Selective, Nontoxic CB₂ Cannabinoid <i>o</i>‑Quinone with in Vivo Activity against Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. Here, we report the synthesis and evaluation of a potent antitumor agent in vivo for this type of breast cancer designed as a combination of quinone/cannabinoid pharmacophores. This new compound (<b>10</b>) has been selected from a series of chromenopyrazolediones with full selectivity for the nonpsychotropic CB₂ cannabinoid receptor and with efficacy in inducing death of human TNBC cell lines. The dual concept quinone/cannabinoid was supported by the fact that compound <b>10</b> exerts antitumor effect by inducing cell apoptosis through activation of CB₂ receptors and through oxidative stress. Notably, it did not show either cytotoxicity on noncancerous human mammary epithelial cells nor toxic effects in vivo, suggesting that it may be a new therapeutic tool for the management of TNBC

Selective, Nontoxic CB₂ Cannabinoid <i>o</i>‑Quinone with in Vivo Activity against Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. Here, we report the synthesis and evaluation of a potent antitumor agent in vivo for this type of breast cancer designed as a combination of quinone/cannabinoid pharmacophores. This new compound (<b>10</b>) has been selected from a series of chromenopyrazolediones with full selectivity for the nonpsychotropic CB₂ cannabinoid receptor and with efficacy in inducing death of human TNBC cell lines. The dual concept quinone/cannabinoid was supported by the fact that compound <b>10</b> exerts antitumor effect by inducing cell apoptosis through activation of CB₂ receptors and through oxidative stress. Notably, it did not show either cytotoxicity on noncancerous human mammary epithelial cells nor toxic effects in vivo, suggesting that it may be a new therapeutic tool for the management of TNBC

New Inhibitors of Angiogenesis with Antitumor Activity in Vivo

Angiogenesis is a requirement for the sustained growth and proliferation of solid tumors, and the development of new compounds that induce a sustained inhibition of the proangiogenic signaling generated by tumor hypoxia still remains as an important unmet need. In this work, we describe a new antiangiogenic compound (<b>22</b>) that inhibits proangiogenic signaling under hypoxic conditions in breast cancer cells. Compound <b>22</b> blocks the MAPK pathway, impairs cellular migration under hypoxic conditions, and regulates a set of genes related to angiogenesis. These responses are mediated by HIF-1α, since the effects of compound <b>22</b> mostly disappear when its expression is knocked-down. Furthermore, administration of compound <b>22</b> in a xenograft model of breast cancer produced tumor growth reductions ranging from 46 to 55% in 38% of the treated animals without causing any toxic side effects. Importantly, in the responding tumors, a significant reduction in the number of blood vessels was observed, further supporting the mechanism of action of the compound. These findings provide a rationale for the development of new antiangiogenic compounds that could eventually lead to new drugs suitable for the treatment of some types of tumors either alone or in combination with other agents