Targeting mitochondrial respiration selectively sensitizes pediatric acute lymphoblastic leukemia cell lines and patient samples to standard chemotherapy.

: The clinical management of pediatric acute lymphoblastic leukemia (ALL) is still changeling and identification of agents that can sensitize standard chemotherapy is needed for its better management. In this work, we demonstrate that tigecycline, a FDA-approved antibiotic, is an attractive candidate for ALL treatment. Tigecycline inhibits growth and induces apoptosis of multiple ALL cell lines. Compared to normal hematopoietic cells, tigecycline is more active against primary lymphocytes and CD34 progenitors from ALL patients through decreasing survival and clonogenic growth. Notably, tigecycline significantly augments the efficacy of chemotherapeutic drugs, such as doxorubicin and vincristine, in ALL cell lines, primary samples and xenograft mouse model. Tigecycline acts on ALL via inhibiting mitochondrial respiration, leading to energy crisis and oxidative stress and damage. We show that the enhanced mitochondrial biogenesis and increased oxygen consumption rate in ALL versus normal hematopoietic cells are important for their different sensitivity to tigecycline. We further show that ATP production and growth rate are largely affected in mitochondrial respiration-deficient ρ0 ALL cells. Our work provides pre-clinical evidence for repurposing tigecycline for ALL treatment and highlights the therapeutic value of targeting mitochondrial metabolism in sensitizing ALL to chemotherapy.