ABSTRACT
Strigolactones (SLs) are a novel class of plant hormones. Previously, we found that analogs of SLs induce growth arrest and apoptosis in breast cancer cell lines. These compounds also inhibited the growth of breast cancer stem cell enriched-mammospheres with increased potency. Furthermore, strigolactone analogs inhibited growth and survival of colon, lung, prostate, melanoma, osteosarcoma and leukemia cancer cell lines. To further examine the anti-cancer activity of SLs in vivo, we have examined their effects on growth and viability of MDA-MB-231 tumor xenografts model either alone or in combination with paclitaxel. We show that strigolactone act as new anti-cancer agents in inhibition of breast cancer in xenograft model. In addition we show that SLs affect the integrity of the microtubule network and therefore may inhibit the migratory phenotype of the highly invasive breast cancer cell lines that were examined.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Heterocyclic Compounds, 3-Ring/pharmacology , Lactones/pharmacology , Paclitaxel/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement , Cell Survival/drug effects , Drug Synergism , Female , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Lactones/therapeutic use , Mice, Inbred BALB C , Mice, Inbred ICR , Mice, Nude , Paclitaxel/therapeutic use , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Halofuginone has been shown to prevent fibrosis via the transforming growth factor-ß/Smad3 pathway in muscular dystrophies. We hypothesized that halofuginone would reduce apoptosis--the presumed cause of satellite-cell depletion during muscle degradation-in the mdx mouse model of Duchenne muscular dystrophy. Six-week-old mdx mouse diaphragm exhibited fourfold higher numbers of apoptotic nuclei compared with wild-type mice as determined by a TUNEL assay. Apoptotic nuclei were found in macrophages and in Pax7-expressing cells; some were located in centrally-nucleated regenerating myofibers. Halofuginone treatment of mdx mice reduced the apoptotic nuclei number in the diaphragm, together with reduction in Bax and induction in Bcl2 levels in myofibers isolated from these mice. A similar effect was observed when halofuginone was added to cultured myofibers. No apparent effect of halofuginone was observed in wild-type mice. Inhibition of apoptosis or staurosporine-induced apoptosis by halofuginone in mdx primary myoblasts and C2 myogenic cell line, respectively, was reflected by less pyknotic/apoptotic cells and reduced Bax expression. This reduction was reversed by a phosphinositide-3-kinase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase inhibitors, suggesting involvement of these pathways in mediating halofuginone's effects on apoptosis. Halofuginone increased apoptosis in α smooth muscle actin- and prolyl 4-hydroxylase ß-expressing cells in mdx diaphragm and in myofibroblasts, the major source of extracellular matrix. The data suggest an additional mechanism by which halofuginone improves muscle pathology and function in muscular dystrophies.
