Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells – The involvement of carbonyl reductase 1 inhibition. (25th February 2019)

• Record Type: Journal Article
• Authors: Piska, Kamil; Koczurkiewicz, Paulina; Wnuk, Dawid; Karnas, Elżbieta; Bucki, Adam; Wójcik-Pszczoła, Katarzyna; Jamrozik, Marek; Michalik, Marta; Kołaczkowski, Marcin; Pękala, Elżbieta
• Is Part Of: Chemico-biological interactions. Volume 300(2019)
• Page Start: 40
• Page End: 48
• Publication Date: 2019-02-25
• Subjects: Anthracyclines -- Resistance -- Carbonyl reductase -- Piperlongumine -- Doxorubicin -- Piplartine; CBR1 carbonyl reductase 1 -- PL piperlongumine -- DOX doxorubicin -- AKRs aldo-keto reductases -- DOXol doxorubicinol -- DU-145 prostate cancer cell line -- CI Combination Index -- ANOVA One-way analysis of variance -- MCF-7 breast cancer cell line -- LDH lactate dehydrogenase -- FITC fluorescein isothiocyanate -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- PARP Poly (ADP-ribose) polymerase -- 7-AAD 7-Aminoactinomycin D -- ANX V Annexin V; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2019.01.003
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: One of the causes of therapeutic failure of chemotherapy is cancer cell resistance. In the case of anthracyclines, many resistance mechanisms have been described. One of them assumes the role of carbonyl reductase 1 (CBR1), a cytosolic enzyme that is responsible for the biotransformation process of anthracyclines to less active, undesirable metabolites. Therefore, CBR1 inhibitors are considered for use as a chemosensitizing agents. In the present study, piperlongumine (PL), a Piper longum L. alkaloid that has previously been described as a CBR1 inhibitor, was investigated for its chemosensitizing properties in co-treatment with doxorubicin (DOX). The biotransformation process of DOX in the presence of PL was tracked using human cytosol fraction and LC-MS, then a molecular modeling study was conducted to predict the interaction of PL with the active site of the CBR1. The biological interaction between DOX and PL was investigated using DU-145 prostate cancer cells. Cytotoxic and antiproliferative properties of DOX and PL were examined, and the type and potency of interaction was quantified by Combination Index. The mechanism of the cell death induced by the agents was investigated by flow cytometry and the anti-invasive properties of the drugs were determined by monitoring the movement of individual cells. PL showed dose-dependent inhibition of DOX metabolism in cytosol, which resulted in less doxorubicinol (DOXol) metabolite being formed. The possible mechanism of CBR1 inhibition was explained through molecular modeling studies by prediction of PL's binding mode in the active site of the enzyme's crystal structure-based model. DOX and PL showed a synergistic antiproliferative and proapoptotic effect on cancer cells. Significant anti-invasive properties of the combination of DOX and PL were found, but when the drugs were used separately they did not alter the cancer cells' motility. Cell motility inhibition was accompanied by significant changes in cytoskeleton architecture. DOX and PL used in co-treatment showed significant synergistic anticancer properties. Inhibition of DOX metabolism by PL was found to be a mechanism that was likely to be responsible for the observed interaction. Graphical abstract: Image 1 Highlights: Activity of the piperlongumine (PL) and doxorubicin (DOX) combination was studied. PL was evaluated as a potential inhibitor of the CBR1-mediated metabolism of DOX to doxorubicinol (DOXol). PL interact with the active site of the CBR-1. PL decrease the level of DOXol. PL act synergistically with DOX, thereby improving its anti-cancer properties.