Molecular mechanisms behind AICAr drug; impact on ALL

AICAr (5-amino-4-imidazolecarboxamide riboside, also called Acadesine) has been found to inhibit cell proliferation and has cytotoxic potential for childhood acute lymphoblastic leukemia (ALL) cells. Much of the drug's cytotoxic mechanisms, however, remain unknown. A new study published in The FASEB Journal explores the mechanisms behind AICAr.

Specifically, the study sought to determine: 1) whether AMP-activated (AMPK) was necessary for the cytotoxic effects of AICAr; and 2) if AICAr had selective effects on nucleotide pool balance—which is critical for cancer cell survival and growth—in childhood ALL cells. Researchers hypothesized that, just as chemotherapeutic agents cause an imbalance in cellular nucleotide pools that results in slowed , AICAr might inhibit ALL by regulating nucleotide metabolism.

Using the CRISPR/Cas9 system, researchers engineered ALL cell lines to study the molecular pathway related to AICAr's cytotoxicity. By knocking out Tumor Protein P53 (TP53) and PRKAA1 (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1) in NALM-6 and Reh , researchers were able to confirm that Acadesine's inhibition of cell proliferation was independent of AMPK activation, but dependent on P53. The researchers then used a liquid chromatography tandem-mass spectrometry system to demonstrate that the drug does indeed generate nucleotide imbalances.

"To our knowledge, this is the first time that the detailed molecular mechanisms of AICAr's cytotoxicity have been carefully characterized in ALL," explained Bin-Bing S. Zhou, Ph.D., director of the Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine. "With being the most common form of childhood leukemia, it is our hope that clinical application of AICAr might one day lead to improved cancer therapy."

"Oncologists treating ALL have had this drug on their for some time and this study advances its mode of action, key to the realization of its full clinical potential," said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal.

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Journal information: FASEB Journal

Citation: Molecular mechanisms behind AICAr drug; impact on ALL (2019, January 31) retrieved 18 October 2019 from
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