image: Figure 1: . (A) Confirmatory screen for hits using CAL27 and VU147 cells exposed to various repurposed drugs at Cmax (or lower), with and without cisplatin (n = 3). (B) Cell viability is compared to untreated controls following 72 (cell lines n = 3-7) or 96 (patient-derived primary tumor cells n = 6) hours exposure to quinacrine alone (black line) at increasing concentrations and also in the presence of cisplatin (red line). IC50 values are highlighted by vertical dotted lines color matched; responses fitted to a five-parameter logistic equation. (C) Viability of cells exposed to 1 μM quinacrine compared to untreated controls. (D) Summary of IC50 values (shaded columns) and inverse log of the IC50 values (pIC50) of quinacrine and standard error of the mean (SEM) in each cell line, with and without the addition of cisplatin. view more
Credit: Hisham Mehanna, email: h.mehanna@bham.ac.uk Nikolaos Batis, email: n.batis@bham.ac.uk
The authors have developed the Accelera TED platform to repurpose drugs for 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 tumor outgrowth, extending median time to reach maximum tumor volume from 20 to 32 days versus control, and from 28 to 32 days versus 2 mg/kg cisplatin alone.
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 tumor suppressive protein, tumor 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 tumor burden in mice bearing HNSCC xenograft tumors, using concentrations that are clinically relevant."
###
Correspondence to - Hisham Mehanna - h.mehanna@bham.ac.uk and Nikolaos Batis - n.batis@bham.ac.uk
Keywords - head and neck cancer, drug repurposing, drug repositioning, quinacrine, mepacrine
About Oncotarget
Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.
Oncotarget is published by Impact Journals LLC.
To learn more about Oncotarget, please visit http://www.ImpactJournals.com
Journal
Oncotarget