University of Milan. Department of Oncology and Hemato-Oncology, Milan, Italy.
IFOM, FIRC Institute of Molecular Oncology, Milan, Italy.
Nat Commun. 2020 May 11;11(1):2332. doi: 10.1038/s41467-020-16243-3.
Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors.
断食模拟饮食可延缓肿瘤进展，并使多种肿瘤对化疗敏感，但人们对其与非细胞毒性化合物联合治疗的潜在疗效知之甚少。本研究表明，维生素 C 的抗癌活性受到应激诱导蛋白血红素加氧酶-1（HO-1）上调的限制。断食模拟饮食可选择性地逆转 KRAS 突变型癌细胞中维生素 C 诱导的 HO-1 和铁蛋白上调，从而增加活性铁、氧自由基和细胞死亡；这种作用可通过化疗进一步增强。为了支持铁蛋白在结直肠癌进展中的潜在作用，对癌症基因组图谱数据库的分析表明，KRAS 突变型结直肠癌患者肿瘤内铁蛋白 mRNA 水平较低，其 3 年和 5 年总生存率较长。总的来说，我们的数据表明，断食模拟饮食与维生素 C 的联合应用代表了一种有前途的低毒性干预措施，值得在针对结直肠癌和可能其他 KRAS 突变肿瘤的随机临床试验中进行测试。
