Computational Drug Repositioning Identifies Potentially Active Therapies for Chordoma
Autor: | Shaan M. Raza, Visweswaran Ravikumar, Hadley E. Sheppard, Jonathan D. Breshears, Shreyaskumar Patel, Jeffrey I. Traylor, Charles Y. Lin, Franco DeMonte |
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Rok vydání: | 2020 |
Předmět: |
musculoskeletal diseases
medicine.medical_treatment Antineoplastic Agents Bone Neoplasms 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Chordoma Animals Humans Medicine Computer Simulation 030304 developmental biology 0303 health sciences Chemotherapy business.industry Venetoclax Drug Repositioning medicine.disease Skull Base Chordoma Drug repositioning chemistry 030220 oncology & carcinogenesis Pharmacogenomics Cancer research Cytarabine Surgery Neurology (clinical) business Toxicogenomics medicine.drug |
Zdroj: | Neurosurgery. 88:428-436 |
ISSN: | 1524-4040 0148-396X |
Popis: | Background Chordomas are aggressive bone tumors that often recur despite maximal resection and adjuvant radiation. To date there are no Food and Drug Administration (FDA)-approved chemotherapies. Computational drug repositioning is an expanding approach to identify pharmacotherapies for clinical trials. Objective To identify FDA-approved compounds for repurposing in chordoma. Methods Previously identified highly differentially expressed genes from chordoma tissue samples at our institution were compared with pharmacogenomic interactions in the Comparative Toxicogenomics Database (CTD) using ksRepo, a drug-repositioning platform. Compounds selected by ksRepo were then validated in CH22 and UM-Chor1 human chordoma cells in Vitro. Results A total of 13 chemical compounds were identified in silico from the CTD, and 6 were selected for preclinical validation in human chordoma cell lines based on their clinical relevance. Of these, 3 identified drugs are FDA-approved chemotherapies for other malignancies (cisplatin, cytarabine, and lucanthone). Cytarabine, a deoxyribonucleic acid polymerase inhibitor approved for the treatment of various leukemias, exhibited a significant concentration-dependent effect against CH22 and UM-Chor1 cells when compared to positive (THZ1) and negative (venetoclax) controls. Tretinoin exhibited a significant concentration-dependent cytotoxic effect in CH22, sacral chordoma-derived cell lines but to a much lesser extent in UM-Chor1, a cell line derived from skull base chordoma. Conclusion Cytarabine administration reduces the viability of human chordoma cells. The equally effective reduction in viability seen with tretinoin seems to be cell line dependent. Based on our findings, we recommend the evaluation of cytarabine and tretinoin in an expanded set of human chordoma cell lines and animal models. |
Databáze: | OpenAIRE |
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