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

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.

Repurposing Quinacrine for Treatment of Malignant Mesothelioma: In-Vitro Therapeutic and Mechanistic Evaluation

“…However, it is important to correlate findings from in-vitro studies to pre-clinical studies and one of the major obstacles is prediction of dose for animal models. Previous reports suggest that QA exhibits an IC 50 value of around 1-2 µM which was successfully correlated to be equivalent to efficacious oral doses around 100-200 mg/kg in mice models [91,92]. However, there have been some oral bioavailability issues with QA administration, including high volume of distribution and accumulation in liver [93].…”

The anti-tumour activity of DNA methylation inhibitor 5-aza-2′-deoxycytidine is enhanced by the common analgesic paracetamol through induction of oxidative stress

“…The mouse xenograft study was performed as described previously [ 24 ] and details of the protocol are in Supplementary Methods. To examine the toxicity and anti-tumour efficacy of DAC and paracetamol, we utilized male NOD/SCID/gamma (NSG) mice (Charles River) in accordance with the UK Home Office Animal (Scientific Procedures) Act 1986 and approved by the local University of Birmingham Ethical Review Committee.…”

Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer

“…QC was shown to synergize CPT or carboplatin anti-proliferative activity in ovarian cancer and head and neck squamous cell carcinoma cell lines [ 113 , 114 ] Importantly chemoresistant cell lines were more prone for QC/CPT co-treatment effect. QC promoted autophagic flux as well as autophagosome accumulation.…”

“…It is necessary for selective autophagy. Moreover, combinations of QC and carboplatin or CPT were shown to reduce tumor growth respectively in chemoresistant ovarian and head and neck squamous cancer xenograft model more efficiently than monotherapy [ 113 , 114 ].…”

“… Poly-unsaturated fatty acids (PUFAs): Arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) - multidirectional positive effects in human organism In vitro : NSCLC, cervical cancer - ↑ apoptosis ( ↑ caspase 3/7 activity) - ↑ autophagy - ↓ cancer cells viability - ↓ caspase 3 and PARP cleavage, but with Bcl-2 downregulation and ↓ LC3B-II expression - limiting CPT-mediated nephrotoxicity in mice [ 111 , 112 ] Other Compounds 34. Quinacrine (QC) - anti-malarial drug - structurally related to CQ In vitro : ovarian cancer and head and neck squamous cell carcinoma - ↑ autophagic flux - ↑ autophagosome accumulation [ 113 , 114 ] 35. Graphene oxide - medical nanotechnology, (drug delivery systems) - may trigger LMO - subsequent ↑ autophagy induction and ↓ late-stage flux ( ↓ lysosomal degradation) In vitro : cervical, prostate, ovarian and colon cancer In vitro : NSCLC - ↑ cell death - ↑ necrosis - ↑ autophagy - no influence [ 115 , 116 ] 36.…”