Efforts to define biochemical andpharmacologic pathways potentially beneficial to bothcancer and COVID-19 patients
Authors: U. Rovigatti, A. Vannacci, S. Del Corto, I. Martin-Loeches, A. Piccin, N. Naji, C. Mothersill
Journal: Clinical Cancer Research (2020)

Since COVID-19 infections have been frequently diagnosed in cancer patients, often associated with worstprognosis (1), an effort was conducted in order to identify biomolecular pathways and repurposable drugs, whichcould benefit patients for COVID-19 and cancer at the same time  Starting from over 3265 PubMed references, wehave screened approximately 650 abstracts in order to identify the two most interesting pathways  Abstract wereindependently read and selected by UR and AV and then discussed in video conferences  Final decision onbiochemical pathways or particular drugs was agreed only after identification of potential underlying molecularmechanism(s) for both COVID-19 and specific cancer types  Both impinge on the basic structure of 4-aminoquinoline, which is the alkaloid backbone of several important compounds effective in parasitology, rheumatology and cancer treatment  Their pharmacologic utilization was initiated with the discovery of quinine fromthe bark of the cinchona tree (1630) with further synthetic drugs developments such as chloroquine (CQ) andhydroxychloroquine (HCQ) in 1949-50, all variants of the 4-aminoquinoline family (2)  1  One pathway targets thePNP enzymes (purine nucleoside phosphorylases), dysregulation of which is often associated with apoptosis incancer cells  PNP has been considered an oncogene, which is downregulated by tumor suppressors in PCa (miR-I;miR-133) (3)  PNP inhibition has been demonstrated by strong binding of the aminoquinoline quinine throughseveral MS technologies (4)  We are investigating whether this is also true for COVID-19  2  A second pathway isassociated with HCQ usage  We have recently reviewed how HCQ at higher dosage could benefit COVID-19patients, if they are treated in the earlier (or prophylactic) phases of the disease (5)  Despite the wide publicity ofHCQ negative effects, the results of Mehra et al  in Lancet have been recently questioned in an open letter onseveral scientific and ethical grounds and the paper has been finally retracted  Furthermore, there are still few andsmall RCTs testing this drug in the early disease phases  HCQ behaves as a weak base that is typically trappedinside the acidic environment of phagocytic organelle such as lysosomes thus raising their pH (2)  Therefore, inthe presence of lysosomotropic HCQ: 1  SARS-CoV-2 appears to be blocked inside lysosomes and devoid of theproteolytic cleavage required for infection (6) and 2  in cancer cells, the important mechanism of autophagy isstrongly inhibited, causing tumor shrinkage or apoptosis (also in association with chemotherapy) (7)  We arepresently investigating HCQ effects in patients' tumors explants or surrogate tissues  Our efforts in identifyingmolecular/pharmacologic pathways that could benefit patients for both COVID-19 and cancer led to the identificationof at least two pathways, PNP and autophagy both associated to 4-aminoquinoline derivatives which are nowbeing studied in experimental models