Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways

Abstract

Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-κB (NF-κB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2–5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-κB, inhibitory κBα (IκBα) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IκBα, hindered the translocation of NF-κB from cytosol to nucleus and increased the expression and nuclear translocation of Nrf2 during DMBA-induced mammary tumorigenesis. These findings, together with our previous results, indicate that PE-mediated prevention of DMBA-evoked mammary carcinogenesis may involve anti-inflammatory mechanisms through concurrent but differential regulation of two interrelated molecular pathways, namely NF-κB and Nrf2 signaling.

17‐allylamino‐17‐demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species‐induced cell death

“…NRF2, a transcription factor which is associated with Keap1, is regarded as a key role in guarding cells against oxidative stress . It binds the antioxidant DNA response element (ARE) to activate critical cytoprotective defense, and NRF2 deletion increased treatment sensitivity .…”

Beneficial Effects of Pomegranate on Lipid Metabolism in Metabolic Disorders

“…Furthermore, multiple lines of evidence have shown the anti‐inflammatory properties of pomegranate extracts. Mandal et al . reported that 0.2–5.0 g kg −1 pomegranate extracts show anti‐inflammatory effects by inhibiting the translocation of NF‐κB from the cytosol to the nucleus in a dose‐dependent manner in vivo.…”

“…[104] Furthermore, multiple lines of evidence have shown the anti-inflammatory properties of pomegranate extracts. Mandal et al [105] reported that 0.2-5.0 g kg −1 pomegranate extracts show anti-inflammatory effects by inhibiting the translocation of NF-κB from the cytosol to the nucleus in a dose-dependent manner in vivo. Harzallah et al [67] showed that pomegranate flower (250 mg kg −1 day −1 ), peel (250 mg kg −1 day −1 ) and seed oil (2 mL kg −1 day −1 ) are capable of reducing the plasma levels of interleukin-6 (IL-6) and TNF-α in HFD-induced obese mice and that pomegranate flower increases the level of the anti-inflammatory cytokine interleukin-10 (IL-10).…”

Quantification of punicalagins in commercial preparations and pomegranate cultivars, by liquid chromatography–mass spectrometry

“…versicolor , A. ochraceus , A. niger , Trichoderma viride , Penicillium funiculosum , P. ochrochloron , P. verrucosum ) and antiradical effects (DPPH • [2,2‐diphenyl‐1‐picrylhydrazyl] and ABTS • [2,2′‐azino‐bis‐(3‐ethylbenzothiazoline‐6‐sulfonic acid]; and anti‐osteoporotic and anti‐obesity properties on ovariectomized rats . Pomegranate increased the prostate‐specific antigen in patients with prostate cancer, had antiproliferative effects on cervical and prostate cancer cells, and rat breast cancer tumors and decreased the expression of heat shock protein 90, cyclooxygenase‐2 and monoamine oxidase‐A enzymes, which are key enzymes in inflammatory and neurotransmitter processes, respectively . Proapoptotic properties have been reported in leukemia cell lines (two lymphoid and two myeloid cell lines) .…”

“…8 Pomegranate increased the prostate-specific antigen in patients with prostate cancer, 9 on cervical and prostate cancer cells, and rat breast cancer tumors and decreased the expression of heat shock protein 90, cyclooxygenase-2 and monoamine oxidase-A enzymes, which are key enzymes in inflammatory and neurotransmitter processes, respectively. 10,11 Proapoptotic properties have been reported in leukemia cell lines (two lymphoid and two myeloid cell lines). 12 However, the most studied aspect is the antioxidant activity.…”