Sodium butyrate increased the sensitivity of drug-resistant cancer cells to treatment in selected laboratory models, a study led by the University of Bari Aldo Moro has found.

The research links acquired drug resistance to changes in a metabolic pathway involved in producing D-lactate.

The findings suggest that this pathway could offer a starting point for investigating ways to improve the response to treatment.

Drug resistance remains a major obstacle to effective cancer treatment.

Cells that survive anticancer drugs can develop changes in the way they generate energy and process the substances they need to grow.

Researchers led by Professor Antonio Mazzocca, of the university’s Interdisciplinary Department of Medicine, compared drug-sensitive cancer cells with cells that had acquired resistance after prolonged exposure to anticancer agents.

The study included liver, colorectal and breast cancer cell models.

Earlier work by the group had identified a metabolic pattern in resistant cells involving impaired mitochondrial energy production, lower oxygen consumption and increased production of L-lactate.

The new investigation focused on D-lactate, a different form of lactate produced through a pathway involving the glyoxalase system.

The resistant cells produced more D-lactate than their drug-sensitive counterparts.

They also showed increased expression and activity of glyoxalase 1, or GLO1, an enzyme involved in this pathway.

The team then examined the effects of sodium butyrate.

Butyrate is a compound produced by gut bacteria during the fermentation of dietary fibre and can influence cellular metabolism and gene activity.

In responsive cell models, sodium butyrate reduced GLO1 activity and increased sensitivity to anticancer treatment.

The effects on drug response were observed in resistant colorectal and breast cancer cells.

For example, combining sodium butyrate with 5-fluorouracil in resistant colorectal cancer cells improved the response to treatment.

The combination also reduced the amount of D-lactate inside the cells to near-background levels.

These observations support a link between changes in the GLO1/D-lactate pathway and drug response.

However, sodium butyrate affects several cellular processes, and further experiments are needed to establish how much this particular pathway contributes to the effects observed.

The researchers also found that sodium butyrate enhanced the effects of agents that promote cellular differentiation in the in vitro models tested.

The study is published in the Journal of Biological Chemistry.

Further work in more complex preclinical models will be needed to assess the relevance of the findings and their potential therapeutic applications.

Professor Mazzocca said: “Understanding how tumour cells change their metabolism to adapt to drugs is an important step towards identifying new strategies to tackle drug resistance. Our results indicate that the GLO1/D-lactate system is associated with this process and that sodium butyrate can modulate some of its components in specific cell models.”

Source: Professor Antonio Mazzocca, University of Bari Aldo Moro