Non-radioactive 2-deoxy-2-fluoro-D-glucose inhibits glucose uptake in xenograft tumours and sensitizes HeLa cells to doxorubicin in vitro

A glucose analog called 2-deoxy-D-glucose (2DG) has been successfully used to sensitize cancer cells to ROS-inducing cancer treatments such as ionizing radiation, through the inhibition of glycolysis. However, the use of 2DG can be limited by several factors such as availability, non-specific cytotoxicity, and chemoresistance under hypoxic conditions. The purpose of this study was to investigate the use of non-radioactive 2-deoxy-2-fluoro-D-glucose (19FDG), a drug that potentially addresses current limitations of 2DG. The effectiveness of using either 2DG or 19FDG in combination with doxorubicin (Dox) in HeLa cells was determined in both normoxia and hypoxia. We have also shown that under both oxygen conditions, 19FDG-treated cells produce less lactate than 2DG-treated cells, an important finding that suggests improved inhibition of glycolysis, the preferential pathway for cancerous cells. When used in combination with Dox, we have demonstrated a significant decrease in the number of viable cells, with the effect of 19FDG remaining stable across both normoxic and hypoxic conditions. Moreover, the assessment of apoptosis and necrosis revealed that 19FDG maintained its ability to sensitize HeLa cells to Dox in hypoxia, but 2DG was only effective under normoxic conditions. The retained effectiveness of 19FDG in combination with Dox under hypoxic conditions, suggests that 19FDG may be efficacious for sensitizing hypoxic regions of solid tumour masses. Importantly, the ability of 19FDG to inhibit glucose uptake in vivo was also confirmed using positron emission tomography (PET) of xenograft tumours. The results displayed here suggest 19FDG is a promising combination therapy, which may lead to decreased ROS scavenging via glycolysis, and enhanced treatment success.葡萄糖类似物2-脱氧-D-葡萄糖(2-deoxy-D-glucose, 2DG)已被证实可通过抑制糖酵解，使癌细胞对电离辐射等诱导活性氧（Reactive Oxygen Species, ROS）的癌症治疗手段增敏。但2DG的临床应用受限于诸多因素，包括药物可及性、非特异性细胞毒性，以及缺氧环境下的化疗耐药性。本研究旨在探究非放射性2-脱氧-2-氟-D-葡萄糖(19FDG)的应用价值，该药物有望解决2DG当前存在的上述局限。我们在常氧与缺氧两种培养条件下，检测了2DG或19FDG分别与阿霉素(doxorubicin, Dox)联合使用时，对海拉(HeLa)细胞的作用效果。研究同时发现，在两种氧环境中，经19FDG处理的细胞乳酸生成量均低于2DG处理组，这一关键结果提示19FDG对癌细胞的偏好代谢通路——糖酵解的抑制效果更为优异。当与Dox联合给药时，两种药物均可显著降低活细胞数量，且19FDG的增敏效果在常氧与缺氧条件下均保持稳定。进一步的细胞凋亡与坏死检测显示，19FDG仍可在缺氧环境下使HeLa细胞对Dox产生增敏作用，而2DG仅在常氧条件下展现出有效增敏效果。19FDG在缺氧条件下与Dox联合使用时仍能维持疗效，这表明其有望用于使实体瘤的缺氧区域获得治疗增敏。值得一提的是，本研究通过异种移植瘤的正电子发射断层扫描(positron emission tomography, PET)，证实了19FDG在体内抑制葡萄糖摄取的能力。本研究结果表明，19FDG是一种极具潜力的联合治疗方案，其可通过削弱糖酵解介导的活性氧清除能力，提升癌症治疗的整体成功率。