Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma.

Bryant, Jennifer and Batis, Nikolaos and Franke, Anna Clara and Clancey, Gabriella and Hartley, Margaret and Ryan, Gordon and Brooks, Jill and Southam, Andrew D and Barnes, Nicholas and Parish, Joanna and Roberts, Sally and Khanim, Farhat and Spruce, Rachel and Mehanna, Hisham (2019) Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma. Oncotarget, 10 (50). pp. 5229-5244. ISSN 1949-2553.

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Abstract

Despite highly toxic treatments, head and neck squamous cell carcinoma (HNSCC) have poor outcomes. There is an unmet need for more effective, less toxic therapies. Repurposing of clinically-approved drugs, with known safety profiles, may provide a time- and cost-effective approach to address this need. We have developed the AcceleraTED platform to repurpose drugs for HNSCC treatment; using assays (cell viability, clonogenic survival, apoptosis) and models (xenograft tumors in NOD/SCID/gamma mice). Screening a library of clinically-approved drugs identified the anti-malarial agent quinacrine as a candidate, which significantly reduced viability in a concentration dependent manner in five HNSCC cell lines (IC50 0.63-1.85 μM) and in six primary HNSCC samples (IC50 ~2 μM). Decreased clonogenic survival, increased apoptosis and accumulation of LC3-II (indicating altered autophagy) were also observed. Effects were additional to those resulting from standard treatments (cisplatin +/- irradiation) alone. , daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days ( < 0.0001) versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone. Importantly, combination therapy enabled the dose of cisplatin to be halved to 1 mg/kg, whilst maintaining the same impairment of tumor growth. Treatment was well tolerated; murine plasma levels reached a steady concentration of 0.5 μg/mL, comparable to levels achievable and tolerated in humans. Consequently, due to its favorable toxicity profile and proven safety, quinacrine may be particularly useful in reducing cisplatin dose, especially in frail and older patients; warranting a clinical trial.

Item Type: Article
Subjects: QZ Pathology. Oncology
WV Otorhinolaryngology. ENT medicine
Divisions: Ambulatory Care > ENT
Related URLs:
Depositing User: Jennifer Manders
Date Deposited: 20 Sep 2019 11:37
Last Modified: 20 Sep 2019 11:37
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2403

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