Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:6538-6539.

A novel therapeutic approach to colorectal cancer in diabetes: role of metformin and rapamycin

Alice Gerges Geagea, Manfredi Rizzo, Abdo Jurjus _, Francesco Cappello, Angelo Leone, Giovanni Tomasello, Céline Gracia, Sahar Al Kattar, Liliane Massaad-Massade and Assaad Eid

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Oncotarget. 2019; 10:1284-1305. https://doi.org/10.18632/oncotarget.26641

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Alice Gerges Geagea1,2, Manfredi Rizzo1, Abdo Jurjus2, Francesco Cappello4, Angelo Leone4, Giovanni Tomasello4, Céline Gracia3, Sahar Al Kattar2, Liliane Massaad-Massade3 and Assaad Eid2

1Department of Internal Medicine, University of Palermo, Palermo, Italy

2Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

3Equipe Nouvelles Thérapies Anticancéreuses, UMR8203 CNRS, Gustave Roussy, Villejuif, France

4Department of Biomedicine, Neurosciences and Advanced Diagnosis, School Of Medicine of Palermo, Palermo, Italy

Correspondence to:

Abdo Jurjus, email: [email protected]

Assaad Eid, email: [email protected]

Keywords: colorectal cancer; diabetes mellitus; probiotics; inflammatory cytokines; mTOR

Received: October 30, 2018     Accepted: January 14, 2019     Published: February 12, 2019


The link between colorectal cancer (CRC), diabetes mellitus (DM) and inflammation is well established, and polytherapy, including rapamycin, has been adopted. This study is a novel approach that aimed at assessing the effect of a combination therapy of metformin and rapamycin on the control or prevention of CRC in diabetic animals, in presence or absence of probiotics.

Fifty NOD/SCIDs male mice developed xenograft by inoculating HCT116 cells. They were equally divided into diabetics (induced by Streptozotocin) and non-diabetics. Metformin was given in drinking water, whereas rapamycin was administered via intra-peritoneal injections. Probiotics were added to the double therapy two weeks before the sacrifice. Assessment was performed by clinical observation, histological analysis, Reactive oxygen species (ROS) activities and molecular analysis of Interleukin 3 and 6, Tumor Necrosis Factor alpha, AMP-activated protein Kinase and the mammalian target of rapamycin. Decreases in the level of tumorigenesis resulted, to various extents, with the different treatment regimens. The combination of rapamycin and metformin had no significant result, however, after adding probiotics to the combination, there was a marked delay in tumor formation and reduction of its size, suppression of ROS and a decrease in inflammatory cytokines as well as an inhibition of phosphorylated mTOR.

Existing evidence clearly supports the use of rapamycin and metformin especially in the presence of probiotics. It also highlighted the possible mechanism of action of the 2 drugs through AMPK and mTOR signaling pathways and offered preliminary data on the significant role of probiotics in the combination. Further investigation to clarify the exact role of probiotics and decipher in more details the involved pathways is needed.

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