Elevated glucose uptake and production of lactate are common features of cancer cells. Among many tumor-promoting effects, lactate inhibits immune responses and is positively correlated with radioresistance. Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase that decreases lactate production. Quercetin is a flavonoid compound found in fruits and vegetables that inhibits glucose uptake and lactate export. We investigated the potential role and mechanisms of DCA, quercetin, and their combination, in the treatment of HPV-positive head and neck squamous cell carcinoma, an antigenic cancer subtype in need of efficacious adjuvant therapies. C57Bl/6-derived mouse oropharyngeal epithelial cells, a previously developed mouse model that was retrovirally transduced with HPV type-16 E6/E7 and activated Ras, were used to assess these compounds. Both DCA and quercetin inhibited colony formation and reduced cell viability, which were associated with mTOR inhibition and increased apoptosis through enhanced ROS production. DCA and quercetin reduced tumor growth and enhanced survival in immune-competent mice, correlating with decreased proliferation as well as decreased acidification of the tumor microenvironment and reduction of Foxp (+) Treg lymphocytes. Collectively, these data support the possible clinical application of DCA and quercetin as adjuvant therapies for head and neck cancer patients.
癌细胞通常具有葡萄糖摄取增加和乳酸生成增多的特征。在众多促癌效应中，乳酸可抑制免疫应答，并与放射抵抗性呈正相关。二氯乙酸（DCA）作为丙酮酸脱氢酶激酶抑制剂，可降低乳酸生成。槲皮素是一种存在于果蔬中的黄酮类化合物，能抑制葡萄糖摄取和乳酸外排。本研究探讨了DCA、槲皮素及其联合用药在治疗HPV阳性头颈部鳞状细胞癌（一种亟需有效辅助疗法的抗原性癌症亚型）中的潜在作用机制。通过使用C57Bl/6来源的小鼠口咽上皮细胞（该模型系通过逆转录病毒转导HPV-16型E6/E7基因并激活Ras构建的小鼠模型）评估这些化合物。研究发现DCA与槲皮素均能抑制细胞集落形成、降低细胞活力，其作用机制与抑制mTOR通路及通过增强活性氧生成促进细胞凋亡相关。在免疫健全小鼠模型中，DCA和槲皮素能抑制肿瘤生长并延长生存期，这与肿瘤增殖减弱、肿瘤微环境酸化程度降低以及Foxp3（+）调节性T淋巴细胞减少密切相关。综上所述，本研究数据支持DCA与槲皮素作为头颈癌患者辅助疗法的潜在临床应用价值。
肿瘤(癌症)患者之家