Review: Ketogenic diet in the treatment of cancer – Where do we stand? 評論:生酮飲食治療癌症-我們的立場是什麼?

中文版谷歌中文翻譯(90% 準確率) | English translation
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3.1. Methodology of the literature review

This is a literature review in which we highlight some major findings from preclinical and clinical studies which have used some variations of KD as a single or combination therapy in cancer. Table 1, Table 2 of the review contain all studies from 1979 to 2019 listed in PubMed for the search terms “ketogenic diet” and “cancer”. Primary outcome parameters were tumor size/weight or survival. Secondary outcome parameters were alterations in vascularization, glucose up-take at the site of the tumor, gene expression patterns, as well as changes of metabolic parameters. In terms of clinical studies, changes in body composition and tolerance of the KD also were considered as outcome parameters. In total, we found 87 studies including 30 clinical studies and 57 original studies for rodents. In Table 1, Table 2, we summarize the key findings of these studies related to tumor progression, effects on blood glucose levels, and ketosis. In addition, Table 2 includes effects on quality of life as reported in the human studies. In both Table 1, Table 2, we indicate any diet given to a control group as being a control diet (CD) regardless of whether it was standard rodent chow, a matched control diet in preclinical studies or a normal (high carbohydrate/fiber, low fat) diet in clinical studies.
3.2. Preclinical evidence

A growing number of preclinical studies suggests that dietary intervention with a KD is a potent anticancer therapy, albeit some studies reported protumor effects or severe side effects in certain cancer models (Table 1). In most preclinical studies, KD slowed tumor growth, prolonged the survival rate, delayed the initiation of tumors [46], and reversed the process of cancer-induced cachexia [47], [48], [49]. In multiple studies, the KD sensitized cancer cells to classic chemo- [50], [51], [52], [53] or radiotherapies [53], [54], [55]. Furthermore, a study on different mouse cancer models, including pancreatic, bladder, endometrial, and breast cancer as well as acute myeloid leukemia, indicated that the KD enhances the efficacy of targeted therapy, in particular phosphatidylinositol-3 kinase (PI3K) inhibitors, and overcomes drug resistance [56], suggesting that the KD could be part of a multimodal treatment regimen to improve the efficacy of classic cancer therapy.

Some preclinical studies investigated the effect of the KD on metastasis formation, indicating a metastasis reducing potential of the KD [57], [58], [59]. However, preclinical data on KD and metastasis is sparse and urgently needs further investigation.

Several studies addressed the importance of optimizing the composition of the KD to enhance its efficacy, by increasing the proportion of fat or supplementing with MCTs, omega-3 fatty acids or ketone esters [46], [51], [58], [60], [61].

Some studies suggest that a number of metabolic features such as OXPHOS deficiency and/or low levels of ketolytic enzyme expression in cancer cells might be able to predict the effectiveness of KDs in cancer therapy [26], [62]. However, tumors seem to respond differently to a KD despite sharing similar metabolic signatures. For instance, we observed that a KD successfully suppressed the growth of neuroblastoma with OXPHOS deficiency [50], [51], [63], whereas the same KD led to different results in renal cell carcinoma (RCC), even though it presents an energetic profile (OXPHOS deficiency) similar to that of neuroblastoma [64]. Furthermore, the KD had no effect on the growth rate of rat glioma irrespective of the ability of the tumor cells to transport and oxidize ketone bodies [65].

Based on preclinical observations, the efficacy of KDs could be influenced by cancer type or even subtype, genetic background, or a tumor-associated syndrome [66]. For example, we observed that the anti-neuroblastoma effect of a KD was considerably attenuated in SK-N-BE(2) neuroblastoma xenografts, which carry MYCN amplification, TP53 mutation (p.C135F) and chromosome 1p loss of heterozygosity, compared to SH-SY5Y xenografts which are TP53 wild-type, non-MYCN-amplified [51].

In addition, in a mouse model of melanoma, acceleration of proliferation in BRAF V600E-mutated melanoma cells upon treatment with a KD was observed, due to selectively increased activation of BRAF V600E mutant-dependent MEK1 signaling by the ketone body AcAc. In contrast, NRAS Q61K- and Q61R-mutated as well as BRAF wild-type melanoma cells were unaffected by the KD [67]. Mice bearing RCC exhibited dramatic weight loss and liver dysfunction in response to the KD, most likely due to having features of Stauffer’s syndrome [64], indicating that in certain patients with RCC, KD could be contraindicated.

Therefore, it is very important to evaluate the effect of a KD in preclinical studies for every specific type of tumor before recommending it to cancer patients, taking into account the different genetic alterations and tumor-associated syndromes. Furthermore, it is important to pay attention to the mechanism behind the antitumor effects of the KD. Understanding the mechanisms of KD therapy could assist in predicting the success rates of KDs against different types of cancer.

In summary, 60% of the preclinical studies shown in Table 1 reported an antitumor effect of KDs, 17% did not detect an influence on tumor growth and 10% reported adverse or pro-proliferative effects. In 10% of the preclinical studies, a statement on the effect on cancer cells cannot be made due to the lack of proper control groups. 3% of the preclinical studies did not report data on tumor progression but investigated the effect of the KD on tumor microvasculature, gene expression or glucose up-take. Most of the studies were performed in glioblastoma models and no adverse effects were observed. Accordingly, a majority of clinical studies are currently being performed on patients with glioblastoma [https://clinicaltrials.gov/].

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