Food supplements could help reverse breast cancer resistance to medication, study suggests

12 Apr 2023 --- Researchers found that the supplement N-acetylcysteine (NAC) restores the effectiveness of alpelisib, a drug approved for use in Switzerland as a treatment for advanced breast cancer. However, the medication’s effectiveness has been limited due to the resistance of tumor cells.

NAC is an antioxidant used as a food supplement and an ingredient in cough medicines.

“As NAC is a safe and widespread additive, this result is highly relevant for clinical research,” says co-author Mohamed Bentires-Alj, head of the research group at the department of biomedicine of the University of Basel, Switzerland. 

He believes a combination of NAC with alpelisib could improve the treatment of advanced breast cancer. 

The antioxidant NAC is a food supplement and an ingredient in cough medicines.Patients with advanced and spread breast cancer lack adequate treatment options as the neurofibromin 1 (NF1) gene is frequently mutated, according to public datasets of human breast cancer. This gene suppresses the growth of tumors and its loss leads to a reduced sensitivity of breast cancer cells to treatment with alpelisib. 

Clinical studies with breast cancer patients are essential to confirm the effects observed in the lab, published in Cell Reports Medicine. 

Genetic basis 
Alpelisib inhibits the PI3Kα pathway, which is often overactive in breast cancer due to mutations that promote the development and growth of tumors. Around 70% of all breast cancers show gene mutations that activate this pathway. 

“Unfortunately, it turned out that the success of the medication is severely limited by resistance,” notes Bentires-Alj. “Hence, we urgently need to find out more about how resistance arises.”

The research team determined that mutations that switched off the NF1 gene made the tumors resistant to treatment with alpelisib, enhanced glycolysis and lower levels of reactive oxygen species. 

Further experiments confirmed that the loss of NF1 also led to resistance in human cancer cells and tissue cultured from tumors. 

“So the absence of NF1 is the elephant in the room. It throws everything into disarray within the cell and hinders successful treatment,” highlights Bentires-Alj.

Reversing the effect of gene loss
The researchers note that the loss of NF1 affects the cell’s energy reserves. 

“They stop producing as much energy using mitochondria. Instead, they switch to other energy production pathways,” explains the study’s lead author, Dr. Priska Auf der Maur.

In experiments, NAC reversed the effect of lost NF1 genes on a cell’s energy metabolism. The substance increased the effectiveness of alpelisib in resistant cancer cells through an additional intervention in another signaling pathway, which plays a vital role in tumor growth. 

After showing the importance of NF1 loss for tumor resistance in vitro, the researchers determined this led to reduced sensitivity to PI3Kα inhibition in mice resulting in disease progression. 

The US Food and Drug Administration (FDA) recently announced that it would allow NAC to be included in products labeled as dietary supplements after months of disputes and a lawsuit by the Natural Products Association. The study found NAC restores the effectiveness of alpelisib in treating advanced breast cancer by reversing the effects of NF1 gene loss. 

The FDA stated before that since NAC was approved as a novel drug before it was promoted as a supplement, it would not be defined as a dietary supplement. 

Further research 
The researchers note that a loss of NF1 also contributes to resistance to other medications. However, the biological effects of NAC should be further investigated to determine if the same mechanisms are responsible for sensitization in other therapies. Mechanisms include scavenging oxidants, replenishing glutathione and reducing disulfide bonds. 

Moreover, further research should test other PI3Kα inhibitors and additional antioxidants. 

The effects of PI3Kα inhibition and NAC on the immune system need to be evaluated. The current study performed all in vivo experiments on mice that do not have an intact immune system. 

A study suggests that interventions with NAC could facilitate improved motivational performance as it targets key oxidative processes. 

Higher vitamin D levels are associated with lower breast cancer rates among women of color, according to a study of Black and Latina women.

By Jolanda van Hal