Schmidt Karen, Thatcher Amber, Grobe Albert, Broussard Pamela, Hicks Linda, Gu Haiwei, Ellies Lesley G, Sears Dorothy D, Kalachev Leonid, Kroll Eugene
Division of Biological Sciences, University of Montana, Missoula, MT, USA.
Silverlake Research Corporation, Missoula, MT, USA.
Transl Med Commun. 2024;9(1). doi: 10.1186/s41231-024-00178-8. Epub 2024 Jun 22.
Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions.
To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a mild reduction in systemic glucose by controlling both dietary carbohydrates with a ketogenic diet and endogenous glucose production by using metformin on two mouse models of triple-negative breast cancer (TNBC).
Here, we showed that animals with TNBC treated with the combination regimen of ketogenic diet and metformin (a) had their tumor burden lowered by two-thirds, (b) displayed 38% slower tumor growth, and (c) showed 36% longer latency, compared to the animals treated with a ketogenic diet or metformin alone. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse TNBC models by 31 days, approximately equivalent to 3 years of life extension in human terms.
This preclinical study demonstrates that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types that can augment existing treatment options to improve patient outcomes.
许多肿瘤因肿瘤血管生成效率低下而存在缺氧微环境。已证明缺氧肿瘤对传统癌症疗法具有抗性。缺氧癌细胞依靠葡萄糖来满足其能量和合成代谢需求，以推动不受控制的增殖和转移。这种对葡萄糖的依赖性与缺氧条件下的代谢转变有关。
为了利用缺氧肿瘤细胞对葡萄糖的依赖性，我们通过采用生酮饮食控制膳食碳水化合物以及使用二甲双胍控制内源性葡萄糖生成，评估了全身性葡萄糖轻度降低对两种三阴性乳腺癌（TNBC）小鼠模型的影响。
在此，我们表明，与单独采用生酮饮食或二甲双胍治疗的动物相比，采用生酮饮食和二甲双胍联合方案治疗的TNBC动物（a）肿瘤负担降低了三分之二，（b）肿瘤生长速度减慢了38%，（c）潜伏期延长了36%。因此，通过这种饮食和药物联合方法降低全身性葡萄糖水平，使我们的小鼠TNBC模型的总生存期延长了31天，按人类寿命计算大约相当于延长了3年。
这项临床前研究表明，联合生酮饮食和二甲双胍降低全身性葡萄糖水平可显著抑制肿瘤增殖并提高总生存期。我们的研究结果提示了一种针对广泛类型的缺氧和糖酵解肿瘤的可能治疗方法，可增强现有治疗方案以改善患者预后。
