Plant-Based Small Molecules May Impact Cancer Drug Effectiveness

A recent study conducted by the Ludwig Institute for Cancer Research has revealed a noteworthy connection between diet, gut microbiota, and the effectiveness of cancer therapies. This research, led by scientists at Ludwig Princeton, could provide insights into the inconsistent responses observed in patients undergoing treatment with PI3 kinase (PI3K) inhibitors. These drugs target a specific biochemical signaling pathway that is often dysregulated in cancer, promoting tumor growth.

Researchers have suggested that variations in individual diets may play a significant role in how these drugs work. The findings indicate that some small molecules found in plant-based foods can be metabolized by gut bacteria into compounds that enhance liver activity, leading to a faster clearance of PI3K inhibitors from the body. This metabolic process ultimately results in reduced drug efficacy, complicating treatment outcomes.

Asael Roichman, a postdoctoral researcher in the Rabinowitz lab and the study's lead author, pointed out that the liver enzymes responsible for the breakdown of these inhibitors are also involved in the metabolism of many other cancer medications. Therefore, the implications of this study may extend beyond PI3K inhibitors, potentially affecting various classes of cancer treatments.

The research findings, published in the latest issue of Cell, emerged from an unexpected observation during experiments designed to explore the relationship between diet and cancer therapy. Previous studies from the same research group showed that ketogenic diets, which are high in fats and low in carbohydrates, significantly improved responses to cancer drugs in animal models. However, the researchers were surprised to find that mice on certain high-carbohydrate diets exhibited positive responses to PI3K inhibitors as well.

Upon further investigation, the team discovered that the beneficial effects of the ketogenic diet were not as closely related to carbohydrate intake, fat content, or insulin levels as originally thought. Instead, the critical factor appeared to be the complexity of the diet, specifically whether it consisted of whole foods or heavily processed items.

The ketogenic diet used in their experiments was a highly refined formulation that lacked the diverse array of plant-derived compounds, also known as phytochemicals, found in typical rodent chow. The study indicated that gut microbes could convert these phytochemicals, notably soyasaponins from soybeans, into molecules that stimulate the production of detoxifying liver enzymes.

The elevated activity of these enzymes was linked to a quicker clearance of PI3K inhibitors, reducing their anticancer effectiveness in the chow-fed mice. The researchers also found that a diet high in carbohydrates but low in phytochemicals, as well as antibiotic treatments that diminished gut microbiota, improved the activity of PI3K inhibitors.

These insights emphasize that certain plant-based diets may inadvertently lower the effectiveness of cancer drugs by enhancing the body's natural drug clearance mechanisms through interactions with gut bacteria. Although human-specific molecules may differ, the study underscores the importance of diet and microbiome composition in shaping the pharmacokinetics of cancer treatments.

The findings pave the way for potential new strategies in cancer therapy that consider dietary habits, the composition of gut microbiota, and the impact of antibiotics on the microbial ecosystem. Future clinical approaches may involve analyzing patient microbiomes and implementing dietary modifications alongside existing cancer treatments to optimize therapeutic outcomes.