Indole-3 acetic acid affects the efficacy of chemotherapy in pancreatic cancer

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Indole-3 acetic acid affects the efficacy of chemotherapy in pancreatic cancer

Nature | Indole-3 acetic acid affects the efficacy of chemotherapy in pancreatic cancer

Due to high incidence of metastases and limited efficacy of treatment, pancreatic ductal adenocarcinoma ( PDAC ) is about to become the second most deadly cancer in the world.

Chemotherapy is only effective for less than half of PDAC patients. Genetic differences alone cannot explain this. Diet is an environmental factor that may affect the efficacy of chemotherapy, but its role in PDAC remains unclear.

On February 22, 2023, the research team of Nicola Gagliani and Joseph Tintelnot from Hamburg-Ebendorf University Medical Center in Germany published an article entitled “Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer” in Nature.

Using shotgun metagenomic sequencing and metabolome screening, the researchers found that indole-3-acetic acid (3-IAA), a microbially produced tryptophan metabolite, was enriched in the plasma of patients responding to chemotherapy, and that a high-tryptophan diet could Promote the effect of chemotherapy, and the mechanism is because neutrophil-derived myeloperoxidase oxidizes 3-IAA, resulting in the accumulation of reactive oxygen species and the decrease of autophagy activity, reducing the proliferation ability of tumor cells, and in humans they also observed The content of 3-IAA was significantly correlated with the effect of chemotherapy.

Indole-3 acetic acid affects the efficacy of chemotherapy in pancreatic cancer

To study the effect of dietary habits or gut microbes on the response to chemotherapy in metastatic pancreatic ductal adenocarcinoma ( mPDAC ), the researchers recruited 30 mPDAC patients, 23 of whom were antibiotic-naïve so that they could provide adequate analysis of gut microbiota.

They divided patients into two groups that responded to chemotherapy (R) and non-response (NR) , and found that the gut microbes of patients in the R group were significantly different from those in the NR group, and then they transplanted the gut microbes of these patients into a pancreatic cancer model In mice, it was found that after chemotherapy, the tumor volume of mice transplanted with microorganisms from patients in the R group was smaller, so they speculated that the metabolites secreted by the microorganisms might affect the chemotherapy effect through blood circulation, and then they analyzed the patients in the R and NR groups As well as the plasma of corresponding transplanted mice, metabolome screening was performed using liquid chromatography tandem mass spectrometry, and it was found that the tryptophan metabolite indole-3-acetic acid (3-IAA) was the most significantly changed metabolite , and Bacteroides fragilis ( The increased abundance of Bacteroides fragilis ) and Bacteroides thetaiotaomicron may be the reason for the increase of 3-IAA content in the blood of patients in group R.

So by regulating the precursor of 3-IAA in the diet, tryptophan, can it affect the level of 3-IAA in the blood and affect the effect of chemotherapy?

Because tryptophan can promote tumor growth, long-term treatment is not advisable, so they finally selected a treatment time of 4-5 days through testing, and found that 4 days of high-tryptophan diet can increase the content of 3-IAA in the blood , and can promote the effect of chemotherapy .

Neutrophils are highly enriched in PDAC, low neutrophil levels are associated with good prognosis in mPDAC, 3-IAA is toxic to cells with high concentrations of myeloperoxidase (MPO) , and high MPO is neutral Sign of granulocytes.

MPO can oxidize 3-IAA to produce the toxic substance 3-methylene-oxindole, and they found that the effect of 3-IAA on chemotherapy is mediated by MPO .

Oxidation of 3-IAA by MPO will generate reactive oxygen species (ROS) , and ROS will mediate the death of chemotherapy cells. They found that during chemotherapy, 3-IAA can lead to an increase in ROS and reduce the autophagy activity of tumor cells, thereby reducing the proliferation ability of tumor cells . Therefore, the effect of 3-IAA on promoting chemotherapy depends on the increase of ROS and the decrease of autophagy activity .

Then they tested the effect of 3-IAA on other tumor types and other types of chemotherapy drugs, and found that 3-IAA can also affect the chemotherapy effect of normal PDAC, colorectal cancer or lung cancer, and it is also effective for other chemotherapy drugs combined with GnP, indicating that 3-IAA has broad potential for tumor therapy .

Finally, they found that neutropenia in patients was associated with better chemotherapy efficacy through human cohort analysis, which was consistent with their mouse experiment results, and the level of neutropenia after chemotherapy was correlated with blood 3- The concentration of IAA is related, and the blood concentration of 3-IAA is related to the progression-free survival (PFS) and overall survival rate of patients .

Overall, this study found that the tryptophan metabolite 3-IAA produced by microorganisms can affect the killing effect of chemotherapy on PDAC tumor cells, and the mechanism is due to the stress of tumor cells due to increased ROS levels and decreased autophagy activity.

Decreased adaptability and reduced cell proliferation. Therefore, increasing the concentration of 3-IAA in plasma during chemotherapy may be a new idea to promote the effect of chemotherapy.

Original link:

https://doi.org/10.1038/s41586-023-05728-y

Indole-3 acetic acid affects the efficacy of chemotherapy in pancreatic cancer

(source:internet, reference only)

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