Synthesis of marmycin A and investigation into its cellular activity

Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels-Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel-Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications

A New Family of IMU based on IFOG Technology

International audienc

A New Family of IMU based on IFOG Technology

International audienc

A New Family of IMU based on IFOG Technology

International audienc

Androgen receptor protein levels are significantly reduced in serous ovarian carcinomas compared with benign or borderline disease but are not altered by cancer stage or metastatic progression

The androgen receptor (AR) is expressed in a majority of ovarian carcinomas, but its role in disease development remains unclear. In this study, AR and a novel AR molecular chaperone called small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) were investigated to assess their potential role in ovarian carcinogenesis. First, an AR and SGTA-positive ovarian cancer cell line was identified to examine whether SGTA influenced AR subcellular localization. Next, relative protein levels of AR and SGTA were measured in two sets of clinical samples: (1) 46 serous ovarian carcinomas (stages I-IV), 9 serous borderline tumors, and 11 benign ovarian tumors; and (2) 24 patient-matched stage III primary and metastatic serous ovarian tumors. Ablation of SGTA protein in OVCAR3 cells significantly increased AR nuclear localization under basal (p ≤ 0.001) and androgen-stimulated (p ≤ 0.001) conditions. In the first clinical set, AR levels were significantly lower in early- (I/II) and late-stage (III/IV) cancers compared with benign (p ≤ 0.001) but not borderline ovarian tumors. SGTA alone did not discriminate between groups but the AR/SGTA ratio was significantly lower in carcinomas and borderline tumors compared with benign tumors (p ≤ 0.001 and 0.015, respectively). In the second clinical set, matched primary and metastatic serous ovarian cancers did not significantly differ for any parameter measured. Collectively, our results suggest that SGTA can influence AR signaling in ovarian cancer cells and that AR signaling capacity may be reduced with the development but not metastatic progression of serous ovarian cancer.Miriam S. Butler, Carmela Ricciardelli, Wayne D. Tilley, Theresa E. Hicke

Targeted next-generation sequencing supports epidermoid metaplasia of the esophagus as a precursor to esophageal squamous neoplasia

Esophageal epidermoid metaplasia is a rare condition that involves the proximal-to-middle third of the esophagus. It is sharply demarcated and defined histologically by epithelial hyperplasia, a prominent granular cell layer, and superficial hyperorthokeratosis. In addition, preliminary studies have suggested an association between esophageal epidermoid metaplasia and esophageal squamous neoplasia (squamous dysplasia and esophageal squamous cell carcinoma). To further characterize esophageal epidermoid metaplasia and better define its relationship to squamous neoplasia of the esophagus, we performed targeted next-generation sequencing on uninvolved esophageal squamous mucosa and matching esophageal epidermoid metaplasia specimens from 18 patients. Further, we evaluated both synchronous and metachronous high-grade squamous dysplasia/esophageal squamous cell carcinoma by next-generation sequencing from 5 of the 18 (28%) patients, and compared these findings to corresponding esophageal epidermoid metaplasia specimens. Targeted next-generation sequencing revealed 12 of 18 (67%) esophageal epidermoid metaplasia specimens' harbored alterations in genes often associated with esophageal squamous cell carcinoma. The most frequently mutated genes consisted of TP53 (n=10), PIK3CA (n=2), EGFR (n=2), MYCN (n=1), HRAS (n=1), and the TERT promoter (n=1). Sequencing of synchronous and metachronous high-grade squamous dysplasia/esophageal squamous cell carcinoma identified shared genetic alterations with corresponding esophageal epidermoid metaplasia specimens that suggests a clonal relationship between these entities. In addition, the presence of a TP53 mutation in esophageal epidermoid metaplasia specimens correlated with concurrent or progression to high-grade squamous dysplasia/esophageal squamous cell carcinoma. No genetic alterations were detected in uninvolved esophageal squamous mucosa. On the basis of these findings, we conclude esophageal epidermoid metaplasia is a precursor to in situ and invasive esophageal squamous neoplasia. Further, the detection of TP53 mutations in esophageal epidermoid metaplasia specimens may serve as an early detection biomarker for high-grade squamous dysplasia/esophageal squamous cell carcinoma