Jin Guanqin, Liu Shihuang, Zheng Kewei, Cheng Xiaobo, Chai Ranran, Ye Wei, Wei Wei, Li Yongguo, Huang Ai, Li Guiling, Yi Huan, Kang Yu
Clinical Research Center, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, 200011, China; Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
Department of Gynecologic Oncology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China; Fujian Province Key Clinical Specialty for Gynecology, Fujian Key Laboratory of Women and Children's Critical Diseases Research, National Key Gynecology Clinical Specialty Construction Institution of China, Fuzhou, 350001, China.
Mol Metab. 2025 Jun;96:102151. doi: 10.1016/j.molmet.2025.102151. Epub 2025 Apr 14.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pivotal target in cancer treatment, driving substantial investigation into PI3K inhibitors (PI3Ki). However, the common on-target adverse effect of hyperglycemia presents a substantial challenge to their clinical application. There is an urgent need to discover an anti-hyperglycemic agent that maintains the efficacy of PI3Ki.
We conducted a comprehensive study to explore the interaction between exogenous hyperinsulinemia and PI3Ki in SKOV3 and OVCAR3 ovarian cancer cell lines. We used Western blotting, CCK-8, and EdU assays to determine the effect of this interaction on cell proliferation. In addition, we evaluated the anti-hyperglycemic effects of dorzagliatin in a PI3Ki-induced hyperglycemic mice model. Cell line-derived xenograft (CDX) models were employed to evaluate the in vivo tumor growth inhibitory effects of combining dorzagliatin with PI3Ki.
Western blot analysis demonstrated that insulin activated the AKT/INSR/mTOR pathway, reversing PI3Ki-induced p-AKT inhibition. Insulin also attenuated the anti-proliferative effects of PI3Ki. In the hyperglycemic mouse model, dorzagliatin significantly reduced blood glucose levels compared to controls. The combination therapy group (Dorzagliatin + PI3Ki) in CDX models showed a marked reduction in tumor volume. Dorzagliatin not only mitigated hyperglycemia but also enhanced the anti-tumor effects of PI3Ki. A clinical trial (NCT06117566) in cervical cancer patients supported these findings, showing that dorzagliatin stabilized blood glucose levels, facilitated body weight recovery, and achieved a confirmed partial response (PR).
Dorzagliatin shows promise for managing PI3Ki-associated hyperglycemia, thereby enhancing its therapeutic efficacy. The activation of liver glycogen kinase and insulin regulation may be key mechanisms underlying its therapeutic benefits.
磷脂酰肌醇3激酶（PI3K）信号通路是癌症治疗的关键靶点，推动了对PI3K抑制剂（PI3Ki）的大量研究。然而，高血糖这一常见的靶向不良反应对其临床应用构成了重大挑战。迫切需要发现一种能维持PI3Ki疗效的抗高血糖药物。
我们进行了一项全面研究，以探讨外源性高胰岛素血症与PI3Ki在SKOV3和OVCAR3卵巢癌细胞系中的相互作用。我们使用蛋白质免疫印迹法、CCK-8和EdU检测来确定这种相互作用对细胞增殖的影响。此外，我们在PI3Ki诱导的高血糖小鼠模型中评估了多扎格列艾汀的抗高血糖作用。采用细胞系来源的异种移植（CDX）模型评估多扎格列艾汀与PI3Ki联合使用时的体内肿瘤生长抑制作用。
蛋白质免疫印迹分析表明，胰岛素激活了AKT/INSR/mTOR通路，逆转了PI3Ki诱导的p-AKT抑制。胰岛素还减弱了PI3Ki的抗增殖作用。在高血糖小鼠模型中，与对照组相比，多扎格列艾汀显著降低了血糖水平。CDX模型中的联合治疗组（多扎格列艾汀+PI3Ki）肿瘤体积明显减小。多扎格列艾汀不仅减轻了高血糖，还增强了PI3Ki的抗肿瘤作用。一项针对宫颈癌患者的临床试验（NCT06117566）支持了这些发现，表明多扎格列艾汀稳定了血糖水平，促进了体重恢复，并实现了确认的部分缓解（PR）。
多扎格列艾汀有望用于管理与PI3Ki相关的高血糖，从而提高其治疗效果。肝糖原激酶的激活和胰岛素调节可能是其治疗益处的关键机制。
