用一种新的葡萄糖激酶激活剂治疗PI3Kα抑制剂诱导的高血糖：推进PI3Kα抑制剂治疗的前沿

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-04-14 DOI:10.1016/j.molmet.2025.102151

Guanqin Jin , Shihuang Liu , Kewei Zheng , Xiaobo Cheng , Ranran Chai , Wei Ye , Wei Wei , Yongguo Li , Ai Huang , Guiling Li , Huan Yi , Yu Kang

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引用次数: 0

摘要

目的：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，常见的高血糖靶不良反应对其临床应用提出了重大挑战。目前迫切需要发现一种能够维持PI3Ki疗效的降糖药物。方法通过对SKOV3和OVCAR3卵巢癌细胞系进行综合研究，探讨外源性高胰岛素血症与PI3Ki的相互作用。我们使用Western blotting、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dorzagliatin的降糖作用。采用细胞系来源的异种移植物（CDX）模型评价dorzagliatin联合PI3Ki的体内肿瘤生长抑制作用。结果western blot分析显示，胰岛素激活AKT/INSR/mTOR通路，逆转pi3ki诱导的p-AKT抑制。胰岛素也能减弱PI3Ki的抗增殖作用。在高血糖小鼠模型中，与对照组相比，dorzagliatin显著降低了血糖水平。联合治疗组（Dorzagliatin + PI3Ki） CDX模型肿瘤体积明显减小。Dorzagliatin不仅可以缓解高血糖，还可以增强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，显示dorzagliatin稳定了血糖水平，促进了体重恢复，并获得了部分缓解（PR）。结论多扎格汀治疗pi3ki相关性高血糖有较好的疗效。肝糖原激酶的激活和胰岛素调节可能是其治疗效果的关键机制。

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Therapeutic management of PI3Kα inhibitor-induced hyperglycemia with a novel glucokinase activator: Advancing the Frontier of PI3Kα inhibitor therapy

Objectives

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.

Methods

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.

Results

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).

Conclusions

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.

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.