (200 mg/kg bw) on lipopolysaccharide (LPS)-induced NF-κB activation in NF-κB-RE-luc (Oslo) luciferase reporter mice. Dietary administration of AUR and ACA ± ATRA was next evaluated in a xenograft mouse model. Female SCID/bg mice were fed diets containing the experimental compounds, injected with 1 × 10⁶SRB12-p9 cells s.c., palpated and weighed twice a week for 28 days following injection.</p> <p>Results</p> <p>Both ACA and AUR suppressed LPS-induced NF-κB activation in the report mice. In the xenograft model, AUR (1000 ppm) and ACA (500 ppm) modestly suppressed tumor volume. However, in combination with ATRA at 5, 10, and 30 ppm, ACA 500 ppm significantly inhibited tumor volume by 56%, 62%, and 98%, respectively. The effect of ATRA alone was 37%, 33%, and 93% inhibition, respectively. AUR 1000 ppm and ATRA 10 ppm were not very effective when administered alone, but when combined, strongly suppressed tumor volume by 84%.</p> <p>Conclusions</p> <p>Citrus AUR may synergize the tumor suppressive effects of ATRA, while ACA may prolong the inhibitory effects of ATRA. Further studies will be necessary to determine whether these combinations may be useful in the control of human SCC.</p

Protandim, a Fundamentally New Antioxidant Approach in Chemoprevention Using Mouse Two-Stage Skin Carcinogenesis as a Model

Oxidative stress is an important contributor to cancer development. Consistent with that, antioxidant enzymes have been demonstrated to suppress tumorigenesis when being elevated both in vitro and in vivo, making induction of these enzymes a more potent approach for cancer prevention. Protandim, a well-defined combination of widely studied medicinal plants, has been shown to induce superoxide dismutase (SOD) and catalase activities and reduce superoxide generation and lipid peroxidation in healthy human subjects. To investigate whether Protandim can suppress tumor formation by a dietary approach, a two-stage mouse skin carcinogenesis study was performed. At the end of the study, the mice on a Protandim-containing basal diet had similar body weight compared with those on the basal diet, which indicated no overt toxicity by Protandim. After three weeks on the diets, there was a significant increase in the expression levels of SOD and catalase, in addition to the increases in SOD activities. Importantly, at the end of the carcinogenesis study, both skin tumor incidence and multiplicity were reduced in the mice on the Protandim diet by 33% and 57% respectively, compared with those on basal diet. Biochemical and histological studies revealed that the Protandim diet suppressed tumor promoter-induced oxidative stress (evidenced by reduction of protein carbonyl levels), cell proliferation (evidenced by reduction of skin hyperplasia and suppression of PKC/JNK/Jun pathway), and inflammation (evidenced by reduction of ICAM-1/VCAM-1 expression, NF-κB binding activity, and nuclear p65/p50 levels). Overall, induction of antioxidant enzymes by Protandim may serve as a practical and potent approach for cancer prevention

Oxidative Stress Induced by MnSOD-p53 Interaction: Pro- or Anti-Tumorigenic?

The formation of reactive oxygen species (ROS) is a result of incomplete reduction of molecular oxygen during cellular metabolism. Although ROS has been shown to act as signaling molecules, it is known that these reactive molecules can act as prooxidants causing damage to DNA, proteins, and lipids, which over time can lead to disease propagation and ultimately cell death. Thus, restoring the protective antioxidant capacity of the cell has become an important target in therapeutic intervention. In addition, a clearer understanding of the disease stage and molecular events that contribute to ROS generation during tumor promotion can lead to novel approaches to enhance target specificity in cancer progression. This paper will focus on not only the traditional routes of ROS generation, but also on new mechanisms via the tumor suppressor p53 and the interaction between p53 and MnSOD, the primary antioxidant enzyme in mitochondria. In addition, the potential consequences of the p53-MnSOD interaction have also been discussed. Lastly, we have highlighted clinical implications of targeting the p53-MnSOD interaction and discussed recent therapeutic mechanisms utilized to modulate both p53 and MnSOD as a method of tumor suppression

Abstract 965: Mechanistic studies of a dietary combination in cancer prevention: The effects of manganese superoxide dismutase on tumor suppressor gene activation

Abstract Mechanistic Studies of a Dietary Combination in Cancer Prevention: The Effects of MnSOD on Tumor Suppressor Gene Activation Reactive oxygen species can act as signaling transduction molecules modulating various pathways, such as the PI3K/Akt pathway. It is known that this pathway is constitutively activated in tumorigenesis contributing to protein synthesis, cell cycle progression, migration and survival. However, the PI3K/Akt pathway is negatively regulated by the major tumor suppressor protein PTEN. PTEN has dual specificity phosphatase activity regulating Akt phosphorylation as a lipid phosphatase; as well as, regulating cyclin D1 expression as a protein phosphotase. However, these are the roles of cytoplasmic PTEN. Recently, the nuclear roles of PTEN have received significant attention. Nuclear PTEN plays a major role in maintaining cellular homeostasis and stability by contributing to chromosome stability, DNA repair and cell cycle arrest. Previous studies have shown that PTEN nuclear localization is mediated by oxidative stress and may play a role in p53 stabilization. Nevertheless, MnSOD is considered to be a novel tumor suppressor gene. MnSOD has been defined as a nuclear encoded primary antioxidant enzyme localized in the mitochondria. We have shown in previous studies that the dietary combination Protandim reduced tumor incidence and multiplicity via the synergistic induction of superoxide dismutase enzymes. It has been shown that overexpression of MnSOD in in vivo models can suppress tumor formation via modulation of AP-1 binding. Therefore, it is imperative to look at how MnSOD may affect the process of apoptosis and the activation of tumor suppressor genes involved (i.e. PTEN and p53). Using our in vivo models (wildtype, MnSOD knockout, non-transgenic and MnSOD transgenic mice), we investigated how modulation of MnSOD expression may affect PTEN-mediated p53 stabilization, and how this contributes to chemoprevention. In addition, we explored how mutations in p53 may affect the PTEN-p53 interaction and its effects on tumor promotion via a gene transfection approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 965.</jats:p