Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment
Abstract
:1. Introduction
2. Methodology for Database Analysis
3. Caloric Restriction
3.1. Definition and Cancer-Associated Molecular Pathways
3.1.1. Energy Sensor Pathways: PI3K-AKT-mTOR and AMPK
3.1.2. Sirtuins
3.1.3. Nrf2
3.1.4. GH/IGF-1 Axis
4. Dietary Interventions and Their Anti-Tumorigenic Effect: Bench to Bedside
Study Design | Type(s) of Cancer | SOC | Intervention | Outcomes | REF. |
---|---|---|---|---|---|
Phase 2. Randomized, controlled, observer-blind | HER- BC | CT with dexamethasone | Fast-mimicking diet | There is no difference in pCR. The toxicity was partially reduced after FMD without the use of dexamethasone. Increase in the MP. Reduction in glucose, insulin, IGF1, and DNA leukocyte damage. | [77] |
Phase 1, non-randomized | Advanced NSCLC and PaCa | CRT | Ketogenic diet | No tolerability of the intervention. Not enough patients to analyze overall survival nor partial response. Increase in carbonylated proteins in serum as an indicator of increased oxidative stress. | [74] |
Phase 1, non-randomized | HNSCC | CRT | Ketogenic diet | Poor tolerability of the diet. Not enough patients to analyze overall survival nor partial response. No evident changes in carbonylated proteins nor GSH as indicators of increased redox stress. | [73] |
Phase 1, non-randomized | Multiple | CT | Short-term fasting | The intervention was well tolerated by all participants.Reduction in blood leukocyte damage after 24 h of fasting. | [13] |
Pilot study, randomized, controlled | PC | Sx or active surveillance | Caloric restriction | The restriction diet was well tolerated. Increase in serum IGFBP-3 levels, along with insulin and C-peptide. | [15] |
Phase 1, single arm | Multiple | SOC | Fast-mimicking diet | FMD along with the SOC decreased glucose, insulin, and IGF1 levels in serum. There was also a reduction in myeloid-derived suppressor cells and PD+ cells. In tumor and blood, there was an increase in CD8+, NK, and macrophage infiltration. | [80] |
Phase 1, randomized, not blind | BC | CT | Ketogenic diet | Dietetic intervention reduced serum TNF-a and insulin levels. Also, CT plus KD reduced tumor size and TNM compared to control. | [81] |
Pilot study, randomized, blind | DLBCL | CT + biologic | Short-term caloric reduction | The intervention was safe and feasible. The intervention improved hematological parameters. | [72] |
Pilot study, randomized, cross-over | BC and OC | CT | Short-term fasting | Short-term fasting is feasible and reduces chemotherapy side effects, improving quality of life. | [83] |
Phase 1, randomized, controlled | BC | SOC | Ketogenic diet | Ketogenic diet improved quality of life, but not in biomarkers after 12 weeks of intervention. | [84] |
5. Caloric Restriction Mimetics (CRM)
5.1. Definition
5.1.1. Metformin
Study Design | Type(s) of Cancer | SOC | CRM | Outcomes | REF. |
---|---|---|---|---|---|
Pilot study, randomized, non-blinded | BC | Sx | Metformin 1 g/12 h | Preoperative use of metformin showed no decrease in tumor size but a significant reduction of Ki-67 and PDE3B cells. | [91] |
Population-based retrospective cohort study | None | None | Metformin | The usage of metformin monotherapy or in combination with other antidiabetic drugs reduced the incidence of cancer in type 2 diabetic patients. | [90] |
Pilot study, single arm | EC | Sx | Metformin 2 g/d | Preoperative use of metformin decreased Ki-67 and Ps6 staining and reduced serum levels of glucose and IGF1. It decreased proliferative markers ERK1/2 and Cyclin D1. | [93] |
Phase 2, randomized | NSCLC | CT | Metformin 2 g/d | Concomitant use of metformin increased progression-free survival by 32% at one year compared to control. | [96] |
Phase 2, randomized | CC | CRT | Metformin | Metformin increased 2-year disease-free survival by up to 67% compared to 33% in the controls. | [103] |
Phase 2, randomized, double-blind, placebo-controlled | BC | Sx | Metformin 850 mg/12 h | Overall, no difference in proliferation rates between groups. In subgroup analysis, metformin showed a heterogeneous effect dependent on insulin resistance. | [104] |
Phase 2, randomized, placebo-controlled | BC | CR | Metformin 850 mg/12 h | There is no difference in progression-free survival nor overall response. | [99] |
Phase 2, randomized | NSCLC | CR | Metformin 1000 mg/12 h | Overall, there was no difference in risk of progression or death compared to control. In high fluorodeoxyglucose-uptake cancers, the addition of metformin to CT decreased the risk of progression and death. | [105] |
5.1.2. Rapamycin and Its Analogs
Study Design | Type(s) of Cancer | SOC | CRM | Outcomes | REF. |
---|---|---|---|---|---|
Phase 2, non-randomized | FTC | None | Everolimus 10 mg/d | Increased stable disease and overall survival compared to other interventions with fewer side effects. | [110] |
Phase 2, single arm | BTC | None | Everolimus 10 mg/d | Median progression-free survival of 5.5 months and median OS of 9.5 months | [111] |
Phase 2 | CRC | CT+ biologic | Everolimus | The addition of Everolimus to standard therapy increased progression-free survival by 20% at 6 months. The subgroup of patients with PTEN mutations might show a better response. | [112] |
Phase 2, single arm | BC | Aromatase inhibitor | Everolimus 10 mg/d | Everolimus and aromatase inhibitor (Exemestane) bitherapy increased progression-free survival by up to 6 months compared to aromatase inhibitor monotherapy. | [109] |
Phase 2, randomized, double-blind, placebo-controlled | TNBC | CT | Everolimus 5 mg/d | Neoadjuvant addition of Everolimus to CT did not increase pathological complete response compared to placebo and added toxicity. | [114] |
Phase 2, randomized | PC | Sx | Everolimus 5 mg/d vs. 10 mg/d | No difference in mTOR markers, nor PSA pre- and post-operative with the intervention. | [117] |
Phase 2, randomized | HER2-BC | CT | Everolimus 5 mg/d | No difference in progression-free survival and overall survival compared to monotherapy alone. | [115] |
Phase 2, non-randomized | FTC | None | Everolimus 10 mg/d | Increased stable disease and overall survival compared to other interventions with fewer side effects. | [110] |
5.1.3. Aspirin
Study Design | Type(s) of Cancer | SOC | CRM | Outcomes | REF. |
---|---|---|---|---|---|
Multicenter, double-blind, placebo-controlled | None | None | Aspirin and/or NSAIDs | The use of aspirin and NSAIDs reduces serum levels of prostate-specific antigen. Aspirin consumption reduced the risk of prostate cancer development. | [125] |
Multicenter, double-blind, randomized, placebo-controlled | None | None | Aspirin 600 mg/d | Obesity-related risk of developing colorectal cancer is reduced after aspirin consumption. | [130] |
Randomized, placebo-controlled | None | None | Aspirin 235 mg | Pre-diagnostic use of aspirin lowered the risk of lethal prostate cancer. Post-diagnostic use improved survival compared to placebo. | [126] |
Pilot study | None | None | Resveratrol 500 mg | Doses up to 2.5 g of resveratrol were well tolerated in healthy patients and were able to reduce IGF-1 and IGFBP-3 levels. | [131] |
Phase 1, non-randomized | CRC | Sx | Resveratrol 0.5 or 1.0 g | Use of resveratrol reduced cell proliferation. | [132] |
Phase 1, randomized, double-blind, placebo-controlled | CRC | None | Resveratrol 5 g (SRT501) | The micronized formulation of resveratrol increases apoptosis rate in CRC. No difference in IGF-1, Ki67, AKT, GSK, ERK, JNK, or beta-catenin. | [133] |
5.1.4. Resveratrol
6. Discussion
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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De-Leon-Covarrubias, U.E.; Perez-Trujillo, J.J.; Villa-Cedillo, S.A.; Martinez-Perez, A.G.; Montes-de-Oca-Saucedo, C.R.; Loera-Arias, M.d.J.; Garcia-Garcia, A.; Saucedo-Cardenas, O.; Montes-de-Oca-Luna, R. Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment. Metabolites 2024, 14, 418. https://doi.org/10.3390/metabo14080418
De-Leon-Covarrubias UE, Perez-Trujillo JJ, Villa-Cedillo SA, Martinez-Perez AG, Montes-de-Oca-Saucedo CR, Loera-Arias MdJ, Garcia-Garcia A, Saucedo-Cardenas O, Montes-de-Oca-Luna R. Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment. Metabolites. 2024; 14(8):418. https://doi.org/10.3390/metabo14080418
Chicago/Turabian StyleDe-Leon-Covarrubias, Ulises Edgardo, Jose Juan Perez-Trujillo, Sheila Adela Villa-Cedillo, Alejandra Guadalupe Martinez-Perez, Carlos Roberto Montes-de-Oca-Saucedo, Maria de Jesus Loera-Arias, Aracely Garcia-Garcia, Odila Saucedo-Cardenas, and Roberto Montes-de-Oca-Luna. 2024. "Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment" Metabolites 14, no. 8: 418. https://doi.org/10.3390/metabo14080418