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Fig. 3 | Experimental Hematology & Oncology

Fig. 3

From: Metabolic cross-talk within the bone marrow milieu: focus on multiple myeloma

Fig. 3

Overview of the altered glutamine and fatty acid metabolism identified in myeloma. Glutamine and fatty acid metabolism have been targeted in MM at several stages during the metabolic process; uptake and enzymatic conversion. Glutamine metabolism can be targeted by either affecting the glutamine uptake (by inhibitors GPNA, BCH, MeAIB or shRNA) or depriving the cells of glutamine by deprivation or l-asparaginase. Conversion of glutamine to glutamate is blocked by CB-839, BPTES and compound 968, while conversion to other metabolites was blocked by DHA and EPA for GSH production, as well as pargyline and siRNA for proline production. Uptake of acyl-carnithine into the mitochondria through CPT1 has been blocked in MM by etomoxir, lovastatin, cerulenin and orlistat affect acetyl-CoA metabolism. Amitriptyline, GW4869 and K145 affect sphingolipid metabolism, while simvastatin, metformin and phenformin affect complex I and II of the electron transport chain. Used inhibitors, genetic approaches (siRNA/shRNA) and deprivations are shown in red. Enzymes are shown in grey. Purple arrows indicate increase or decrease in a hypoxic environment. Successful combination approaches are shown in orange: *bortezomib, **melphalan, ***carfilzomib, $doxorubicin, $$dexamethasone, $$$daunorubicin, °metformin, °°venetoclax, °°°MG-123. CPT1: carnithine palmitoyltransferase I, GSH: glutathione, GPNA: l-γ-Glutamyl-p-nitroanilide, BCH: 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, MeAIB: α-(Methylamino)isobutyric acid, BPTES: Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulphide, DHA: docosahexaenoic acid, EPA: eicosapentaenoic acid, siRNA: small interfering ribonucleic acid, AA: amino acid, FAS: fatty acid synthase, HMG: β-hydroxy β-methylglutaryl, SK-2: sphingokinase 2, aSMase: acid sphingomyelinase, nSMase: neutral sphingomyelinase, LAT1: large amino acid transporter 1, ASCT2: alanine, serine, cysteine transporter 1, SNAT1: sodium-coupled neutral acid transporter 1, GLS: glutaminase, PYCR: pyrroline-5-carboxylate reductase, GSH: glutathione. Created with BioRender.com

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