PO.TB10.05 · 肿瘤生物学
研究SGLT2抑制剂达格列净对肥胖小鼠急性淋巴细胞白血病的影响
Investigating the effect of SGLT2 inhibitor dapagliflozin on acute lymphoblastic leukemia in obese mice
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
在急性淋巴细胞白血病（ALL）诊断时肥胖的患者复发率高出50%。我们已证明饮食和运动可改善小鼠和患者的ALL治疗结局，但由于经济和后勤障碍，这些干预措施可能难以实施。诱导减重或代谢改变的替代干预措施在现实治疗中可能更易获得。SGLT2抑制剂达格列净（DAPA）是一种糖尿病药物，可抑制肾脏葡萄糖重吸收、降低血糖并诱导适度减重。已证明其可改善心力衰竭和慢性肾病的结局。在小鼠中，SGLT2抑制剂已被证明可减缓肿瘤生长，并在肝癌、结肠癌和乳腺癌中与化疗协同。然而，尚无研究在ALL中检验SGLT2抑制剂。我们研究了SGLT2抑制是否可能成为饮食和运动的替代方案以改善ALL结局。人（BV173、RS4;11）和小鼠（8093）ALL细胞系经qPCR检测表达Sglt2（n=4）。DAPA在体外与化疗药物长春新碱（VCR）显示协同效应（见表）。对肥胖雄性C57Bl/6小鼠给予DAPA治疗（3 mg/kg/天，溶于水中，28天）诱导尿糖丢失（2 g/dL对不可检测，n=12）并降低血糖（179±17对203±14 mg/dL，p=0.008，n=6）。作为单药治疗，DAPA在同基因ALL模型中减缓但未阻止ALL进展（中位生存期：18对21天，p=0.027 log rank检验，n=6）。令人意外的是，DAPA与VCR联用导致的死亡率高于VCR单用（83%对33%死亡率，p=0.047 log rank检验，n=6）。开发基于药物的饮食/运动干预替代方案对于确保所有ALL患者都能从代谢干预中获益十分重要。我们的研究表明，SGLT2抑制在体外有效，但体内数据提示其可能不是改善ALL治疗结局的可行选择。
表 细胞系 对照（x10^6） VCR（2-2.5 nM） DAPA（10 μM） VCR+DAPA P值（VCR对VCR+DAPA） BV173 1.95±0.45 1.70±0.25 1.73±0.38 1.21±0.51 0.037 RS4;11 1.27±0.42 1.15±0.28 1.19±0.33 0.71±0.19 0.035 8093 3.61±0.58 3.30±0.46 2.74±0.48 1.95±0.63 0.048
查看英文原文 English abstract
Patients who are obese at diagnosis of acute lymphoblastic leukemia (ALL) have a 50% higher relapse rate. We showed that diet and exercise can improve ALL treatment outcome in mice and patients, but these interventions can be difficult due to financial and logistical barriers. Alternative interventions that induce weight-loss or metabolic changes could prove more accessible in real-world treatment. The SGLT2 inhibitor dapagliflozin (DAPA) is a diabetes medication that inhibits renal glucose reabsorption, lowers blood glucose, and induces modest weight loss. It has been shown to improve outcomes of heart failure and chronic kidney disease. In mice, SGLT2 inhibitors have been shown to slow tumor growth and synergize with chemotherapy in liver, colon, and breast cancer. However, no studies have tested SGLT2 inhibitors on ALL. We investigated whether SGLT2 inhibition might be an alternative to diet and exercise to improve ALL outcome. Human (BV173, RS4;11) and mouse (8093) ALL cell lines expressed Sglt2 by qPCR (n=4). DAPA showed synergistic effects with chemotherapy vincristine (VCR) in vitro (Table). DAPA treatment (3 mg/kg/day in water, 28 days) in obese male C57Bl/6 mice induced glucose loss in urine (2 g/dL vs. undetectable, n=12) and decreased blood glucose (179±17 vs. 203±14 mg/dL, p=0.008, n=6). As monotherapy, DAPA slowed but did not halt ALL progression in a syngeneic ALL model (median survival: 18 vs. 21 days, p=0.027 log rank, n=6). Surprisingly, combining DAPA with VCR resulted in higher mortality than VCR alone (83 vs. 33% mortality, p=0.047 log rank, n=6). Developing medication-based alternatives to diet/exercise interventions is important to ensure all patients with ALL can benefit from metabolic-interventions. Our study shows that SGLT2 inhibition is effective in vitro, but in vivo data imply it may not be a viable option for improving ALL treatment outcome.
Table Cell Line Control (x10 6 ) VCR (2-2.5 nM) DAPA (10 μM) VCR+DAPA P value (VCR vs VCR + DAPA) BV173 1.9 5± 0.45 1.70 ± 0.25 1.73 ±0.38 1.21±0.51 0.037 RS4;11 1.27±0.42 1.15±0.28 1.19±0.33 0.71±0.19 0.035 8093 3.61 ±0.5 8 3. 30± 0.46 2.74 ± 0.48 1.95±0.63 0.048
利益披露 Disclosure
J. Tan, None..
T. Tran, None..
T. Kuk, None..
H. Leng, None..
M. Cohen, None..
E. Orgel, None..
S. D. Mittelman, None.