Khan Tashbib, He Yaowu, Kryza Thomas, Harrington Brittney S, Gunter Jennifer H, Sullivan Mitchell A, Cuda Tahleesa, Rogers Rebecca, Davies Claire M, Broomfield Amy, Gough Madeline, Wu Andy C, McGann Thomas, Weroha S John, Haluska Paul, Forbes Josephine M, Armes Jane E, Barry Sinead C, Coward Jermaine I, Jagasia Nisha, Chetty Naven, Snell Cameron E, Lourie Rohan, Perrin Lewis C, Hooper John D
Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, Brisbane, QLD 4102, Australia.
Cancers (Basel). 2020 Apr 3;12(4):869. doi: 10.3390/cancers12040869.
High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses-of more than 10-fold lower than previously reported for other cancers-significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.
高级别和复发性卵巢透明细胞癌（OCC）预后较差且对化疗耐药。OCC的一个显著组织学特征是细胞质中以糖原形式存在的丰富葡萄糖储备，可用于细胞代谢。在此，我们报告了使用葡萄糖类似物2-脱氧-D-葡萄糖（2DG）破坏糖原利用对OCC临床前模型的影响。在远低于先前报道的其他癌症的浓度下，2DG显著提高了卡铂化疗对化疗敏感的TOV21G和化疗耐药的OVTOKO OCC细胞系的体外疗效，同时伴随着糖原的消耗。值得注意的是，2DG的剂量比先前报道的其他癌症低10倍以上，能显著提高卡铂对模拟OCC化疗反应性的小鼠细胞系和患者来源异种移植模型的疗效。这些发现令人鼓舞，因为2DG的剂量远低于先前报道的在癌症患者中引起不良事件的剂量，可安全且显著提高卡铂对OCC的疗效。因此，我们的结果为评估低剂量2DG是否能提高卡铂对OCC患者疗效的临床试验提供了依据。
