Novel merosesquiterpene exerts a potent antitumor activity against breast cancer cells in vitro and in vivo.
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.
Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18071 Granada, Spain; PhD Program in Biomedicine, University of Granada, 18071 Granada, Spain.
Esther
E
Carrasco
Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18071 Granada, Spain.
Pablo Juan
PJ
Álvarez
Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18071 Granada, Spain.
Consolación
C
Melguizo
Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18071 Granada, Spain.
José
J
Prados
Department of Organic Chemistry, Institute of Biotechnology, University of Granada, 18071 Granada, Spain.
Enrique
E
Álvarez-Manzaneda
Department of Organic Chemistry, Institute of Biotechnology, University of Granada, 18071 Granada, Spain.
Rachid
R
Chahboun
Department of Organic Chemistry, Institute of Biotechnology, University of Granada, 18071 Granada, Spain.
Ibtissam
I
Messouri
Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18071 Granada, Spain.
María Isabel
MI
Vázquez-Vázquez
Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18071 Granada, Spain.
Antonia
A
Aránega
Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18071 Granada, Spain. Electronic address: fernrs@ugr.es.
Fernando
F
Rodríguez-Serrano
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012717:Sesquiterpenes
Allografts; Apoptosis; Cancer; Cell cycle arrest; Merosesquiterpene; Oxidative stress