# Caloric Restriction Enhances Chemotherapy Efficacy and Reshapes Stress Responses in Sarcoma

## TL;DR

Reducing calorie intake combined with chemotherapy improves cancer treatment outcomes and reduces side effects in mice with sarcoma.

## Contribution

The study shows that caloric restriction enhances chemotherapy efficacy and reduces toxicity in a sarcoma model.

## Key findings

- Caloric restriction combined with doxorubicin reduced tumor growth more effectively than chemotherapy alone.
- The combination protected blood, liver, and DNA from treatment-related damage and improved survival.
- It lowered oxidative stress and increased antioxidant activity in the tumor.

## Abstract

Cancer treatments often cause strong side effects and do not always stop tumor growth. Recent research suggests that reducing calorie intake for a short period may help the body respond better to chemotherapy while protecting healthy cells. In this study, it was investigated whether combining caloric restriction with the chemotherapy drug doxorubicin could enhance treatment outcomes in mice with sarcoma. It was found that this combined approach reduced tumor growth more effectively than chemotherapy alone and helped protect the blood, liver, and DNA from treatment-related damage. It also lowered oxidative stress and improved survival. These findings suggest that controlled caloric restriction may be a safe and promising approach to enhance the effects of chemotherapy and mitigate its adverse effects. This approach may guide future research on how nutrition can support cancer treatment.

Background: Oncological treatment remains a major clinical challenge. Despite therapeutic advances and the diversity of available approaches, many tumors continue to exhibit limited responsiveness to chemotherapy. In this context, nutrition has emerged as a promising complementary strategy to support cancer therapy. In particular, interventions based on nutritional deprivation have gained prominence due to their ability to modulate tumor metabolism, inducing alterations that may increase the sensitivity of cancer cells to conventional treatments. Accordingly, the present study aimed to evaluate the safety and efficacy of caloric restriction combined with chemotherapy in a Sarcoma-180 model, investigating its effects on immunological and hematological parameters, antioxidant activity, oxidative stress, and tumor and liver morphology, as well as DNA damage. Methods: Mice bearing Sarcoma-180 were randomly assigned to four groups: Ad Libitum (AL), Ad Libitum + Doxorubicin (ALDOX), Caloric Restriction (CR), and Caloric Restriction + Doxorubicin (CRDOX). Assessment included tumor weight and volume, food and caloric intake, hematotoxicity, lipid metabolism, oxidative stress and antioxidant markers, genotoxicity, morphological alterations in the tumor and liver, and overall survival. Results: The data obtained demonstrate that caloric restriction combined with doxorubicin is both safe and feasible, as it preserves body weight and does not induce metabolic disturbances. Importantly, this combined strategy produced a marked reduction in tumor volume and mass while also mitigating the hematotoxicity typically associated with doxorubicin. In peripheral blood, the regimen decreased chemotherapy-induced DNA damage, supporting a systemic protective effect. Consistently, the combination reduced oxidative stress markers (NOx and MDA) and enhanced antioxidant activity within the tumor. Histological analyses further confirmed these outcomes, showing tumor cell death with features compatible with apoptosis and reduced local invasion. Together, these data indicate that caloric restriction enhances the antitumor efficacy of doxorubicin while simultaneously improving treatment tolerance. Conclusions: This study demonstrates that caloric restriction, combined with doxorubicin, is safe, well-tolerated, and enhances the antitumor response in the Sarcoma-180 model.