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2018 ; 13
(3
): e0194224
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Comparative oncology approach to drug repurposing in osteosarcoma
#MMPMID29579058
Parrales A
; McDonald P
; Ottomeyer M
; Roy A
; Shoenen FJ
; Broward M
; Bruns T
; Thamm DH
; Weir SJ
; Neville KA
; Iwakuma T
; Fulbright JM
PLoS One
2018[]; 13
(3
): e0194224
PMID29579058
show ga
BACKGROUND: Osteosarcoma is an orphan disease for which little improvement in
survival has been made since the late 1980s. New drug discovery for orphan
diseases is limited by the cost and time it takes to develop new drugs.
Repurposing already approved FDA-drugs can help overcome this limitation. Another
limitation of cancer drug discovery is the lack of preclinical models that
accurately recapitulate what occurs in humans. For OS using dogs as a model can
minimize this limitation as OS in canines develops spontaneously, is locally
invasive and metastasizes to the lungs as it does in humans. METHODS: In our
present work we used high-throughput screens to identify drugs from a library of
2,286 FDA-approved drugs that demonstrated selective growth inhibition against
both human and canine OS cell lines. The identified lead compound was then tested
for synergy with 7 other drugs that have demonstrated activity against OS. These
results were confirmed with in vitro assays and an in vivo murine model of OS.
RESULTS: We identified 13 drugs that demonstrated selective growth inhibition
against both human and canine OS cell lines. Auranofin was selected for further
in vitro combination drug screens. Auranofin showed synergistic effects with
vorinostat and rapamycin on OS viability and apoptosis induction. Auranofin
demonstrated single-agent growth inhibition in both human and canine OS
xenografts, and cooperative growth inhibition was observed in combination with
rapamycin or vorinostat. There was a significant decrease in Ki67-positive cells
and an increase in cleaved caspase-3 levels in tumor tissues treated with a
combination of auranofin and vorinostat or rapamycin. CONCLUSIONS: Auranofin,
alone or in combination with rapamycin or vorinostat, may be useful new treatment
strategies for OS. Future studies may evaluate the efficacy of auranofin in dogs
with OS as a prelude to human clinical evaluation.
|*Drug Repositioning
[MESH]
|Animals
[MESH]
|Antineoplastic Agents/chemistry/*pharmacology/therapeutic use
[MESH]
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