In a recently published overview Cell metabolismResearchers present the role of cyclic fasting and fasting-like diets (FMD) in cancer therapy.
FMDs have anti-cancer properties that enhance conventional therapies and protect normal tissues. In Phase 1/2 clinical trials, cyclic FMD was safe, convenient, and associated with positive metabolic and immunomodulatory benefits in cancer patients. Altering the extracellular concentration of metabolites such as glucose, amino acids, or fatty acids exerts anti-cancer effects via tumor cell-autonomous and immune system-dependent pathways.
About the review
In the present review, researchers discuss existing preclinical and clinical research findings as well as the biological mechanisms underlying the effects of FND in oncology treatment.
Mechanisms underlying the anticancer effect of FMD
In breast cancer expressing hormone receptors, FMD-induced reduction in growth factor (GF) levels suppresses the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTORC1) axis. In contrast, in triple-negative breast cancer (TNBC), starvation activates the mTORC1 and PI3K-AKT pathways and increases tumor sensitivity to chemotherapeutic agents by inhibiting deoxyribonucleic acid (DNA) repair. FMD leads to prolonged remissions with mTORC1 and PI3K-AKT inhibitors.
The decrease in glucose availability caused by fasting/FMD may induce tumor cells to maximize the generation of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) of glucose or other metabolic compounds such as amino and fatty acids in the mitochondria. Increased glutathione availability and mitochondrial oxidation, as well as lower nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) levels due to impaired pentose phosphate pathways, increase the levels of reactive oxygen species (ROS), which can directly damage DNA and other intracellular structures.
FMD has immunomodulatory properties at the tumor and systemic level. It reduces the number of serum inflammatory monocyte cells, regulatory T cells (Treg) and immunosuppressive myeloid cells, while increasing the activation of natural killer T (NK) lymphocytes. FMD, in combination with immunotherapy or chemotherapy, infiltrates activated NK and T cells into tumors, slows tumor progression and prolongs survival.
FMD lowers insulin-like growth factor-1 (IGF-1) levels in blood, which inhibits IGF-1R activity in tumor cells and recruits cytotoxic clusters of differentiation 8-expressing (CD8+) T cells into the tumor. It also lowers CD73 levels, which reduces M2 macrophage infiltration and chemokine CC motif ligand 2 (CCL2) levels in tumors. FMD increases the number of ketones such as 3-hydroxybutyrate (3HB) in blood, which inhibits the activation of programmed cell death ligand 1 (PD-L1) on myeloid cells and facilitates the differential regulation of heme oxygenase 1 (HO-1) in cancer and non-cancer cells. Fasting enhances the anti-cancer effects of cholesterol biosynthesis inhibitors by reducing circulating insulin, IGF-1 and leptin levels, resulting in lower cholesterol production and higher cholesterol efflux from cancer cells. In tumor cells, low levels of intracellular cholesterol inhibit signal transducer and activator of transcription 3 (STAT3) and AKT activity, as well as oxidative phosphorylation.
Preclinical and clinical evidence for fasting-based combination strategies against cancer
Fasting has demonstrated anticancer properties in various cancer models, including breast, colon, lung, liver, ovarian, and pancreatic carcinomas, gliomas, neuroblastoma, melanoma, acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Fasting enhances the anticancer effects of gemcitabine in pancreatic cancer models by increasing gemcitabine absorption and making mesothelioma cancer cells more sensitive to cisplatin through adenosine monophosphate-activated protein kinase (AMPK)-dependent activation of the ataxia-telangiectasia mutated protein (ATM)/checkpoint kinase 2 (Chk2)/p53 tumor protein signaling axis.
In triple-negative breast cancer (TNBC), FMD improves the efficacy of anti-PD-L1/anti-tumor necrosis factor receptor (anti-OX40) anticancer immunotherapy by modifying the intratumoral immune system. In combination with chemotherapy, PI3K-AKT, mTORC1 inhibitors, and immunotherapy, FMD improves long-term tumor responses. Cyclic FMD in combination with ETs plus cyclin-dependent kinase 4/6 (CDK4/6) inhibitors leads to long-lasting tumor remissions in mouse models of hormone receptor-positive human epidermal GF receptor 2 (HER2)-negative breast cancer. FMD also works with anti-PD-1 therapy in non-small cell lung cancer (NSCLC) to reduce plasma levels of tumor IGF-1 and downregulate the IGF-1R axis.
FMD enhances the anticancer effects of tyrosine kinase receptor inhibitors, including EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase)/ROS1 (C-Ros oncogene 1), and VEGFR (vascular endothelial growth factor receptor), in various cancers. Combining FMD with CDK4/6 inhibitors results in long-term tumor remission and higher cure rates. FMD acts synergistically with metformin in the treatment of colorectal cancer with mutation in the Ki-ras2 Kirsten rat sarcoma virus oncogene homolog (KRAS) gene by generating ROS and disrupting iron metabolism. FMD activates proteasome activity in CLL models, a famine escape mechanism that bortezomib can target.
Based on the findings, FMD in combination with standard cancer treatments has promising antitumor, metabolic and immunomodulatory effects. However, patient adherence is crucial for the anticancer effect. This requires regular communication between patients and clinicians to avoid treatment discontinuation. Clinical care of patients receiving FMD with conventional drugs and the discovery of predictive biomarkers and tumor sensitivity and resistance mechanisms are crucial for the further use of FMD in cancer treatment.
