In a recent review published in Cell Metabolism, researchers present the role of cyclic fasting and fasting-mimicking diets (FMD) in cancer therapy.
FMDs have anticancer properties that potentiate conventional therapies and protect normal tissues. In phase 1/2 clinical studies, cyclic FMD was safe, practical, and related to beneficial metabolic and immunomodulatory benefits in cancer patients. Modifying the extracellular concentration of metabolites such as glucose, amino acids, or fatty acids exerts anticancer effects via tumor cell-autonomous and immune system-dependent pathways.
About the review
In the present review, researchers discuss existing preclinical and clinical research and biological mechanisms underlying the effects of FND in oncological treatment.
Mechanisms underlying the anticancer actions of FMD
In hormonal-receptor-expressing breast cancers, FMD-induced growth factor (GF) level reductions suppress the phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTORC1) axis. Contrastingly, among triple-negative-type breast cancers (TNBC), starvation activates mTORC1 and PI3K-AKT pathways, increasing tumor sensitivity to chemotherapeutic agents by inhibiting deoxyribonucleic acid (DNA) repair. FMD results in longer remissions with mTORC1 and PI3K-AKT inhibitors.
The decrease in glucose obtainability caused by fasting/FMD may induce tumor cells to maximize adenosine triphosphate (ATP) generation by oxidative phosphorylation (OXPHOS) in mitochondria of glucose or other metabolic compounds such as amino and fatty acids. Increased glutathione availability and mitochondrial oxidation, along with lower nicotinamide adenine dinucleotide-phosphate hydrogen (NADPH) levels caused by impaired pentose-phosphate pathways, increases reactive oxygen species (ROS) levels, which can directly damage DNA and other intracellular structures.
FMD has immunomodulatory properties at the tumor and systemic levels. It lowers serum inflammatory monocyte cells, regulatory T (Treg) cells, and immunosuppressive myeloid cells while increasing natural killer T (NK) lymphocyte activation. FMD, combined with immunotherapy or chemotherapy, infiltrates activated NK and T cells in tumors, slowing tumor development and prolonging survival.
FMD lowers blood insulin-like growth factor-1 (IGF-1) levels, which inhibits IGF-1R activity in tumor cells and recruits cytotoxic clusters of differentiation 8-expressing (CD8+) T cells into the tumor. It also reduces CD73 levels, which reduce M2 macrophage infiltration and chemokine C-C motif ligand 2 (CCL2) levels in tumors. FMD raises the number of ketones such as 3-hydroxybutyrate (3HB) in blood, which inhibits programmed death-ligand 1 (PD-L1) activation on myeloid-type cells and facilitates heme oxygenase 1 (HO-1) differential regulation in cancerous and non-cancerous cells. Fasting enhances the anticancer effects of cholesterol biosynthesis inhibitors by lowering circulating insulin, IGF-1, and leptin levels, resulting in lower cholesterol production and higher cholesterol efflux from cancer cells. In tumor cells, low amounts of intracellular cholesterol inhibit signal transducer and activator of transcription 3 (STAT3) and AKT activity, and oxidative phosphorylation.
Preclinical and clinical evidence of fasting-based combination strategies against cancer
Fasting has shown anticancer characteristics in various cancer models, including breast, colorectal, lung, liver, ovarian, and pancreatic carcinomas, gliomas, neuroblastomas, melanomas, acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Fasting improves gemcitabine anticancer efficacy in pancreatic cancer models by boosting gemcitabine absorption and making mesothelioma cancer cells more sensitive to cisplatin via 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 anticancer effectiveness of anti-PD-L1/antitumor necrosis factor receptor (anti-OX40) immunotherapy by modifying the intratumor immune system. When paired with chemotherapy, PI3K-AKT, mTORC1 inhibitors, and immunotherapy, FMD enhances long-term tumor responses. Cyclic FMD coupled with ETs plus cyclin-dependent kinase 4/6 (CDK4/6) inhibitors results in long-lasting tumor remissions in murine models of hormone-receptor-positive human epidermal GF receptor 2 (HER2)-negative BC. FMD also works with anti-PD-1 therapy in non-small cell lung cancer (NSCLC to lower tumor IGF-1 plasma levels and downregulate the IGF-1R axis.
FMD improves the anticancer effects of tyrosine kinase receptor inhibitors, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1), and vascular endothelial growth factor receptor (VEGFR), in various cancers. Combining FMD with CDK4/6 inhibitors results in long-term tumor remission and higher cure rates. FMD synergizes with metformin to treat Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene-mutated colorectal cancers by generating ROS and disrupting iron metabolism. FMD activates proteasome activity in CLL models, a famine escape mechanism that bortezomib can address.
Based on the findings, FMD has promising antitumor, metabolic, and immunomodulatory effects when combined with standard anticancer treatments. However, patient adherence is critical for its anticancer benefits, necessitating regular communication between patients and clinical personnel to avoid treatment cessation. Implementing clinical care of patients undergoing FMD with conventional medicines, and discovering predictive biomarkers and tumor sensitivity and resistance mechanisms, is critical to further FMD use in cancer treatment.
