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Repurposed quinacrine synergises with cisplatin, reducing the effective dose required for head and neck cancer treatment

The authors have developed a platform to repurpose drugs for head and neck squamous cell carcinoma (HNSCC) treatment; using in vitro assays and in vivo models.

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 and in six primary HNSCC samples.

In vivo, daily treatment with 100 mg/kg oral quinacrine plus cisplatin significantly inhibited tumour outgrowth, extending median time to reach maximum tumour volume from 20 to 32 days versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone.

These findings have been published in the journal Oncotarget.

Dr Hisham Mehanna and Dr Nikolaos Batis said: "Head and neck squamous cell carcinoma is a debilitating disease comprising 600,000 cases per year worldwide."

Due to the high morbidity of current treatments, quality of life is severely impaired, with evident unmet need necessitating more effective therapies with lower toxicity; especially as recent studies examining cetuximab as a less toxic alternative for low risk human papillomavirus positive HNSCC have shown similar toxicity, and lower efficacy compared to cisplatin.

On initial screening against HNSCC cell lines, quinacrine was identified as a potential hit.

Quinacrine is a potent late-stage autophagy inhibitor and has been shown to prime cells to the effects of cisplatin via apoptosis in cervical and endometrial cancer.

Further mechanistic insights have been demonstrated in HNSCC whereby quinacrine was able to restore the function of the tumour suppressive protein, tumour protein 53, leading to enhanced capabilities of initiating apoptotic cell death following DNA damage with cisplatin chemotherapy.

Moreover, quinacrine treatment has been shown to suppress phosphoinositide 3-kinase, protein kinase B, mechanistic target of rapamycin and nuclear factor kappa-light-chain-enhancer of activated B cells pathways.

The Mehanna/Batis Research team concluded: "Notably, our study is the first to demonstrate that quinacrine is able to reduce tumour burden in mice bearing HNSCC xenograft tumours, using concentrations that are clinically relevant."

Source: Oncotarget

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