Future Aspects for Cannabinoids in Breast Cancer Therapy

Abstract

Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients. Additionally, they may decelerate tumor progression in breast cancer patients. Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models. The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way. THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both. In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway. They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis. Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor. In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.

Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment

“…The interactions between HR+ BC and cannabinoids are complex and the clinical significance of such interactions is currently impossible to predict. Use of cannabinoids in palliative medicine is well established [76], however clinical trials are needed to determine safety of cannabinoid treatment in other BC settings. Until further evidence is available, caution should be exercised by physicians and patients when using cannabinoid preparations in a HR+ (as well as in any other) BC setting.…”

Breast cancer pathogenesis is linked to the intra-tumoral estrogen sulfotransferase (hSULT1E1) expressions regulated by cellular redox dependent Nrf-2/NFκβ interplay

“…Cannabinoids (CBs) from Cannabis sativa CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B-and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis [94]. Proper staging is critical for determining the appropriate clinical treatment course and surgical planning.…”

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

“…For example, in the case of neurons, the CB1 receptor dominates; whereas, in the case of tumors, the CB2 receptor is usually dominant [123]. This could indicate that the CB2 receptor is responsible for the proapoptotic activity of CBD, which is confirmed by evidence that inhibition of CB2 abolishes the proapoptotic activity, at least in the case of breast cancer cells [135]. In contrast, the protective effect of CBD appears to be independent of any receptors because CB1, CB2, transient receptor potential cation channel subfamily V member 1 (TRPV1), and peroxisome proliferator-activated receptor γ (PPARγ) antagonists do not affect the CBD pro-survival effect [136].…”