New hexahydrocannabinol analogs have been found to have anti-cancer capabilities, suppressing cell proliferation and tumor angiogenesis.
Recent research has revealed that novel analogs of the psychoactive compound hexahydrocannabinol (THC) may possess anti-cancer properties. The analogs could potentially be used as novel agents for the treatment of cancer.
Studies show that cannabinoids can inhibit tumor growth by impacting signaling pathways, so a new series of analogs has been synthesized to find anti-cancer agents with no psychoactive side effects. Two analogs, LYR-7 and LYR-8, were chosen for further study due to their anti-angiogenic activity and lack of cannabinoid receptor binding.
Compounds LYR-7 and LYR-8 effectively inhibited VEGF-induced cell proliferation, migration, and tube formation in endothelial cells in vitro, and new blood vessel formation in vivo. LYR-7 and LYR-8, novel synthetic hexahydrocannabinol analogs, inhibit tumor growth by targeting VEGF-mediated angiogenesis signaling and suppressing VEGF production and cancer cell growth.
Recent studies have demonstrated that both natural and synthetic cannabinoids can inhibit the growth of tumor cells by impacting vital signaling pathways, such as angiogenesis – a factor integral to tumor development, attack and spread. In order to discover cannabinoid-based anti-cancer agents which do not possess psychoactive side effects, a novel series of hexahydrocannabinol analogs were synthesized and assessed for their anti-angiogenic properties.
Two analogs, LYR-7 [(9S)-3,6,6,9-tetramethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-1-ol] and LYR-8 [(1-((9S)-1-hydroxy-6,6,9-trimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2yl)ethanone)], were selected for further study due to their anti-angiogenic activity and lack of binding affinity for cannabinoid receptors.
In a concentration-dependent manner, the compounds LYR-7 and LYR-8 both effectively inhibited VEGF-induced cell proliferation, migration, and capillary-like tube formation of HUVECs. Our findings showed more selectivity in inhibition of proliferation for endothelial cells compared to breast cancer cells (MCF-7 and tamoxifen-resistant MCF-7). Moreover, the compounds also had a notable impact on VEGF-induced new blood vessel formation in a chick chorioallantoic membrane (CAM) assay in vivo.
Both analogs of LYR potently inhibited the production of VEGF and NF-B transcriptional activity in cancer cells. Furthermore, LYR-7 and LYR-8 were found to strongly inhibit angiogenesis and tumor growth induced by breast cancer cells. These findings suggest that novel synthetic hexahydrocannabinol analogs, LYR-7 and LYR-8, inhibit tumor growth by targeting VEGF-mediated angiogenesis signaling in endothelial cells and suppressing both VEGF production and cancer cell growth.
Cannabinoids have been found to possess anti-proliferative properties on a range of tumor cells, both in vitro and in vivo. This is achieved through direct cell death, impeding tumor angiogenesis, and halting metastasis (Galve-Roperh et al., 2000; Guzman et al., 2002; Guzman, 2003). Despite these promising results, the potential of cannabinoids as anti-cancer agents has been limited by their psychoactive tendencies.
Studies suggest that the activation of central cannabinoid receptors (cannabinoid CB1receptors) found primarily in the brain is linked to psychoactive effects. In contrast, peripheral cannabinoid receptors (cannabinoid CB2receptors) are mainly located in the immune system. Although selective CB2agonists display no psychoactivity, they exhibit other side-effects such as immunosuppression (Pertwee, 2005; Zhu et al., 2000). Hence, for cancer treatment, cannabinoids with little to no affinity for CB receptors offer a promising alternative.
Angiogenesis plays an influential role in the development and spread of tumors (Folkman, 1995). Vascular endothelial growth factor (VEGF) production is a crucial regulator controlling tumor angiogenesis. Accordingly, suppressing the production of VEGF is a promising approach for cancer treatment. In recent years, the clinical use of anti-angiogenic drugs such as bevacizumab, sorafenib, and sunitinib has marked a major breakthrough in cancer treatment.
The monoclonal anti-VEGF antibody, Bevacizumab, has been approved for the first-line treatment of metastatic breast cancer when used in combination with taxane (Kerbel, 2009). An alternate approach for anti-angiogenic therapy is Sunitinib, a VEGF receptor tyrosine kinase inhibitor which acts directly on endothelial cells. In addition, several classes of cannabinoids have demonstrated their ability to suppress tumor growth by either inhibiting the production of proangiogenic factors (Casanova et al., 2003, Blazquez et al., 2004, Preet et al., 2008) or by directly inducing apoptosis of vascular endothelial cells (Kogan et al. 2006).
The purpose of this study was to analyze the potential for novel synthetic hexahydrocannabinol analogs to inhibit tumor-angiogenesis through the suppression of vascular endothelial growth factor (VEGF) in cancer cells and VEGF-mediated signaling in endothelial cells. Tamoxifen-resistant MCF-7 (TAMR-MCF-7) cells were used as the model cancer cell line for the study, as these cells have been linked to a heightened production of VEGF, which may cause a more aggressive phenotype (Kim et al., 2008, Kim et al., 2009).
The chick chorioallantoic membrane (CAM) assay, which has been widely used to assess angiogenesis and metastasis, was employed in order to imitate the tumor microenvironment (Ribatti et al., 2001; Tufan and Satiroglu-Tufan, 2005). This technique involved inoculating the membrane with cancer cells.
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [2010-0001661] and by the Regional Technology Innovation Program of the Ministry of Commerce, Industry, and Energy (MOCIE) [grant No. RTI04-01-04].