Dataset related to article "Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment"

This record contains data related to article: Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment

Introduction: Treatment options for neuroendocrine tumors (NETs) are rarely curative, as NETs frequently show resistance to medical therapy. The use of everolimus, an mTOR inhibitor, is limited by the development of resistance, probably due to the activation of Akt signaling. In this context, the antidiabetic drug metformin is able to inhibit mTOR, providing a rationale for the use of metformin and everolimus in combination. Methods: We investigated the effects of the metformin and everolimus combination on NET cell proliferation, apoptosis, colony formation, cell viability, NET spheroids growth and the involvement of the Akt and mTOR pathways, and also developed everolimus-resistant NET cells to further study this combination. Results: Metformin and everolimus in combination are more effective than monotherapy in inhibiting pancreatic NET (PAN-NET) cell proliferation (−71% ± 13%, p < 0.0001 vs. basal), whereas no additive effects were observed on pulmonary neuroendocrine tumor (PNT) cell proliferation. The combinatorial treatment is more effective than monotherapy in inhibiting colony formation, cell viability, NET spheroids growth rate and mTOR phosphorylation in both NET cell lines. In a PAN-NET cell line, metformin did not affect Akt phosphorylation; conversely, it significantly decreased Akt phosphorylation in a PNT cell line. Using everolimus-resistant NET cells, we confirmed that metformin maintained its effects, acting by two different pathways: Akt-dependent or independent, depending on the cell type, with both leading to mTOR suppression. Conclusions: Considering the promising effects of the everolimus and metformin combination in NET cells, our results provide a rationale for its use in NET patients.

本数据集关联的研究文章为：《二甲双胍与依维莫司：神经内分泌肿瘤治疗的极具潜力联合方案》

引言：神经内分泌肿瘤（neuroendocrine tumors, NETs）的治疗方案极少可实现根治，因该类肿瘤常对内科治疗产生耐药性。依维莫司作为mTOR抑制剂（mTOR inhibitor），其临床应用受限于耐药性的产生，该耐药性可能与Akt信号通路的激活相关。在此背景下，抗糖尿病药物二甲双胍可抑制mTOR通路，这为二甲双胍与依维莫司的联合使用提供了理论依据。

方法：本研究考察了二甲双胍与依维莫司联合用药对神经内分泌肿瘤细胞增殖、凋亡、集落形成、细胞活力、肿瘤球体生长的影响，以及Akt与mTOR通路的参与机制；同时构建了依维莫司耐药的神经内分泌肿瘤细胞系，以进一步深入探究该联合疗法的作用机制。

结果：相较于单一疗法，二甲双胍与依维莫司联合用药可更有效地抑制胰腺神经内分泌肿瘤（pancreatic NET, PAN-NET）细胞的增殖，抑制率达71% ±13%，p<0.0001（与基础对照组相比），但未观察到其对肺神经内分泌肿瘤（pulmonary neuroendocrine tumor, PNT）细胞增殖产生协同增效作用。联合疗法在抑制两种神经内分泌肿瘤细胞系的集落形成、细胞活力、肿瘤球体生长速率以及mTOR磷酸化水平方面，均优于单一用药方案。在胰腺神经内分泌肿瘤细胞系中，二甲双胍未对Akt磷酸化产生显著影响；而在肺神经内分泌肿瘤细胞系中，其可显著降低Akt磷酸化水平。借助依维莫司耐药的神经内分泌肿瘤细胞系，本研究证实二甲双胍仍可发挥调控作用，其通过两种不同通路实现mTOR抑制：依细胞类型不同，分别为Akt依赖型或非依赖型，且两种通路均可有效抑制mTOR活性。

结论：鉴于二甲双胍与依维莫司联合疗法在神经内分泌肿瘤细胞中展现出的良好应用前景，本研究结果为该联合方案应用于神经内分泌肿瘤患者提供了坚实的理论支撑。