New research suggests soy phytochemicals and microbiome affect cancer drug effectiveness

Scientists indicate that diet affects cancer therapy efficacy through interactions between phytochemicals in the liver and gut microbiome. In a new study, they suggest that ketogenic or high-carbohydrate diets low in phytochemicals, especially soyasaponins from soybeans, help treat cancer in mice.

The study investigates phosphoinositide 3-kinase (PI3K) inhibitors, a class of cancer medications that blocks the PI3K signaling pathway to slow down cancer. This insulin-signaling pathway is among the most frequently activated pathways in human cancer. 

In their preclinical research on mice, the investigators found that the compound soyasapogenol lowers the activity of P450 enzymes, which inhibit the pathway and thus lower anticancer activity. The microbiome creates these compounds from the soy phytochemicals soyasaponins. 

“Many cancer drugs don’t work equally well for all patients, and one emerging possibility is that diet plays a role in this variability,” says corresponding author Joshua Rabinowitz, branch director at the Ludwig Institute for Cancer Research at Princeton University, US. 

“We found in this study that diet can alter cancer treatment outcomes in preclinical models and can do so unexpectedly, unrelated to its immediate nutritional effects,” he adds. 

“It turns out that certain small molecules in plant-based foods are transformed in mice by commensal gut bacteria into compounds that activate the liver to clear PI3K inhibitors more quickly, lowering the drug’s efficacy.”

The researchers say their findings open opportunities to develop new strategies for cancer therapy that consider a patient’s diet, microbiome composition, and recent antibiotics use, which alter the gut microbiome composition. 

Although more research is needed, they suggest such strategies could involve prescribing dietary changes or pharmaceutical intervention to modulate cancer therapy metabolism based on a patient’s analyzed gut microbiome. 

Ketogenic benefits?

The study published in Cell refers to previous studies that have shown that ketogenic diets enhance responses to cancer drugs in preclinical mouse models of cancer. Researchers have suggested that these high-fat and low-carbohydrate diets and their ability to enhance therapeutic responses are linked to their tendency to lower insulin and blood sugar levels. 

However, the current paper’s research team found that mice fed high-carbohydrate diets — which should raise blood sugar and spike insulin production — responded well to PI3K inhibitors. They discovered that the key determinant was the diet’s molecular complexity. 

The researchers call to consider a patient’s diet, microbiome composition, and recent antibiotics use in cancer treatment strategies.In preclinical studies on mice, their ketogenic food is a highly processed formulation that lacks a mix of phytochemicals common in standard foods, specifically those from legumes and soy. 

Experiments determined that when gut microbes break down soyasaponins from soybeans into other molecules, these compounds induce the expression of a detoxifying liver enzyme P450. The increased production of this specific enzyme led to the clearance of PI3K inhibitors, reducing the efficacy of anticancer treatment. 

“While we focused in this study on PI3K inhibitors, the liver enzymes involved in clearing these drugs break down many others,” says lead author Asael Roichman, a postdoctoral student in the Rabinowitz lab. “This suggests our findings could be relevant to multiple drugs used to treat cancer and other diseases.”

The team also found that a high-carbohydrate, low-phytochemical diet, and antibiotics that suppress the gut microbiome enhanced PI3K inhibitor activity in mice. 

“These findings suggest that some plant-based diets, through their interactions with gut microbes, may lower cancer drug exposure by ramping up the body’s drug clearance systems,” adds Roichman. 

“While the specific molecules that exert such an influence may differ in humans, our work highlights diet and the microbiome as key factors that can shape how cancer drugs behave in the body.”

Nutritional impact on cancer

Last year, the WHO International Agency for Research on Cancer predicted over 35 million new cancer cases globally by 2050, a 77% from its 2022 estimate. 

The study suggests that some plant-based diets, such as those high in soy phytochemicals, may lower cancer drug exposure.At the same time, industry and academia both highlight the potential for nutrition to help prevent cancer or support patients undergoing treatment. 

For example, research has linked vitamin D to better cancer immunity through the gut of mice, while healthy diets can help reduce the risk of developing certain cancers, such as breast cancer. 

Meanwhile, the US nonprofit Physicians Committee for Responsible Medicine has called for a dietary shift to prevent colorectal cancer in young adults, specifically focusing on reducing processed meat intake. In the EU, experts have predicted an increase in bowel cancer death rates among people aged 25–49 due to obesity and alcohol consumption.

In other dietary research, a recent study has linked omega-6 fatty acids in seed oils and animal products to increased prevalence of a hard-to-treat breast cancer subtype.