Dados do Resumo

Título

Cyclic Caloric Restriction Enhances Chemotherapy Efficacy and Modulates Genetic Signatures Associated with Tumor Metabolism in Triple-Negative Breast Cancer: An RNA-Seq Analysis

Introdução

Chemoresistance and treatment-associated toxicity remain significant challenges in oncology. Although numerous treatments have been developed, there is still a need for adjuvant strategies that can increase tumor cell sensitivity while minimizing systemic treatment toxicity. In this context, caloric restriction emerges as a promising approach capable of modulating pathways related to antitumor activity and, consequently, enhancing treatment efficacy.

Objetivo

This study evaluated the antitumor effect of cyclical caloric restriction (CR) combined with chemotherapy (CT) in a breast cancer model.

Métodos

We used a triple-negative breast cancer model induced by 4T1 cells in female Balb/c mice. The animals were pre-anesthetized, and 50 µL of PBS containing 1.0 x 10⁶ 4T1 cells was inoculated into the right fourth mammary gland. The mice were then randomized into four experimental groups: control, caloric restriction, doxorubicin, and a combination of caloric restriction with doxorubicin. The experiment was conducted over 18 days. The animals in the CR group were subjected to an initial 9-day cycle of 40% caloric restriction, followed by 3 days of normal feeding, and then another 6-day period of 20% caloric restriction. In the CT groups, doxorubicin was administered at a dose of 2 mg/kg via intraperitoneal injection every 3 days. Tumor growth (weight and volume), food intake, body weight, and gene expression related to antitumor activity were assessed using RNA-Seq transcriptome analysis. The study was conducted under the protocol approved by CEUA/UFPI, number 738/2022.

Resultados

Cyclical caloric restriction combined with chemotherapy significantly delayed tumor development. Although the animals experienced weight loss during the initial phase of caloric restriction, the refeeding period effectively restored body weight to baseline levels. The combination of doxorubicin and caloric restriction suppressed the activity of the KRAS signaling pathway, highlighting the potential of this strategy to enhance treatment effects and reduce resistance risk. Moreover, the combined treatment led to decreased expression of SERPINA 12, a gene linked to tumorigenesis that hyperactivates the AKT/β-catenin pathway. This modulation is crucial, as in breast cancer, the AKT pathway is often hyperactivated, contributing to tumor initiation, progression, and metastasis by increasing energy availability for tumor cells. We also observed a reduction in the expression of Klk 6 and 7, suggesting a decrease in the tumor's invasive capacity and regulation of growth factors.

Conclusões

Cyclical caloric restriction combined with doxorubicin not only delays tumor development but also suppresses the expression of genes associated with cancer aggressiveness. Additionally, we confirmed that cyclical caloric restriction is a safe approach, as the animals quickly regained body weight during refeeding. We conclude that restrictive diets in oncology may represent a promising "therapeutic window of opportunity."

Financiador do resumo

CAPES (Financial code 001)

Palavras Chave

Breast cancer; Tumor metabolism; Dietary restriction