Fig. 2

Overview of the altered glucose and lactate metabolism identified in myeloma. Glucose and lactate metabolism have been targeted in MM at several stages during the metabolic process; uptake, enzymatic conversion and export. Glucose transport in myeloma was blocked by targeting GLUT transporters (8-aminoadenosine, phloretin, STF-31, compound 20, ritonavir and siRNA/shRNA) or limiting the amount of glucose present for uptake (deprivation). Apart from the uptake, several glycolytic enzymes have also been targeted to reduce glycolytic function by inhibitors (3-bromopyruvate, 2-DG, 5MPN, PFK158 and JX06, dichloroacetate) and/or shRNAs. Moreover, serine metabolism can be inhibited by affecting PHGDH through shRNA, CBR5884 and NCT503. Serine deprivation also reduced MM viability. Lactate import through MCT1 was blocked by several metabolic inhibitors: AR-C155858, α-cyano-4-hydroxy-cinnamic acid and syrosingopine, while lactate production and export has been targeted through shRNA and syrosingopine. ACSS2 targeting by shRNA inhibited acetyl-CoA production. Used inhibitors, genetic approaches (siRNA/shRNA) and deprivations to affect these metabolic pathways are shown in red. Purple arrows indicate increase or decrease in a hypoxic environment. Enzymes are shown in grey. Successful combination approaches, resulting in lower viability or higher apoptotic cell death are shown in orange: *bortezomib, **melphalan, ***carfilzomib, $doxorubicin, $$dexamethasone, $$$daunorubicin, °metformin, °°venetoclax, °°°MG-123. HK: hexokinase, PGI: phosphoglucose isomerase, PFK: phosphofructokinase, GAPDH:  glyceraldehyde-3-phosphate dehydrogenase, PGK: phosphoglycerate kinase, PGM: phosphoglyceromutase, PK: pyruvate kinase, LDH: lactate dehydrogenase, PDK: pyruvate dehydrogenase kinase, MCT: monocarboxylate transporter, GLUT: glucose transporter, shRNA: short hairpin ribonucleic acid, siRNA: small interfering ribonucleic acid, PPP: pentose phosphate pathway, G6PD: glucose-6-phosphate dehydrogenase, FBPase: fructose-1,6-biphosphatase, PRL-3: phosphatase of regenerating liver 3, STOML2: stomatin-like protein 2, 5MPN: 5-(n-(8-methoxy-4-quinolyl)amino)pentyl nitrate, STF-31: 4-[[[[4-(1,1-dimethylethyl)phenyl]sulfonyl]amino]methyl]-N-3-pyridinyl-benzamide, PGC1β: peroxisome proliferator-activated receptor-gamma (PPAR-gamma) coactivator-1 beta, PDIA3P: protein disulfide isomerase family A member 3 pseudogene 1, 2-DG: 2-deoxyglucose, MALAT1: metastasis associated lung adenocarcinoma transcript 1, NEK2: NIMA-related kinase 2, ACSS2: acyl CoA synthetase short. Created with BioRender.com