Journal article Open Access

Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation

Stevens, Alexandra M.; Xiang, Michael; Heppler, Lisa N.; Tosic, Isidora; Jiang, Kevin; Munoz, Jaime O.; Gaikwad, Amos S.; Horton, Terzah M.; Long, Xin; Narayanan, Padmini; Seashore, Elizabeth L.; Terrell, Maci C.; Rashid, Raushan; Krueger, Michael J.; Mangubat-Medina, Alicia E.; Ball, Zachary T.; Sumazin, Pavel; Walker, Sarah R.; Hamada, Yoshimasa; Oyadomari, Seiichi; Redell, Michele S.; Frank, David A.


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    <dct:description>&lt;p&gt;Atovaquone, a US Food and Drug Administration&amp;ndash;approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 mM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 ,30 mM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2a, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2a led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.&lt;/p&gt;</dct:description>
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