Targeting Nrf2 Signaling Pathway in Cancer Prevention and Treatment: The Role of Cannabis Compounds

Abstract

The development and progression of cancer are associated with the dysregulation of multiple pathways involved in cell proliferation and survival, as well as dysfunction in redox balance, immune response, and inflammation. The master antioxidant pathway, known as the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, regulates the cellular defense against oxidative stress and inflammation, making it a promising cancer prevention and treatment target. Cannabinoids have demonstrated anti-tumor and anti-inflammatory properties, affecting signaling pathways, including Nrf2. Increased oxidative stress following exposure to anti-cancer therapy prompts cancer cells to activate antioxidant mechanisms. This indicates the dual effect of Nrf2 in cancer cells-influencing proliferation and apoptotic processes and protecting against the toxicity of anti-cancer therapy. Therefore, understanding the complex role of cannabinoids in modulating Nrf2 might shed light on its potential implementation as an anti-cancer support. In this review, we aim to highlight the impact of cannabinoids on Nrf2-related factors, with a focus on cancer prevention and treatment. Additionally, we have presented the results of several research studies that combined cannabidiol (CBD) with other compounds targeting Nrf2. Further studies should be directed toward exploring the anti-inflammatory effects of cannabinoids in the context of cancer prevention and therapy.

Keywords: cancer; cannabidiol (CBD); cannabinoids; inflammation; nuclear factor erythroid 2-related factor 2 (Nrf2); oxidative stress.

Figure 2

Dualistic mechanism of cannabidiol (CBD) as a chemopreventive and anti-cancer agent. An arrow-ended line indicates cellular stimulation, while a dash-ended line represents cellular inhibition. The asterisk (*) denotes variability in the impact of the stimulus or inhibition depending on the type of cells involved; ROS, reactive oxygen species; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; IL-1β, interleukin-1β; IL-6, interleukin-6; GPx, glutathione peroxidase; GR, glutathione reductase; SOD, superoxide dismutase; HMOX-1, heme oxygenase-1; NQO1, NAD(P)H dehydrogenase quinone 1; CAT, catalase; GSH/GSSH, reduced/oxidized glutathione.

Figure 3

Mechanisms of Nrf2 pathway activation and signaling alterations induced by cannabidiol (CBD) in regard to various types of cancer. Oxidative stress is the main trigger for the antioxidant response through activation of the Nrf2 pathway. Firstly, it leads to the disruption of the Nrf2-Keap1 complex. The Nrf2 detachment facilitates its translocation to the nucleus, where it dimerizes with Maf proteins and binds to ARE, promoting gene transcription. Other proteins, such as p21 and p65, also contribute to enhancing Nrf2 activation. Conversely, under normal conditions, Nrf2 and p62 are ubiquitinated and degraded in the proteasome. In multiple types of cancer, CBD enhances ROS production, inducing oxidative stress [70,73,74,75,76,86,87]. After exposure of colorectal cancer cells to CBD, an increase in the p65 level was observed [71], while in gastric cells, an increase in the p21 level was demonstrated [88]. In NSCLC cells, CBD causes massive oxidative stress while at the same time reducing Nrf2 activation [73,86]. CBD treatment modulates enzyme and protein levels associated with the Nrf2 pathway and antioxidant response. An increase in GSH/GSSH ratio and a decrease in GPx, GR, and SOD levels were observed in colorectal cancer cells [70]. In turn, in GBM the level of GPx, GR, and HMOX-1 were elevated [75,76], while in leukemia, the level of NADPH oxidases increased [74]. An arrow-ended line indicates stimulation, while a dash-ended line represents inhibition; P denotes phosphorylation. Frames and lines in red indicate CBD’s impact on Nrf2 pathway in specified cancer’s type. NRF2, nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; BACH1, BTB domain and CNC homolog 1; Maf, musculoaponeurotic fibrosarcoma proteins; ARE, antioxidant response element; GBM, glioblastoma multiforme; NSCLC, non-small-cell lung cancer; GPx, glutathione peroxidase; GR, glutathione reductase; SOD, superoxide dismutase; HMOX-1, heme oxygenase-1; GSH/GSSH, reduced/oxidized glutathione.

Figure 1

An overview of the structures of representative compounds within phytocannabinoid subclasses; CBD, cannabidiol; 9-THC, (-)-Δ9-trans-tetrahydrocannabinol; CBG, cannabigerol; CBT, cannabitriol; CBE, cannabielsoin; CBN, cannabinol; 8-THC, (-)-Δ8-trans-tetrahydrocannabinol; CBL, cannabicyclol; CBND, cannabinodiol; CBC, cannabichromene.