Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Ampliﬁed Neuroblastoma Xenografts

Metabolites, 2023 · DOI: 10.3390/metabo13080910 · Published: August 3, 2023

Simple Explanation

This study investigates a new treatment approach for neuroblastoma, a childhood cancer with poor prognosis when the MYCN gene is amplified. The approach combines a ketogenic diet (KD), metformin (MET), and a low dose of cyclophosphamide (CP). The researchers hypothesized that combining MET, which disrupts energy production in cells, with a KD and CP could improve treatment outcomes. They found that this triple therapy reduced tumor growth and improved survival in mice with MYCN-amplified neuroblastoma. The triple therapy affected the transcription of genes involved in fatty acid oxidation. This suggests that the combined treatment hampers mitochondrial energy production, making it a potentially effective adjuvant therapy.

Study Duration

33-36 days

Participants

6-10 female CD-1 nude mice per group

Evidence Level

Level 1, In vivo xenograft study

Key Findings

1
MET reduces cell proliferation and mitochondrial respiration in MYCN-amplified NB cell lines.
2
The triple therapy (KD, CP, and MET) significantly reduced tumor growth and enhanced survival in both SKNBE(2) and KELLY tumor-bearing mice.
3
The triple therapy increased the level of FGF-21, a hepatokine, and augmented the expression of CPT1A, a crucial enzyme involved in fatty acid β-oxidation.

Research Summary

The study investigates the efficacy of combining a ketogenic diet (KD), metformin (MET), and metronomic cyclophosphamide (CP) as a triple therapy for MYCN-amplified neuroblastoma (NB). Results showed that MET inhibits mitochondrial respiration and cell proliferation in MYCN-amplified NB cells. Furthermore, the triple therapy significantly reduced tumor growth and enhanced survival in NB xenograft models. The combination therapy altered metabolic pathways, upregulating fatty acid β-oxidation and increasing FGF-21 levels. These metabolic changes suggest a potential mechanism for the observed anti-tumor effects.

Practical Implications

Adjuvant Therapy Potential

The triple therapy could serve as an effective adjuvant treatment to conventional chemotherapy for high-risk MYCN-amplified neuroblastoma.

Metabolic Vulnerabilities Targeting

The study highlights the importance of targeting metabolic vulnerabilities in cancer cells, particularly MYCN-amplified neuroblastoma, by combining metabolic interventions with conventional therapies.

Fatty Acid Oxidation Modulation

Modulating fatty acid oxidation in combination with complex I inhibition could be a promising strategy to disrupt energy production in cancer cells.

Study Limitations

1
The study used immunodeficient mice, which may not fully represent the inflammatory response in immunocompetent individuals.
2
The concentration of MET required to reduce cell respiration in vitro is much higher than the plasma levels of MET detected in vivo.
3
The long-term effects and potential toxicities of the triple therapy were not evaluated.

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