Novel merosesquiterpene exerts a potent antitumor activity against breast cancer cells in vitro and in vivo

• Published in: European journal of medicinal chemistry 2014-05, Vol.79, p.1-12
• Main Authors: Carrasco, Esther, Álvarez, Pablo Juan, Melguizo, Consolación, Prados, José, Álvarez-Manzaneda, Enrique, Chahboun, Rachid, Messouri, Ibtissam, Vázquez-Vázquez, María Isabel, Aránega, Antonia, Rodríguez-Serrano, Fernando
• Format: Article
• Language: English
• Subjects: Allografts; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell Cycle - drug effects; Cell cycle arrest; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; HT29 Cells; Humans; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; MCF-7 Cells; Merosesquiterpene; Mice; Mice, Inbred C57BL; Molecular Structure; Oxidative stress; Sesquiterpenes - chemical synthesis; Sesquiterpenes - chemistry; Sesquiterpenes - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.03.071

This article describes the antitumor properties of a new family of merosesquiterpenes, which were synthesized by Diels–Alder cycloaddition of the labdane diene trans-communic acid, highly abundant in Cupressus sempervirens, or its methyl ester, with the appropriate dienophile. These compounds demonstrated potent cytotoxic activity in vitro against human breast, colon, and lung tumor cells. We highlight the elevated activity (IC50: 0.35 ± 0.10 μM) and specificity (TI: 9) of compound 13 against the MCF-7 line, which corresponds to the most prevalent breast cancer cell subtype, luminal A. It was found that compound 13 exerts its anti-tumor action by inducing oxidative stress, arresting the cell cycle in stages G0–G1, and activating apoptosis, which are all associated with low cyclin D1 regulation, pRb hypophosphorylation, increased expression of p27 and p53, and poly (ADP-ribose) polymerase (PARP) fractioning. Epithelial–mesenchymal transition, a phenomenon associated with metastasis promotion and a worsened prognosis also appeared to be inhibited by compound 13. In addition, it markedly reduced tumor development in immunocompetent C57BL/6 mice with allografts of E0771 mouse breast tumor cells (luminal A subtype). According to these findings, this new family of compounds, especially compound 13, may be highly useful in the treatment of human breast cancer. [Display omitted] •A series of new merosesquiterpenes with antitumor activity.•One of these, 13, induces oxidative stress in MCF7 breast cancer cells.•Action mechanisms of 13 include cell cycle arrest and apoptosis.•13 inhibits tumor development in an in vivo murine model of breast cancer allograft.