Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth

Abstract

Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy.

Uncovering the Lipid Web: Discovering the Multifaceted Roles of Lipids in Human Diseases and Therapeutic Opportunities

“…By understanding the specific alterations in lipid metabolism associated with different diseases, studies can develop targeted interventions to restore lipid homeostasis and mitigate disease progression. The potential of modulating lipid metabolism, such as targeting C5a/C5aR1 pathway in PD and lysosomal storage diseases [58,[87][88][89], ACAT1/SOAT1 inhibition in Alzheimer's disease [85], or modifying nutrient availability in cancer cells [70], opens new avenues for therapeutic approaches.…”

“…Turchi et al investigated the possibility of targeting nutrient availability as a complementary option for anti-cancer therapy, focusing on breast cancer models. By modifying the diet to be poor in proteins and sulfur amino acids while rich in oxidizable polyunsaturated fatty acids, the study revealed promising results in inhibiting breast cancer cell growth in vitro and in vivo [70]. Targeting the specific nutrient dependencies of cancer cells holds great potential for the development of personalized and effective therapeutic strategies.…”

“…The sophisticated relationship between lipid metabolism and cancer has become increasingly evident, with lipid droplets, lipolysis, and lipophagy emerging as crucial players in cancer cell growth and survival. The studies discussed in this editorial highlight the multifaceted roles of lipid metabolism in cancer and highlight their therapeutic implications [70,71]. Targeting lipid metabolism pathways, nutrient availability, and key regulatory molecules such as leptin holds promise for developing innovative and effective cancer therapies.…”

Micronutrient Status and Breast Cancer: A Narrative Review

“…Furthermore, a homemade fresh garlic extract has also been predicted to show anticancer activity, as it reduced tumor growth in preclinical mouse models with breast cancer [267]. Furthermore, a study from 2022 pointed to a low-sulfur amino acid diet as another possible inhibitor of breast cancer growth as it leads to decreased angiogenesis within the tumor mass as well as lower immune cell infiltrates and inflammatory cytokine production [268]. A lot of studies also focus on the iron-sulfur (Fe-S) clusters that form a protein, the nutrient deprivation autophagy factor-1, which is correlated with different cancer types [269][270][271][272].…”