Dichloroacetate and Quercetin Prevent Cell Proliferation, Induce Cell Death and Slow Tumor Growth in a Mouse Model of HPV-Positive Head and Neck Cancer.
Yongxian ZhuangJoseph D CoppockAllison B HaugrudJohn H LeeShanta M MesserliW Keith MiskiminsPublished in: Cancers (2024)
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.
Keyphrases
- cell death
- mouse model
- cell proliferation
- immune response
- high grade
- endoplasmic reticulum stress
- dna damage
- papillary thyroid
- signaling pathway
- blood pressure
- regulatory t cells
- type diabetes
- tyrosine kinase
- adipose tissue
- mass spectrometry
- cell cycle
- electronic health record
- peripheral blood
- reactive oxygen species
- skeletal muscle
- wild type
- high speed
- squamous cell