Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities
Authors: Duaa Jamal
Asma Ismail Mahmod
Aya M D Alashqar
Wamidh H Talib
Ayah Kamal
Samar Khater
Hasan M Rashid
Mostafa Waly
Journal: Current Issues in Molecular Biology (2021)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: alternative cancer therapies; anticancer diet; calories restriction; targeting cancer metabolism.

Abstract:  Although cancer is still one of the most significant global challenges facing public health, the world still lacks complementary approaches that would significantly enhance the efficacy of standard anticancer therapies. One of the essential strategies during cancer treatment is following a healthy diet program. The ketogenic diet (KD) has recently emerged as a metabolic therapy in cancer treatment, targeting cancer cell metabolism rather than a conventional dietary approach. The ketogenic diet (KD), a high-fat and very-low-carbohydrate with adequate amounts of protein, has shown antitumor effects by reducing energy supplies to cells. This low energy supply inhibits tumor growth, explaining the ketogenic diet's therapeutic mechanisms in cancer treatment. This review highlights the crucial mechanisms that explain the ketogenic diet's potential antitumor effects, which probably produces an unfavorable metabolic environment for cancer cells and can be used as a promising adjuvant in cancer therapy. Studies discussed in this review provide a solid background for researchers and physicians to design new combination therapies based on KD and conventional therapies. 

Retracted: No

PubPeer comments:
 # This review article is the latest in a long line of similar review articles over more than a decade, each rehashing the same, largely unsupported, claims of emerging evidence for the ketogenic diet as a promising prevention and treatment modality for various types of cancer. With each subsequent review article, some fundamental errors, unfounded claims, and misrepresentations are propagated throughout the literature as the list of references grows longer each time. The present article s abstract: Although cancer is still one of the most significant global challenges facing public health, the world still lacks complementary approaches that would significantly enhance the efficacy of standard anticancer therapies. One of the essential strategies during cancer treatment is following a healthy diet program. The ketogenic diet (KD) has recently emerged as a metabolic therapy in cancer treatment, targeting cancer cell metabolism rather than a conventional dietary approach. The ketogenic diet (KD), a high-fat and very-low-carbohydrate with adequate amounts of protein, has shown antitumor effects by reducing energy supplies to cells. This low energy supply inhibits tumor growth, explaining the ketogenic dietu2019s therapeutic mechanisms in cancer treatment. This review highlights the crucial mechanisms that explain the ketogenic dietu2019s potential antitumor effects, which probably produces an unfavorable metabolic environment for cancer cells and can be used as a promising adjuvant in cancer therapy. Studies discussed in this review provide a solid background for researchers and physicians to design new combination therapies based on KD and conventional therapies. ## Compare the similarities to  Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism 2014 from Bryan G. Allen et al Abstract: Cancer cells, relative to normal cells, demonstrate significant alterations in metabolism that are proposed to result in increased steady-state levels of mitochondrial-derived reactive oxygen species (ROS) such as O2u2022u2212and H2O2. It has also been proposed that cancer cells increase glucose and hydroperoxide metabolism to compensate for increased levels of ROS. Given this theoretical construct, it is reasonable to propose that forcing cancer cells to use mitochondrial oxidative metabolism by feeding ketogenic diets that are high in fats and low in glucose and other carbohydrates, would selectively cause metabolic oxidative stress in cancer versus normal cells. Increased metabolic oxidative stress in cancer cells would in turn be predicted to selectively sensitize cancer cells to conventional radiation and chemotherapies. This review summarizes the evidence supporting the hypothesis that ketogenic diets may be safely used as an adjuvant therapy to conventional radiation and chemotherapies and discusses the proposed mechanisms by which ketogenic diets may enhance cancer cell therapeutic responses. Or Rainer Klement s 2017  Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation ( https: doi.org 10.1007 s12032-017-0991-5) Abstract: Ketogenic diets (KDs) have gained popularity among patients and researchers alike due to their putative anti-tumor mechanisms. However, the question remains which conclusions can be drawn from the available human data thus far concerning the safety and efficacy of KDs for cancer patients. A realist review utilizing a matrix analytical approach was conducted according to the RAMESES publication standards. All available human studies were systematically analyzed and supplemented with results from animal studies. Evidence and confirmation were treated as separate concepts. In total, 29 animal and 24 human studies were included in the analysis. The majority of animal studies (72%) yielded evidence for an anti-tumor effect of KDs. Evidential support for such effects in humans was weak and limited to individual cases, but a probabilistic argument shows that the available data strengthen the belief in the anti-tumor effect hypothesis at least for some individuals. Evidence for pro-tumor effects was lacking completely. Feasibility of KDs for cancer patients has been shown in various contexts. The probability of achieving an anti-tumor effect seems greater than that of causing serious side effects when offering KDs to cancer patients. Future controlled trials would provide stronger evidence for or against the anti-tumor effect hypothesis. Or  Ketogenic diet in the treatment of cancer u2013 Where do we stand? 2020 from Daniela D.Weber, Sepideh Aminzadeh-Gohari, Julia Tulipan, Luca Catalano, Renu00e9 G .Feichtinger, BarbaraKofler Scope of review To critically evaluate available preclinical and clinical evidence regarding the ketogenic diet in the context of cancer therapy. Furthermore, we highlight important mechanisms that could explain the potential antitumor effects of the ketogenic diet. Major conclusions The ketogenic diet probably creates an unfavorable metabolic environment for cancer cells and thus can be regarded as a promising adjuvant as a patient-specific multifactorial therapy. The majority of preclinical and several clinical studies argue for the use of the ketogenic diet in combination with standard therapies based on its potential to enhance the antitumor effects of classic chemo- and radiotherapy, its overall good safety and tolerability and increase in quality of life. However, to further elucidate the mechanisms of the ketogenic diet as a therapy and evaluate its application in clinical practice, more molecular studies as well as uniformly controlled clinical trials are needed. *** # In addition to striking similarities and overlap with existing published reviews, the following claims from the present review are **unsupported by the references cited** (examples to follow).  This review highlights the crucial mechanisms that explain the ketogenic dietu2019s potential antitumor effects, which probably produces an unfavorable metabolic environment for cancer cells and **can be used as a promising adjuvant in cancer therapy** (from Abstract) and  The published data of the preclinical and clinical trials **support the use of a ketogenic diet as a preventive and adjuvant cancer therapy.** (from Conclusion) *** ## The following passage is wholly unsupported by its referenced citations: 7.2. Clinical Studies Although the combined use of radiation, chemotherapy, and surgery is a good strategy of care in different cancers [258], no effective standard therapy is available for highly aggressive cancer types with poor prognosisu2014for example, triple negative breast cancer [263]. u201c **REF 258** (Xia, S.; Lin, R.; Jin, L.; Zhao, L.; Kang, H.-B.; Pan, Y.; Liu, S.; Qian, G.; Qian, Z.; Konstantakou, E. Prevention of dietary-fat-fueled ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 2017, 25, 358u2013373) **does not mention the words radiation, chemotherapy, or surgery.** **REF 263** (Magee, B.A.; Potezny, N.; Rofe, A.M.; Conyers, R.A. The inhibition of malignant cell growth by ketone bodies. Aust. J. Exp. Biol. Med. Sci. 1979, 57, 529u2013539.) **is from 1979, long before triple negative breast cancer was even identified and therefore has no bearing on whether or not  effective standard therapy...for [this]highly aggressive cancer type with poor prognosis was available.** *** ## The following citation is wholly unsupported by its referenced citations: The Warburg effect can reduce the concentration of insulin and other growth-stimulating hormones and factors, improve immune modulation, and reduce the side effects of chemotherapy and radiation [160,264]. **REF 160** (Li, R.J.; Liu, Y.; Liu, H.Q.; Li, J. Ketogenic diets and protective mechanisms in epilepsy, metabolic disorders, cancer, neuronal loss, and muscle and nerve degeneration. J. Food Biochem. 2020, 44, e13140. ) **has nothing to do with chemotherapy or radiation, much less reducing their side effects.** **REF 264** (Ludwig, D.S. The ketogenic diet: Evidence for optimism but high-quality research needed. J. Nutr. 2020, 150, 1354u20131359) is misrepresented by the above claim. Table 1 in Ludwig s presentation shows that the **proposed mechanism of research in progress, a far cry from the definitive claim being made.** ![file] *** ## Table 3 propagates a misleading conclusion from the original research. **It is extremely irresponsible to definitively claim that changes to a single patient s changes to HER2 and PR status after a 3-week dietary change were causally related.** **REF271** (REF 271: Branca, J.J.V.; Pacini, S.; Ruggiero, M. Effects of Pre-surgical Vitamin D Supplementation and Ketogenic Diet in a Patient with Recurrent Breast Cancer. Anticancer Res. 2015, 35, 5525. ** ![file] *** ## Table 3 also includes the unsupported claim that  KD appears to be a good adjuvant therapy for glioma when, in fact the study says in conclusion: **u2018Whether MKD is an effective adjuvant therapy for glioma tumors remains to be proven.** ![file] **REF 267** (Martin-McGill, K.J.; Marson, A.G.; Tudur Smith, C.; Jenkinson, M.D. The Modified Ketogenic Diet in Adults with Glioblastoma: An Evaluation of Feasibility and Deliverability within the National Health Service. Nutr. Cancer 2018) is **misrepresented.** *** # After reviewing just a small subset of the 281 included references in this  review article, it is unclear to this reviewer whether the present authors are familiar with the body of literature or the publications they ve cited here, and a thorough review correction should be issued as soon as possible to ensure the integrity of this data synthesis and in order to not misguide readers. **In terms of citation references, present authors would do well to remember that quantity is not a substitute for quality.** ,