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Seminars in Cell & Developmental Biology Seminars in Cell and Developmental Biology 98 (2020) 181–191 Contents lists available at ScienceDirect Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb Metabolic and non-metabolic pathways that control cancer resistance to T anthracyclines Tânia Capelôa, Zohra Benyahia, Luca X. Zampieri, Marine C.N.M. Blackman, Pierre Sonveaux* Pole of Pharmacology & Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium ARTICLE INFO ABSTRACT Keywords: Anthracyclines Doxorubicin, Epirubicin, Daunorubicin and Idarubicin are used to treat a variety of tumor types Chemoresistance in the clinics, either alone or, most often, in combination therapies. While their cardiotoxicity is well known, the Multidrug resistance emergence of chemoresistance is also a major issue accounting for treatment discontinuation. Resistance to Cancer stem cells anthracyclines is associated to the acquisition of multidrug resistance conferred by overexpression of perme- Cancer metabolism ability glycoprotein-1 or other efflux pumps, by altered DNA repair, changes in topoisomerase II activity, cancer Glycolysis stemness and metabolic adaptations. This review further details the metabolic aspects of resistance to anthra- Lipid metabolism cyclines, emphasizing the contributions of glycolysis, the pentose phosphate pathway and nucleotide bio- synthesis, glutathione, lipid metabolism and autophagy to the chemoresistant phenotype. 1. Introduction produced by bacterium Streptomyces peucetius species [8]. Experimen- tally, DNR induced important tumor regression in mice [1,7], and its Anthracyclines are a family of antitumor antibiotics used in children clinical efficacy was rapidly demonstrated in a clinical trial conducted and adult patients to treat a wide variety of solid tumors, including between 1963 and 1964 on patients with acute leukemias [1]. Un- breast, lung and stomach cancers, leukemia and lymphomas [1,2]. fortunately, its development was halted because of its high cardiac Despite their efficacy, their use is limited by toxicity to normal tissues toxicity [3]. In order to avoid, or at least to limit, this toxicity, several and treatment resistance. The major side effect of anthracyclines is anthracyclines were produced by genetic and chemical modifications cardiotoxicity due to cumulative doses [3]. On the long term, other [1,8], which led to the synthesis of more than 2,000 compounds, among organs, e.g., the brain, kidneys and the liver, can be affected [4], and which only few have been approved for clinical use [2,5]. Doxorubicin secondary cancers can be induced [5]. Tumor resistance to anthracy- (DOX) was derived from DNR by genetic modifications in bacteria [9]. clines involves mechanisms that can differ from tumor to tumor. Here, The main difference between DNR and DOX is the presence ofahy- we discuss cellular resistance mechanisms with a special focus on those droxyl group on the carbon 14 of DOX (Fig. 1B) [8]. Due to its broad that involve tumor metabolism. spectrum of action on liquid and solid tumors, DOX largely replaced Anthracyclines possess a common structure that consists in a tet- DNR for anticancer therapy, but, unfortunately, heart toxicity remained racyclic ring with quinone-hydroquinone groups linked to (3S, 4S, 5S)- a strong issue [9]. Among efforts to overcome this side effect, liposomal 3-amino-4,5-dihydroxyhexanal (Daunosamine) by a glycosidic bound formulation was the one showing better results: when used in ovarian (Fig. 1)[5,6]. The presence of Daunosamine accounts for the hydro- and breast cancers, this drug formulation had better therapeutic and philic properties of the drugs [6]. Specific anthracyclines are dis- safety profiles than conventional treatment [9]. tinguished by minor chemical changes that nevertheless profoundly Epirubicin (EPI) was then designed by introducing a chemical influence their half-lifes, capacity to bind to DNA, targetable tumor modification to DOX consisting in an inversion of the 4′-hydroxyl group types and toxicities [2,5]. on the amino-sugar moiety [10](Fig. 1C). The activity of EPI in tumors The first anthracyclines were identified by an Italian team who, is equivalent to that of DOX [5]. However, EPI is less toxic and is more between 1950 and 1960, was analyzing different natural compounds for easily eliminated in urine because it is more glucuronidated than DOX their activity against murine cancer cells [7]. The first anthracycline, [2,11]. Daunorubicin (DNR, Fig. 1A), was isolated from a red pigment The last anthracycline used in the clinics is Idarubicin (IDA). It was ⁎ Corresponding author at: Pole of Pharmacology & Therapeutics, Université catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200, Brussels, Belgium. E-mail address: [email protected] (P. Sonveaux). https://doi.org/10.1016/j.semcdb.2019.05.006 Received 29 March 2019; Received in revised form 9 May 2019; Accepted 9 May 2019 Available online 01 July 2019 1084-9521/ © 2019 Elsevier Ltd. All rights reserved. T. Capelôa, et al. Seminars in Cell and Developmental Biology 98 (2020) 181–191 Fig. 1. Chemical structure of anthracyclines. A, Daunorubicin (DNR). B, Doxorubicin (DOX). Compared to DNR, DOX is char- acterized by the presence of a hydroxyl group (OH) ①. C, Epirubicin (EPI). Dotted line ② indicates an inversion of the 4′- hydroxyl group on the daunosamine amino-sugar moiety of EPI compared to DOX. D, Idarubicin (IDA). Dotted line ③ indicates the absence of a methoxy group at carbon 4 on the structure of IDA compared to DNR. generated by a chemical modification of DNR consisting in removing fatty acids by ceramide synthase and serine palmitoyltransferase (SPT). the methoxy group at carbon 4 (Fig. 1D). Compared to DNR, IDA is A first evidence of the existence of this pathway was provided bythe characterized by a high lipophilicity and cellular uptake due to its observation that DNR triggers apoptosis by stimulating cycles of chemical structure that, additionally, allows oral delivery [12]. sphingomyelin hydrolysis with concomitant ceramide generation [17,18]. Ceramide production was proposed to involve de novo synth- esis via activation of ceramide synthase [17] or, alternatively, neutral 2. Modes of action of anthracyclines sphingomyelinase (SMAse) [18]. Similarly, Denard et al. [19] recently observed that the treatment of cancer cells with DOX induced de novo Despite their use to treat a variety of tumors, several studies were ceramide synthesis. Mechanistically, they reported that, in response to needed to understand the mode of action of anthracyclines. It has been DOX, ceramide accumulation in the endoplasmic reticulum (ER) led to widely proved that anthracyclines passively diffuse through plasmatic the translocation of transmembrane protein c-AMP-responsive element and nuclear cell membranes [13]. However, recent studies demon- binding protein 3 like 1 (CREB3L1) from the ER to the Golgi apparatus, strated that the proteasome is a nuclear transporter of DOX: cytosolic where it was cleaved by site-1 and site-2 proteases, thus releasing its DOX forms a complex with the proteasome that is translocated from the cytoplasmic NH -terminal domain. Upon release, the free CREB3L1 cytoplasm into the cell nucleus owing to the fact that the proteasome 2 protein fragment can translocate into the cell nucleus where it acts as a possesses nuclear translocation signals [2,14]. This process requires transcription factor that stimulates the transcription of cyclin-depen- ATP. Once inside the nucleus, the high affinity of DOX for DNA dis- dent kinase inhibitors, which ultimately blocks cell proliferation. The sociates the complex, and DOX, like other anthracyclines, intercalates whole pathway was blocked when DOX-treated cells received either with DNA bases to form adducts and to stop the activity of DNA and ceramide synthase inhibitor fumonisin B1 or SPT inhibitor myoricin RNA polymerases, consequently blocking DNA and RNA synthesis and [19]. triggering apoptosis [6]. Of note, the toxicity of anthracyclines can also be mediated by alterations of the proteasome. Indeed, DOX binding to the proteasome reduces its chymotrypsin-like protease activity, which 3. Antitumor use of anthracyclines in the clinics reduces the processing and degradation of regulatory proteins that control cell growth, thus triggering apoptosis [14]. Since their discovery, anthracyclines have been widely used in an- Anthracyclines were also found to induce cytotoxicity by inhibiting titumor therapies, not only as single treatments but also in combination topoisomerase II (TOPO II) [4], the enzyme that decreases DNA su- (Table 1). DOX is currently used as a standard therapy in breast cancers, percoiling by cutting DNA double strands during transcription and re- sarcomas, leukemias, Wilm’s tumors, Hodgkin’s disease and non- plication. Anthracyclines indeed block the catalytic activity of TOPO II. Hodgkin’s lymphomas [2,20], whereas EPI is indicated to treat breast, Thereby, they stabilize DNA breaks, thus contributing to inhibition of stomach, lung, ovarian and prostate cancers, as well as soft tissue sar- DNA replication and, consequently, initiating cell death [4,6]. An- comas [2,11]. DNR is mainly used for the treatment of myeloblastic and thracyclines are also capable to generate reactive oxygen species (ROS) lymphoblastic leukemias [20], and IDA is indicated for the treatment of through a redox reaction in the presence of cytochrome
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