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

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

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 affectingcytotoxic drug potency by altering mitochondria-related cell stress responses(MRCSR) including mitophagy, mitochondrial biogenesis, and mitochondrialproteostasis. We evaluated in CLL cells from nine patients, the singleand multiple-combined drug potency of arsenic trioxide (ATO), valproic acid(VPA), vincristine (VCR) and MG132 as four pharmacologicalsensors influencing mitochondrial apoptosis, mitochondrial biogenesis,mitophagy, and mitochondrial proteostasis respectively, under normoxia andhypoxia to force hypoxia-inducedmetabolic reprogramming (HMR). Untreated cells from all patients remainedviable under O2 levels below0.5% for 72 h. We obtained 21 measures of drug potency and interaction at 50% effect levelthat we denoteddrug potency signature (DPS). Using the comparative DPS between normoxia andhypoxia, two nonsupervised classification algorithms discriminated CLL patients with activedisease (ADT) and stable disease (NAD) and showed complete consistency with their clinicalcharacteristics. In ADT group under hypoxia, the potencyof MG132 was increased, the interaction of ATO + VPA and ATO + VPA + VCRshifted towards antagonism, and ATO + VPA + VCR + MG132 shiftedtowards synergism, indicating a prominent role of mitochondrialproteostasis. Classification of patients based on DPS, depended on the contrastingresponse of drugsunder hypoxia and normoxia, owing to HMR. Using these drugs as pharmacologicalsensors, we linked the metabolic arrangement of CLLcells under hypoxia, to potency of drugs targeting MRCSR, and to the clinicalfeatures of individual patients, therefore providing new sources of dataon disease progression, drug response and risk prognosis.