Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma.
Repurposed quinacrine synergizes with cisplatin, reducing the effective dose required for treatment of head and neck squamous cell carcinoma.
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DOI：
10.18632/oncotarget.27156
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发表时间：
2019-08-27
期刊：
影响因子：
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通讯作者：
Mehanna, Hisham
中科院分区：
文献类型：
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作者：
Bryant, Jennifer;Batis, Nikolaos;Mehanna, Hisham
尽管有高毒性的治疗，头颈部鳞状细胞癌（HNSCC）的结果很差。对更有效、毒性更小的治疗存在未满足的需求。重新使用临床批准的药物，已知的安全性，可以提供一个时间和成本效益的方法来满足这一需求。我们已经开发了AcceleraTED平台来重新利用药物治疗HNSCC;使用体外试验（细胞活力，克隆存活，凋亡）和体内模型（NOD/SCID/γ小鼠中的异种移植肿瘤）。筛选临床批准的药物库，将抗疟疾剂奎纳克林鉴定为候选物，其在五种HNSCC细胞系（IC 50 0.63-1.85 μ M）和六种原发性HNSCC样品（IC 50 ~2 μ M）中以浓度依赖性方式显著降低存活力。还观察到克隆形成存活减少、细胞凋亡增加和LC 3-II积累（表明自噬改变）。效果是额外的标准治疗（顺铂+/-照射）单独。在体内，每天口服100 mg/kg奎纳克林加顺铂治疗显著抑制肿瘤生长，与对照组相比，达到最大肿瘤体积的中位时间从20天延长至32天（p < 0.0001），与2 mg/kg顺铂单独治疗相比，从28天延长至32天。重要的是，联合治疗使顺铂的剂量减半至1 mg/kg，同时保持相同的肿瘤生长损伤。治疗耐受性良好;鼠血浆水平达到0.5 μ g/mL的稳定浓度，与人可达到和耐受的水平相当。因此，由于其良好的毒性特征和已证实的安全性，奎纳克林可能特别适用于减少顺铂剂量，特别是在虚弱和老年患者中;从而避免了临床试验。
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 muM) and in six primary HNSCC samples (IC50 ~2 muM). 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 mug/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.