Cyclic fasting bolsters cholesterol biosynthesis inhibitors' anticancer activity

Area of Science:

• Oncology
• Metabolic pathways
• Drug discovery

Background:

• Rising cancer treatment costs necessitate novel therapeutic strategies.
• Drug repurposing offers a cost-effective approach to identify new cancer treatments.
• Nutritional interventions like fasting may potentiate existing drug efficacy.

Purpose of the Study:

• To investigate if fasting enhances the anti-cancer properties of non-oncological drugs.
• To identify specific drug classes that benefit from combination with fasting.
• To elucidate the mechanisms by which fasting augments anti-tumorigenic drug effects.

Main Methods:

• Screening of drug libraries under fasting conditions.
• Assessing the anti-cancer activity of cholesterol biosynthesis inhibitors (CBIs) with and without fasting.
• Measuring changes in circulating hormones (insulin, IGF-1, leptin) and tumor metabolic markers.

Main Results:

• Fasting significantly increased the anti-cancer activity of CBIs, including simvastatin, across various cancer types.
• The enhanced efficacy was linked to reduced circulating insulin, IGF-1, and leptin, leading to decreased cholesterol biosynthesis and increased cholesterol efflux from cancer cells.
• Combined fasting and CBIs lowered tumor cholesterol, subsequently reducing AKT and STAT3 signaling, oxidative phosphorylation, and energy reserves.

Conclusions:

• Fasting potentiates the anti-tumor effects of cholesterol biosynthesis inhibitors.
• The combination therapy impacts key cancer cell signaling pathways and energy metabolism.
• This study supports further investigation of CBIs with fasting-based regimens for cancer therapy and highlights fasting's role in drug repurposing for oncology.