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Oncotarget. 2019 Aug 27;10(50):5229-5244. doi: 10.18632/oncotarget.27156. eCollection 2019 Aug 27.

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

Author information

1
Institute of Head and Neck Studies and Education (InHANSE), University of Birmingham, Birmingham, UK.
2
Joint first authors.
3
School of Biosciences, University of Birmingham, Birmingham, UK.
4
Phenome Centre Birmingham, University of Birmingham, Birmingham, UK.
5
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
6
School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
7
School of Biomedical Sciences, Institute of Clinical Sciences, University of Birmingham, Birmingham, UK.
8
Joint senior authors.
9
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

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 in vitro assays (cell viability, clonogenic survival, apoptosis) and in vivo 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. In vivo, 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 (p < 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.

KEYWORDS:

drug repositioning; drug repurposing; head and neck cancer; mepacrine; quinacrine

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