{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:56:18Z","timestamp":1791114978089,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T00:00:00Z","timestamp":1398297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T00:00:00Z","timestamp":1398297600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["NIH COBRE P20RR015563"],"award-info":[{"award-number":["NIH COBRE P20RR015563"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012482","name":"University of Michigan Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["NCI : P30CA046592"],"award-info":[{"award-number":["NCI : P30CA046592"]}],"id":[{"id":"10.13039\/100012482","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["World j. surg."],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis, as a majority of patients present with advanced disease. Current adjuvant strategies for metastatic patients include mitotane or other cytotoxic agents and carry a significant morbidity as well as a low (&lt;10 %) 5\u2010year survival. Withanolides, including withaferin A, are novel chemotherapeutic agents with potent targeted effects in medullary thyroid cancer and a number of solid malignancies with low toxicity in vivo. We hypothesize that novel naturally derived withanolides will have potent targeted anti\u2010cancer activity against ACCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In vitro cell viability of ACC cell lines (Y1 and SW13) was measured using MTS cell proliferation assay. Cell cycle and apoptotic analysis studied using annexin V\/propidium iodide staining on flow cytometry (FC) and targeted molecular mechanisms of withanolide cytotoxicity were assessed using standard Western blot analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All the withanolides potently reduced ACC cell viability on MTS assay with 7\u2010 to 185\u2010fold higher selectivity than normal fibroblasts. Cell cycle analysis demonstrated a shift in cell cycle arrest from G1\/G0 to G2\/M with induction of apoptosis at nanomolar concentrations of withanolides. Unlike current ACC therapeutics, withanolides modulated expression of several key oncogenic pathway proteins in ACCs by Western blot, including Jagged 1, MAPK, and Akt\/mTOR pathway proteins in a dose\u2010dependent manner after 24 h drug treatment of SW13 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results demonstrate the first evidence of the anticancer efficacy of withanolides in ACC cells and provide support for future translational evaluation of these compounds as novel therapeutic agents for ACC patients.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s00268-014-2532-0","type":"journal-article","created":{"date-parts":[[2014,4,23]],"date-time":"2014-04-23T23:14:44Z","timestamp":1398294884000},"page":"1343-1352","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Withanolides are Potent Novel Targeted Therapeutic Agents Against Adrenocortical Carcinomas"],"prefix":"10.1002","volume":"38","author":[{"given":"Chitra","family":"Subramanian","sequence":"first","affiliation":[{"name":"Division of Endocrine Surgery, Department of Surgery University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Kansas Lawrence KS USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Kansas Lawrence KS USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Hammer","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, Department of Medicine University of Michigan Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Timmermann","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Kansas Lawrence KS USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Cohen","sequence":"additional","affiliation":[{"name":"Division of Endocrine Surgery, Department of Surgery University of Michigan Hospital and Health Systems Ann Arbor MI 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