PO.MCB09.01 · 分子与细胞生物学
在高脂/高果糖饮食喂养期间，基于二甲双胍的预防与治疗策略对三阴性乳腺癌（TNBC）相关异常代谢信号/分子特征的差异性影响
Differential impact of metformin based prevention and therapeutic strategies on aberrant metabolic signals/ molecular signatures associated with triple negative breast cancer (TNBC) during high fat/ high fructose diet feeding
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摘要 Abstract
中文摘要
二甲双胍常规用于 2 型糖尿病（T2D）的管理，以其改变线粒体呼吸驱动的能量应激的潜力而著称。有趣的是，二甲双胍也一直是癌症研究的焦点，因为多项研究结果将其摄入与抗癌益处联系起来。在本研究中，我们确定了口服二甲双胍预防性方案与治疗性方案对 TNBC 肿瘤发生的比较性抗癌效应。鉴于二甲双胍的抗癌益处主要在与肥胖/T2D 等代谢异常相关的病例中观察到，相应地，该体内临床前研究在饮食诱导肥胖小鼠模型（DIO 小鼠）中进行，其中四周龄 C57Bl/6 雌性小鼠在整个研究过程中被喂食高脂饮食（HFD，60 kcal% 脂肪）或高果糖饮食（HFR，60 kcal% 果糖），以在全身和局部乳腺微环境中诱导可影响乳腺肿瘤发生的肥胖相关变化。在分别进行 10 周 DIO 喂养后（小鼠 14 周龄时），通过在第 4 乳腺脂肪垫（左侧或右侧）皮下注射 2×10^6 个 PY230 乳腺癌细胞诱导原位乳腺肿瘤。在预防性方案中，二甲双胍（预处理）治疗（每日灌胃：300mg/kg 体重）在细胞接种前 4 周开始，持续至细胞接种后 2 周，随后为约 6 周的洗脱期直至研究结束（细胞接种后约 8 周）。另一方面，在治疗性方案中，二甲双胍（后处理）治疗（每日灌胃：300mg/kg 体重）在细胞接种后 2 周开始，持续至细胞接种后约 6 周（直至研究结束）。总体而言，结果表明，尽管二甲双胍的预防性和治疗性方案对 TNBC 生长和进展均具有抗肿瘤效应，但预防性方案即使在洗脱期后（无药物给药）仍具有持久的抗癌效应，相对优于对 TNBC 肿瘤的治疗性处理。在非靶向代谢组学分析中，HFD 和 HFR 两组中观察到的代谢改变提示二甲双胍具有恢复肿瘤微环境代谢稳态的潜力。在非靶向脂质组学分析中，二甲双胍的预防和治疗效应体现在对多种脂质类别的调节上。具体而言，预防性方案似乎产生更显著的脂质改变，提示早期干预在调节癌症进展方面的潜在益处。
查看英文原文 English abstract
Metformin is routinely used in the management of type-2 diabetes (T2D) and is known for its potential to alter mitochondrial respiration-driven energetic stress. Interestingly, metformin has also been the focus of cancer research because various study outcomes have associated its intake with anti-cancer benefits. In the present study, we determined the comparative anti-cancer effects of preventive versus therapeutic regimen of oral metformin against TNBC tumorigenesis. Given that the anti-cancer benefits of metformin are observed mostly in cases associated with metabolic aberrations such as obesity/T2D, accordingly, the in vivo preclinical study was performed in diet-induced obese mice model (DIO mice) wherein four week old C57Bl/6 female mice were fed either a high fat diet (HFD, 60 kcal% fats) or high fructose diet (HFR, 60 kcal% fructose ) throughout the course of the study so as to induce obesity-associated changes in both systemic and local mammary gland microenvironment that could impact breast tumorigenesis. After 10 weeks of respective DIO feeding (at 14 weeks of mice age), orthotopic mammary tumors were induced by subcutaneous injection of 2x10 6 PY230 breast cancer cells in the 4 th mammary fat pad (either left or right). In the preventive regimen metformin (pre) treatment (daily oral gavage: 300mg/kg body wt.) was started 4 weeks before the cell inoculation and continued till 2 weeks after the cell inoculations followed by a wash out period of 6 weeks till study end (8 weeks following cell inoculations). On the other hand, in the therapeutic regimen, metformin (post) treatment (daily oral gavage: 300mg/kg body wt.) was started 2 weeks after the cell inoculation and continued till 6 weeks after the cell inoculations (till study end). Overall, the results indicated that while both preventive and therapeutic regimens of metformin had an anti-tumorigenic effect on TNBC growth and progression, the preventive regimen even after the washout period (no drug administration) had long lasting anti-cancer effect which was comparatively better than therapeutic treatment of TNBC tumors. In untargeted metabolomic profiling, the observed metabolic alterations in both the HFD and HFR groups suggest that metformin has the potential to restore metabolic homeostasis in the tumor microenvironment. In untargeted lipidomics profiling, metformin's preventive and therapeutic effects were evident in the modulation of multiple lipid classes. Specifically, the preventive regimen appeared to yield more pronounced lipid alterations, indicating the potential benefits of early intervention in modulating cancer progression.
利益披露 Disclosure
M. I. Kabir, None..
R. Kumar, None..
L. Bugata, None..
M. N. Islam, None..
S. A. Mitu, None..
K. Raina, None.