Roles of 2-Deoxyglucose in the Treatment of Papillary Thyroid Carcinoma and Neuroblastoma

• Main Authors: Shuo Yu Wang, 王碩郁
• Other Authors: J. H. Chuang
• Format: Others
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/81117773642412890544

博士 === 長庚大學 === 臨床醫學研究所 === 103 === The purpose of this research was to investigate the changes in mitochondrial DNA (mtDNA) associated with the BRAFV600E mutation in papillary thyroid carcinoma (PTC), and the role of 2-deoxyglucose (2-DG), a glycolysis inhibitor, in PTC and neuroblastoma (NB). PTC is the most common form of thyroid cancer, and the BRAFV600E mutation is the most common genetic aberration. MtDNA mutations and the changes of mtDNA content were thought to facilitate chemotherapy resistance in cancer cells. Less than 20% of human PTC shows somatic D-loop mutation and mtDNA 4977 bp deletion. Moreover, an increase of mtDNA content in PTC is associated with the BRAFV600E mutation. The bioenergetic function and response to 2-DG of two PTC cell lines, BCPAP cells (with the BRAFV600E mutation) and CG3 cells (without the BRAFV600E mutation), were studied. BCPAP cells are more glycolytic than CG3 cells, and energy depletion is responsible for inhibiting proliferation of both PTC cells. Chemosensitivity to doxorubicin and sorafenib, two USFDA-approved drugs for treating advanced PTC, increased in both cell lines when combination with 2-DG for 48 h. The IC50 of doxorubicin in BCPAP and CG3 cells fell by more than 30%, and the IC50 of sorafenib in both cells also fell by more than 50% when combined therapy with only 0.0625 mM 2-DG. This suggests that 2-DG with lower doses of either doxorubicin or sorafenib will provide anticancer effects which can otherwise be achieved only with high doses of doxorubicin or sorafenib alone, regardless of the status of the BRAFV600E mutation. Because of its significantly positive effects on PTC, the effects of 2-DG on NB was investigated. NB is the most common extracranial solid tumor in childhood with wide genetic variations. MYCN amplification in NB is correlated with glycolysis and resistance to treatment. We implanted the MYCN-amplified SK-N-DZ and the MYCN-nonamplified SK-N-AS cell lines into the subcutaneous tissue of NOD/SCID mice with 6 intraperitoneal injections of normal saline or 2-DG (2 doses per week). Our results demonstrated tumor shrinkage was significant in mice treated with 2-DG, regardless of MYCN amplification or not. 2-DG inhibited tumor growth by downregulating HIF-1, PDK1, and p-BAD in both NB xenografts and downregulating c-Myc in SK-N-AS xenografts. Moreover, 2-DG inhibited angiogenesis by apoptosis and suppressing lamellipodia and filopodia formation of endothelial cells. Our findings indicate that 2-DG treatment in mice simultaneously targeted tumor cells and cancerous endothelial cells. Taken together, our findings indicate that 2-DG, alone or combined with other chemotherapeutic agents, might provide novel and more efficacious therapy for patients with PTC and NB.