Cyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity

Amr Khalifa, Ana Guijarro, Silvia Ravera, Nadia Bertola, Maria Pia Adorni, Bianca Papotti, Lizzia Raffaghello, Roberto Benelli, Pamela Becherini, Asmaa Namatalla, Daniela Verzola, Daniele Reverberi, Fiammetta Monacelli, Michele Cea, Livia Pisciotta, Franco Bernini, Irene Caffa () and Alessio Nencioni ()
Additional contact information
Amr Khalifa: University of Genoa
Ana Guijarro: University of Genoa
Silvia Ravera: University of Genoa
Nadia Bertola: University of Genoa
Maria Pia Adorni: University of Parma
Bianca Papotti: University of Parma
Lizzia Raffaghello: IRCCS Istituto Giannina Gaslini
Roberto Benelli: Ospedale Policlinico San Martino IRCCS
Pamela Becherini: University of Genoa
Asmaa Namatalla: University of Genoa
Daniela Verzola: University of Genoa
Daniele Reverberi: Ospedale Policlinico San Martino IRCCS
Fiammetta Monacelli: University of Genoa
Michele Cea: University of Genoa
Livia Pisciotta: University of Genoa
Franco Bernini: University of Parma
Irene Caffa: University of Genoa
Alessio Nencioni: University of Genoa

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Identifying oncological applications for drugs that are already approved for other medical indications is considered a possible solution for the increasing costs of cancer treatment. Under the hypothesis that nutritional stress through fasting might enhance the antitumour properties of at least some non-oncological agents, by screening drug libraries, we find that cholesterol biosynthesis inhibitors (CBIs), including simvastatin, have increased activity against cancers of different histology under fasting conditions. We show fasting’s ability to increase CBIs’ antitumour effects to depend on the reduction in circulating insulin, insulin-like growth factor-1 and leptin, which blunts the expression of enzymes from the cholesterol biosynthesis pathway and enhances cholesterol efflux from cancer cells. Ultimately, low cholesterol levels through combined fasting and CBIs reduce AKT and STAT3 activity, oxidative phosphorylation and energy stores in the tumour. Our results support further studies of CBIs in combination with fasting-based dietary regimens in cancer treatment and highlight the value of fasting for drug repurposing in oncology.

Date: 2023
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DOI: 10.1038/s41467-023-42652-1

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