Inhibition of mTORC1/P70S6K pathway by Metformin synergistically sensitizes Acute Myeloid Leukemia to Ara-C

• Published in: Life sciences (1973) Vol. 243; p. 117276
• Main Authors: Yuan, Fang, Cheng, Cong, Xiao, Feiyan, Liu, Hongcai, Cao, Shan, Zhou, Gan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.02.2020; Elsevier BV
• Subjects: Acute myeloid leukemia; Acute Myeloid Leukemia (AML); Animals; Anticancer properties; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - therapeutic use; Antitumor activity; Antitumor agents; Apoptosis; Biocompatibility; Cell Line, Tumor; Cytarabine (Ara-C); Cytarabine - administration & dosage; Cytarabine - therapeutic use; Diabetes mellitus; Drug delivery systems; Drug Synergism; Humans; In vivo methods and tests; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - metabolism; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metformin; Metformin - administration & dosage; Metformin - therapeutic use; Mice; Mice, Inbred BALB C; Mice, Nude; mTORC1/P70S6K pathway; Myeloid leukemia; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Synergistic anti-tumor effect; TOR protein; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; mTORC1/P70S6K pathway; Metformin; Synergistic anti-tumor effect; Cytarabine (Ara-C); Acute Myeloid Leukemia (AML)
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.117276

Chemo-resistance still was the main obstacle for AML patients, more effective and less toxic forms of therapies were desperately needed. Metformin, a classic hypoglycemic drug for diabetes recently delivered us a new identity that it exerted anti-tumor activity through suppressing mTOR in various tumors. But the anti-tumor effect of metformin in AML was not clear. In this study, we used CCK8 assay and apoptosis assay to determine the anti-leukemia activity of metformin combined with AraC, and explore the mechanism of the joint role of Ara-C/metformin in AML. We finally used xenograft experiment in mice to determine the anti-leukemia effect of Ara-C/metformin in vivo. We found that metformin could synergistically sensitize AML cells to Ara-C via inhibiting mTORC1/P70S6K pathway. In vivo experiment also verified metformin in aid of Ara-C caused an obviously synergistic anti-tumor effect. We firstly found the synergistic anti-tumor effect of Ara-C/metformin in AML through inhibiting mTORC1/P70S6K pathway.