The ketogenic diet (KD), characterized by high fat and low carbohydrate intake, has garnered attention as a potential complementary therapy for cancer. While the concept of using diet to influence cancer dates back to the early 20th century, recent research has explored the mechanisms behind the KD's effects on tumor growth, metastasis, and overall patient health. This article aims to provide a comprehensive overview of the current state of ketogenic diet cancer research, considering both potential benefits and risks.
Historical Context
The ketogenic diet isn't a new concept; its origins trace back to the 1920s when Dr. Russell Wilder at the Mayo Clinic developed it as a treatment for epilepsy. This high-fat, low-carb diet works by shifting the body's primary fuel source from glucose to ketones. This shift occurs because, in the absence of carbohydrates, glucose levels fall, and the liver breaks down fats into ketones, which then circulate in the blood and serve as the main energy source for cells.
Later, in the 1970s, Dr. Atkins revived interest in low-carb, high-fat diets for weight loss, leading to the popular "Atkins Diet." The ketogenic diet's potential role in cancer management emerged from observations that cancer cells exhibit a strong preference for glucose and are unable to efficiently use ketones for energy. This stems from the work of Dr. Otto Warburg, who won a Nobel Prize in 1931 for his research on tumor metabolism.
How Ketogenic Diets Work
The standard American diet derives approximately 50% to 60% of its calories from carbohydrates. In contrast, a ketogenic diet consists of 65% to 70% fat, 5% to 10% carbohydrates, and 20% to 25% protein. This macronutrient distribution forces the body into a state of ketosis, mimicking the metabolic effects of starvation.
When glucose is scarce, the liver produces ketones and fatty acids, which normal cells can use for energy. Cancer cells, however, often have dysfunctional mitochondria and defects in their electron transport chain, disrupting normal ATP production. This dependence on glucose can be exploited through KD use.
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Potential Benefits of Ketogenic Diets in Cancer
Slowing Tumor Growth
Several studies have shown that ketogenic diets can slow tumor growth in certain cancers. In mice with pancreatic and colorectal cancer, keto diets slowed the growth of tumors by inducing ferroptosis, a process that kills cancer cells through a buildup of toxic fatty molecules. The ketogenic diet inhibits insulin/IGF and downstream intracellular signaling pathways like phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR). The diet also amplifies adenosine monophosphate-activated protein kinase (AMPK), which inhibits aerobic glycolysis and suppresses tumor proliferation, invasion, and migration.
Sensitizing Tumors to Therapy
Both intermittent fasting and the keto diet have shown some benefit to patients undergoing chemotherapy, such as a reduction in some drug toxicity and improved quality of life.
Impact on Gut Microbiome
The gut microbiome may affect CRC development either by directly interacting with host cells (attachment, invasion and translocation), or indirectly, through bacterial metabolism (genotoxins, SCFAs and others). The anti-cancer effects of the KD are mediated by the gut microbiome. Ketogenic diet induces a distinct fecal microbial profile. Differential analysis revealed Phocea spp., Faecalitalea spp. and Akkermansia spp., Intestimonas spp., Lachnoclostridium spp., Bilophila spp. to be more abundant in KD, while Barnesiella spp., Eisenbergiella spp., Ruminococcus 1 and 2 spp., and Bifidobacterium spp., Turicibacter spp., and others were depleted.
Specific Cancer Types
A ketogenic diet may possibly provide some benefit, especially with gliomas, or brain cancers. Studies in animals show promise, but human studies are still inconclusive. The good news is that no adverse effects were observed in those following a keto diet. It seemed to be safe to at least give it a try.
Potential Risks and Considerations
Cachexia
In mice with pancreatic and colorectal cancer, keto accelerates a lethal wasting disease called cachexia. Patients and mice with cachexia experience loss of appetite, extreme weight loss, fatigue, and immune suppression. Researchers found that pairing keto with common drugs called corticosteroids prevented cachexia in mice with cancer.
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Tumor Metastasis
The ketogenic diet - a high-fat, low-carbohydrate diet purported to have benefits for people with cancer - may increase the risk of tumor metastasis, according to a new study. In a mouse model of breast cancer, mice fed with a ketogenic diet experienced significantly more lung metastases compared to those on a control diet. The cancer cells detect that this place deprived of glucose is not nutritionally comfortable, so they want to escape. They don’t want to stay in the wrong place.
Metabolic Stress
The cancer cells detect that this place deprived of glucose is not nutritionally comfortable, so they want to escape. They don’t want to stay in the wrong place.
Individual Variability
Cancer is a whole-body disease. It reprograms normal biological processes to help it grow. Because of this reprogramming, mice can’t use the nutrients from a keto diet, and waste away. But with the steroid, they did much better.
Long-term Effects
Long-term KD feeding induced fatty liver and fibrosis in all sub-groups, as previously reported for long-term KD consumption.
Current Research and Clinical Trials
Researchers are actively exploring the role of KD in cancer treatment. Duke University has initiated a randomized study (NCT00932672) of the Atkins diet and androgen deprivation therapy for patients with prostate cancer. Tel Aviv Sourasky Medical Center in Israel is recruiting previously treated chemoradiation patients with high-grade glial tumors for an open-label study (NCT01092247) of the efficacy of KD in preventing tumor growth and recurrence. St. Joseph’s Hospital and Medical Center (Phoenix, AZ) is recruiting newly diagnosed glioblastoma patients for a phase 1/2 prospective trial (NCT02046187) involving upfront resection followed by KD with radiotherapy and concurrent temozolomide, followed by adjuvant temozolomide chemotherapy. The primary endpoint is number of patients with AEs and the secondary endpoints are overall survival, time to progression, and QOL.
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Expert Perspectives
Experts at Memorial Sloan Kettering Cancer Center (MSK) are at the forefront of this research. Hematologic oncologist Urvi Shah cares for people with plasma cell disorders, including multiple myeloma. Medical oncologist Neil Iyengar treats people with breast cancer. Both conduct research aimed at understanding the interplay between nutrition and cancer.
Drs. Shah and Iyengar recently conducted a review of studies that examine the relationship between diet and cancer. There is growing evidence that weight loss is helpful for reducing cancer risk, particularly for obese and older people, including the postmenopausal age group. Both keto and plant-based diets have proven effective for weight loss. However, there is less available data to answer whether the benefits of these diets extend to cancer. Most of the available data support a whole foods, plant-based diet over a ketogenic diet for reducing the risk of cancer. After a cancer diagnosis, a plant-based diet still appears to be superior. Currently, there is no evidence to suggest that a specific diet by itself can treat cancer. There is preliminary evidence to suggest that certain dietary patterns can help make some cancer treatments work better or reduce side effects.
The Gut Microbiome's Role
The gut microbiome may affect CRC development either by directly interacting with host cells or indirectly through bacterial metabolism. Studies have shown that the anti-cancer effects of the KD are mediated by the gut microbiome. A ketogenic diet induces a distinct fecal microbial profile, with certain bacterial species becoming more abundant while others are depleted.