antrocin and Breast-Neoplasms

The total synthesis of (-)-antrocin and its enantiomer are presented. Antrocin (-)-

Topics: Biological Products; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cyanides; Female; Humans; Lactones; Neoplasm Metastasis; Sesquiterpenes; Stereoisomerism; Tartrates; Trimethylsilyl Compounds

We identified increased β-catenin and Atk expression was associated with drug resistance and poor prognosis in breast cancer patients using public databases. Antrocin treatment suppressed breast tumorigenesis and stemness properties.. We aimed to provide preclinical evidence for antrocin, an active component of Antrodia cinnamomea, as a potential small-molecule drug for treating drug-resistant breast cancer.. Various in vitro assays including SRB, Boyden chamber, colony formation, drug combination index and tumor sphere generation were used to determine the anti-cancer and stemness effects of antrocin. Mouse xenograft models were used to evaluate antrocin's effect in vivo.. Antrocin treatment suppressed the viability, migration colony formation and mammosphere generation. Antrocin-mediated anti-cancer effects were associated with the decreased expression of oncogenic and stemness markers such as β-catenin, Akt and Notch1. A sequential regimen of antrocin and paclitaxel synergistically inhibit breast cancer viability in vitro and in vivo.. Our preclinical evidence supports antrocin's ability of inhibiting tumorigenic and stemness properties in breast cancer cells. Further develop of antrocin should be encouraged; the combined use of antrocin and paclitaxel may also be considered for future clinical trials.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antrodia; beta Catenin; Breast Neoplasms; Carcinogenesis; Cell Proliferation; Cell Transformation, Neoplastic; Down-Regulation; Drug Synergism; Female; Fibroblasts; Humans; Lactones; MCF-7 Cells; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Paclitaxel; Proto-Oncogene Proteins c-akt; Receptor, Notch1; Sesquiterpenes; Signal Transduction; Xenograft Model Antitumor Assays

The PI3K/Akt/mTOR pathway is considered to be an attractive target for the development of novel anticancer molecules. This paper reports for the first time that a small molecule, antrocin (MW = 234), from Antrodia camphorata was a potent antagonist in various cancer types, being highest in metastatic breast cancer MDA-MB-231 cells (MMCs) with an IC(50) value of 0.6 μM. Antrocin was a superior antiproliferator in MMCs as compared with doxorubicin and cisplatin, prevents colony formation, and was nontoxic to nontumorgenic MCF10A and HS-68 cells. Antrocin induced dose-dependent apoptosis in MMCs and caused cleavage of caspase-3 and poly(ADP-ribose) polymerase. Antrocin also caused a time-dependent decrease in protein expression of anti-apoptotic Bcl-2, Bcl-xL, survivin, and their mRNA, with concomitant increase in pro-apoptotic Bax and cytosolic cytochrome c. In a mechanistic study, antrocin suppressed the phosphorylation of Akt and its downstream effectors mTOR, GSK-3β, and NF-κB. Furthermore, down-regulation of Akt by small interfering RNA prior to antrocin treatment resulted in enhanced cell growth inhibition and apoptosis. Thus, antrocin as an Akt/mTOR dual inhibitor has broad applicability in the development of a clinical trial candidate for the treatment of metastatic breast cancer.

Topics: Antineoplastic Agents; Antrodia; Apoptosis; Breast Neoplasms; Cell Proliferation; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lactones; Models, Molecular; Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-akt; Sesquiterpenes; Signal Transduction; TOR Serine-Threonine Kinases