Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Cell Cycle. 2012 Jun 15;11(12):2314-26. doi: 10.4161/cc.20770.
Hyperglycemia during hyper-CVAD chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL) (Cancer 2004; 100: 1179-85). The optimal clinical strategy to manage hyperglycemia during hyper-CVAD is unclear. To examine whether anti-diabetic pharmacotherapy can influence chemosensitivity of ALL cells, we examined the impacts of different anti-diabetic agents on ALL cell lines and patient samples. Pharmacologically achievable concentrations of insulin, aspart and glargine significantly increased the number of ALL cells, and aspart and glargine did so at lower concentrations than human insulin. In contrast, metformin and rosiglitazone significantly decreased the cell number. Human insulin and analogs activated AKT/mTOR signaling and stimulated ALL cell proliferation (as measured by flow cytometric methods), but metformin and rosiglitazone blocked AKT/mTOR signaling and inhibited proliferation. Metformin 500 μM and rosiglitazone 10 μM were found to sensitize Reh cells to daunorubicin, while aspart, glargine and human insulin (all at 1.25 mIU/L) enhanced chemoresistance. Metformin and rosiglitazone enhanced daunorubicin-induced apoptosis, while insulin, aspart and glargine antagonized daunorubicin-induced apoptosis. In addition, metformin increased etoposide-induced and L-asparaginase-induced apoptosis; rosiglitazone increased etoposide-induced and vincristine-induced apoptosis. In conclusion, our results suggest that use of insulins to control hyperglycemia in ALL patients may contribute to anthracycline chemoresistance, while metformin and thiazolidinediones may improve chemosensitivity to anthracycline as well as other chemotherapy drugs through their different impacts on AKT/mTOR signaling in leukemic cells. Our data suggest that the choice of anti-diabetic pharmacotherapy during chemotherapy may influence clinical outcomes in ALL.
高血糖症在高剂量环磷酰胺、阿霉素、长春新碱和地塞米松化疗期间与急性淋巴细胞白血病（ALL）的不良预后相关（Cancer 2004; 100: 1179-85）。目前，尚不清楚在高剂量环磷酰胺、阿霉素、长春新碱和地塞米松化疗期间管理高血糖症的最佳临床策略。为了研究抗糖尿病药物治疗是否会影响 ALL 细胞的化疗敏感性，我们研究了不同的抗糖尿病药物对 ALL 细胞系和患者样本的影响。在可达到的药理学浓度下，胰岛素、门冬氨酸和甘精胰岛素显著增加了 ALL 细胞的数量，且门冬氨酸和甘精胰岛素所需的浓度低于人胰岛素。相比之下，二甲双胍和罗格列酮显著减少了细胞数量。人胰岛素和类似物激活了 AKT/mTOR 信号通路，并刺激了 ALL 细胞增殖（通过流式细胞术方法测量），但二甲双胍和罗格列酮阻断了 AKT/mTOR 信号通路并抑制了增殖。发现二甲双胍 500 μM 和罗格列酮 10 μM 可使 Reh 细胞对柔红霉素敏感，而门冬氨酸、甘精胰岛素和人胰岛素（均为 1.25 mIU/L）则增强了耐药性。二甲双胍和罗格列酮增强了柔红霉素诱导的细胞凋亡，而胰岛素、门冬氨酸和甘精胰岛素则拮抗了柔红霉素诱导的细胞凋亡。此外，二甲双胍增加了依托泊苷诱导的和 L-天冬酰胺酶诱导的细胞凋亡；罗格列酮增加了依托泊苷诱导的和长春新碱诱导的细胞凋亡。总之，我们的结果表明，在 ALL 患者中使用胰岛素控制高血糖症可能导致蒽环类药物耐药性增加，而二甲双胍和噻唑烷二酮类药物可能通过对白血病细胞中 AKT/mTOR 信号通路的不同影响，改善蒽环类药物以及其他化疗药物的化疗敏感性。我们的数据表明，在化疗期间选择抗糖尿病药物治疗可能会影响 ALL 的临床结局。
