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Identification of repurposed small molecule drugs for chordoma therapy.

Identification of repurposed small molecule drugs for chordoma therapy.

Authors

Xia M,     et al. Show all    

Xia M, Huang R, Sakamuru S, Alcorta D, Cho MH, Lee DH, Park DM, Kelley MJ, Sommer J, Austin CP.

Journal

Cancer Biol Ther. 2013 May 10;14(7). [Epub ahead of print]

Affiliation

NIH Chemical Genomics Center; National Center for Advancing Translational Sciences; National Institutes of Health; Bethesda, MD USA; These authors contributed equally to this manuscript.

Abstract

Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2,800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potent in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine and bortezomib showed similar inhibitory effect on cell lines and three primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.

PMID

       23792643 [PubMed - as supplied by publisher]    

Free full text: Landes Bioscience

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