Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition

Abstract

BackgroundErbB2-positive breast cancer is characterized by highly aggressive phenotypes and reduced responsiveness to standard therapies. Although specific ErbB2-targeted therapies have been designed, only a small percentage of patients respond to these treatments and most of them eventually relapse. The existence of this population of particularly aggressive and non-responding or relapsing patients urges the search for novel therapies. The purpose of this study was to determine whether cannabinoids might constitute a new therapeutic tool for the treatment of ErbB2-positive breast tumors. We analyzed their antitumor potential in a well established and clinically relevant model of ErbB2-driven metastatic breast cancer: the MMTV-neu mouse. We also analyzed the expression of cannabinoid targets in a series of 87 human breast tumors.ResultsOur results show that both Δ9-tetrahydrocannabinol, the most abundant and potent cannabinoid in marijuana, and JWH-133, a non-psychotropic CB2 receptor-selective agonist, reduce tumor growth, tumor number, and the amount/severity of lung metastases in MMTV-neu mice. Histological analyses of the tumors revealed that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis, and impair tumor angiogenesis. Cannabinoid antitumoral action relies, at least partially, on the inhibition of the pro-tumorigenic Akt pathway. We also found that 91% of ErbB2-positive tumors express the non-psychotropic cannabinoid receptor CB2.ConclusionsTaken together, these results provide a strong preclinical evidence for the use of cannabinoid-based therapies for the management of ErbB2-positive breast cancer.

The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model

“…This was in agreement with the work of others that suggested the effects of cannabinoids on MAPK was both dose-dependent and cell line specific (15,23). In addition to MAPK, the PI3-kinase/AKT pathway was also considered as it has also been linked to cannabinoid action and is an important determinant of cell fate (28). Our results showed modest reductions in pAKT, which was most apparent at the higher concentrations of CBD.…”

Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer

“…Phosphorylated Akt has been shown to correlate with poor survival and several clinical trials are concerned with inhibiting the PI3K/Akt /mTOR pathway (29)(30)(31)(32). In this work we have shown that reported that deletion of Akt2 in both mice and humans can provoke insulin resistance (33,34).…”

Cannabis sativa Extract Reduces Cytoskeletal Associated Proteins in Breast Cancer Cell Line

“…Cannabinoids (the active components of C. sativa) and their derivatives have received great attention in recent years due to their applications as anti-tumour drugs (15)(16)(17)(18). Due to the fact that cannabinoid receptors (CB1 and CB2) are overexpressed in primary human breast tumors compared to normal breast tissues, agonists of cannabinoid receptors are offered as a novel strategy to treat cancer (1,4).…”

“…Cannabis sativa may cause antitumor effects by various mechanisms, including inhibition of cell growth and tumor angiogenesis invasion, induction of cell death, and metastasis (15)(16)(17)(18).…”