Dichloroacetate and Quercetin Prevent Cell Proliferation, Induce Cell Death and Slow Tumor Growth in a Mouse Model of HPV-Positive Head and Neck Cancer.

Simple Summary: The metabolism of cancer cells and the tumor microenvironment are of increasing interest as part of ongoing efforts to develop potential adjuvant therapies to be used along with conventional chemotherapy and radiation. In this report, the antitumor properties of two compounds that affect glucose metabolism, dichloroacetate and quercetin, are examined. Both DCA and quercetin, a naturally occurring plant flavonoid found in fruits and vegetables, demonstrate inhibitory effects on the growth of head and neck cancer both in cell culture and in a preclinical mouse model of head and neck cancer. These two compounds have synergistic antitumor effects when combined, both in vitro and in vivo. The drug combination inhibited tumor growth and induced cell death with the maintenance of an unfavorable tumor microenvironment. The altered tumor microenvironment appears to enhance immune-mediated clearance of tumors. Thus, this study supports additional preclinical research to further explore the antitumor effects of DCA and quercetin. 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. [ABSTRACT FROM AUTHOR]