A drug potency signature links progression of chronic lymphocytic leukemia to mitochondria-related stress responses and metabolic reprogramming under hypoxia

KORNBLIHTT, LAURA I.; CABRAL LORENZO, MARÍA C.; GIL FOLGAR, MARTIN L.; MINISSALE, CLELIA J.; MALUSARDI, CECILIA; ROJAS, FRANCISCA; LOMBARDO, TOMÁS; BLANCO, GUILLERMO A.

TOXICOLOGY AND APPLIED PHARMACOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2020 vol. 398

0041-008X

Chronic lymphocytic leukemia (CLL) cells change their metabolic program between normoxia and hypoxia,possibly affecting cytotoxic drug potency by altering mitochondria-related cell stress responses (MRCSR) includingmitophagy, mitochondrial biogenesis, and mitochondrial proteostasis. We evaluated in CLL cells fromnine patients, the single and multiple-combined drug potency of arsenic trioxide (ATO), valproic acid (VPA),vincristine (VCR) and MG132 as four pharmacological sensors influencing mitochondrial apoptosis, mitochondrialbiogenesis, mitophagy, and mitochondrial proteostasis respectively, under normoxia and hypoxia to forcehypoxia-induced metabolic reprogramming (HMR). Untreated cells from all patients remained viable under O2levels below 0.5% for 72 h. We obtained 21 measures of drug potency and interaction at 50% effect level that wedenoted drug potency signature (DPS). Using the comparative DPS between normoxia and hypoxia, two nonsupervisedclassification algorithms discriminated CLL patients with active disease (ADT) and stable disease(NAD) and showed complete consistency with their clinical characteristics. In ADT group under hypoxia, thepotency of MG132 was increased, the interaction of ATO + VPA and ATO + VPA + VCR shifted towardsantagonism, and ATO + VPA + VCR + MG132 shifted towards synergism, indicating a prominent role ofmitochondrial proteostasis. Classification of patients based on DPS, depended on the contrasting response ofdrugs under hypoxia and normoxia, owing to HMR. Using these drugs as pharmacological sensors, we linked themetabolic arrangement of CLL cells under hypoxia, to potency of drugs targeting MRCSR, and to the clinicalfeatures of individual patients, therefore providing new sources of data on disease progression, drug responseand risk prognosis.