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Inhibitors of Carbohydrate Processing: a New Class of Anticancer Agents1’2

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Inhibitors of Carbohydrate Processing: a New Class of Anticancer Agents1’2 Vol. 1, 935-944, September 1995 Clinical Cancer Research 935 Minireview Inhibitors of Carbohydrate Processing: A New Class of Anticancer Agents1’2 Paul E Goss,3 Michael A. Baker, clinical applications of this new class of anticancer agents Jeremy P. Carver, and James W. Dennis are emphasized. The Toronto Hospital, Department of Medical Oncology, Faculty of Medicine [P. E. G., M. A. B.] and Department of Medical Genetics Carbohydrate Processing and Malignancy [J. P. C., J. W. D.], University of Toronto, Toronto, Ontario, and Malignant transformation is associated with a variety of Samuel Lunenfeld Research Institute, Mt. Sinai Hospital [J. W. D], structural alterations in the carbohydrate portion of glycopro- Toronto, Ontario M4X 1K9, Canada teins (1-4). Glycoprotein glycosylation (Fig. 1) begins in the lumen of the rough endoplasmic reticulum (5-8) where a subset Abstract of Asn (i.e., N-linked) and SeriThr (i.e., 0-linked) residues on There is a need for anticancer agents with novel mech- newly synthesized proteins are subject to the addition of anisms of action. Recently identified molecular targets for sugars (reviewed in Ref. 6). For N-linked carbohydrates, new anticancer agents include inducers of cell differentia- Glc3Man9GlcNAc2 s preassembled on dolichol PP1 and then tion, cell cycle arrest, and apoptosis, as well as signaling transferred as a unit to Asn-X-Ser/Thr sequences of glycopro- pathways for growth factors and cytokines. teins while they are being synthesized. This initial glycosylating Another unexplored opportunity is presented by the event is required for many glycoproteins to fold into their native ubiquitous intracellular glycoprotein glycosylation pathway. or active conformation. The Glc3Man9GlcNAc2 structures are This complex process, concerned with the addition of sugars then remodeled or processed as the newly synthesized glyco- onto newly synthesized proteins, occurs in the lumen of the proteins are transported through the Golgi on route to the cell rough endoplasmic reticulum and in the Golgi. There are surface. As depicted in Fig. 1, this begins with trimming by estimates of over 200 glycosyltransferase enzymes in this a-glucosidases and a-mannosidases I, leaving Man5GlcNAc2-N pathway, which results in considerable structural diversity which is then substituted by GIcNAc-TI and trimmed by a-man- of carbohydrates found on secreted and transmembrane nosidase II producing GlcNAcMan3GlcNAc2-N. The latter glycoproteins. The specificity of glycosyltransferases for ac- structure is a substrate for the GlcNAc-Ts (i.e., G1cNAc-T-II, ceptors and sugar-nucleotide donors dictates linkage posi- -IV, -V); each enzyme substitutes a distinct position on the tions between sugars, anomeric configuration of linkages, trimannose core to initiate “branches” (6). Cancer cells corn- and monosaccharide composition. Specific carbohydrate monly show increased 31-6-N-acetylglucosamine (G1cNAc)- structures participate in cell-cell and cell-substratum inter- branching at the trimannosyl core of N-linked carbohydrates actions affecting processes such as lymphocyte trafficking, (9-12). For example, increased branching has been noted in immune cell stimulation, embryogenesis, and cancer metas- primary tumors of human carcinoma of the breast, colon, and tasis. skin, and appears also to correlate with disease progression (13, Of the carbohydrate-processing inhibitors presently 14). In normal tissues, the 31-6GlcNAc branched carbohydrate available, the alkaloid swainsonine, a Golgi a-mannosidase structures are restricted to cells capable of invasion including II inhibitor, is the first to have been selected for clinical trophoblasts, endothelial cells, interstitial fibroblasts, and acti- testing based on its anticancer activity, p.o. availability, and vated lymphocytes (14, 15). The key enzyme which initiates the low toxicity in mice. Herein, we review the rationale for 31-6 branching is 31-6GlcNAc TV” (see Fig. 1 and Ref. 9). targeting Golgi carbohydrate processing pathways in the The antenna or branch initiated by G1cNAc-TV is preferred treatment of cancer, and summarize the preclinical and by subsequent enzymes in the pathway for extension with clinical results with swainsonine. Prospects for the develop- polylactosamine (i.e., repeating Gal31-4GlcNAc31-3), Lewis ment of second generation inhibitors with improved speci- antigens, and blood-group sequences (Refs. 16-18 and Fig. 1). ficity for Golgi-processing enzymes are discussed. Potential These sequences are developmentally regulated structures with limited distribution in normal tissues, but they are expressed in human carcinoma and therefore appear to be markers of malig- nancy (19, 20). Polylactosamine and Lewis antigen expression Received 3/31/95; revised 6/26/95; accepted 7/5/95. on tumor cells may contribute to cell-cell adhesion via selectins 1 This work was supported by research grants from the National Cancer and 3Gal-binding lectins, which are found on the vascular Institute of Canada and Medical Research Council of Canada. J. W. D. endothelium, and thereby enhance invasion and metastasis by is a senior research scientist of the National Cancer Institute of Canada. 2 We dedicate this review to the memory of Dr. Martin L. Breitman, a colleague and good friend who died of cancer February 13, 1994 at the age of 41 years. Among the many accomplishments in Martin’s scien- tific career, we are grateful for his contribution to the development of 4 The abbreviations used are: TV, transferase V; CPI, carbohydrate- this area, and we will greatly miss his inspiration and friendship. processing inhibitor; TIMP, tissue inhibitor of metalloproteinases; NK, 3 To whom requests for reprints should be addressed, at The Toronto natural killer; IL, interleukin; LAK, lymphokine-activated killer; TNF, Hospital, General Division, 200 Elizabeth Street, mlw 2-022, Toronto, tumor necrosis factor; PBL, peripheral blood lymphocytes; L-PHA, Ontario M4X 1K9, Canada. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 1995 American Association for Cancer Research. 936 Carbohydrate Processing Inhibitors I r y IlL II other -‘:; termini ; ,, polylactosamlne r hybrid-type complex-type t f t t Lex,1. cpp L k ‘ . .- -#{248} *T TiLT Y- I Y!!1 Slex Tun cast DMJ SW _____ Tl/’ Ley -*? otMl 7 alternate pathway GIcNAc Gic A Man 0 Gal #{149} Fuc V SA Fig. 1 The Golgi N-linked carbohydrate-processing pathway. A large number of sequences, examples of which are shown on the rig/it. can be added to the termini. with preference for addition to the 3 I -6GIcNAc-branched complex-type structures. A minor alternate processing pathway that circumvents the need for a-mannosidase Il is also shown. Enzymes: aG. -glucosida.se: aM!. a-mannosidase I: aM/I, -mannosidase II; TI, TI!, TIV, and TV, respective GlcNAc-Ts. Glucosidase inhibitors:SW. swainsonine; cast, ca.stanospermine; DNJ. 1-deoxynojirimycin: DMJ. 1-deoxymannojirimycin. Table / Studies on the MDAY-D2 lymphoma Metastasis” Phenotype” Tumor (cm3) Spontaneous (s.c.) Experiments (iv.) Wild-type 4.55 ± 0.40 1(X), 173. 227, 464. 446 >5()0. 500, 5(X), 5(X). 5()0 NeuNGc 2.13 ± 0.49 3. 243. 308. 409. SOt) 312. 4(X). 410. >500, 5(X) a2-#{212}SA-T 1.81 ± 0.39 61. 98, 137, 144 0, 3, 8. 8. 11 GIcNAc-TC 1.57 ± 1.32 0. 0. 0, 0. 1 . I . I 0. 0. 0, 0. 0 UDP-Gal 0.10 ± 0.05 0, 0, 0, 0, 0 0, 0. 0. 0, 0 Swainsonine-treated 1.53 ± 0.50 0. 0. 0, 20. 36 5()-90% decrease (1 NeuNAc and NeuNGc are two naturally occurring and developmentally regulated forms of sialic acids, N-acetylneuraminic acid and N-glycolylneuraminic acid, respectively. The NeuNGc mutation is due to expression of the enzyme CMP-SA hydroxylase. resulting in glycoconju- gates with NeuNGc rather than NeuNAc. the a2-6SA-T mutation is due to overexpression of a2-6SA transferase. resulting in SA-linked a2-6 rather than a2-3; the GlcNAc-TV mutation is due to loss of this activity, resulting in decreased I-6GlcNAc-branching of N-linked oligosaccharides: and the UDP-Gal mutation is a defect in transport of this sugar nucleotide into the Goli, resulting in loss of Gal and SA from glycoproteins. I) Metastasis and solid tumor size were measured I 7 days after tumor cells were injected. Summary based on data from multiple experiments. blood-borne tumor cells (21-23). However, it is important to highly malignant tumor cell lines (27, 28). By examining the note that cancer-associated changes in carbohydrate processing biochemical defects and malignant properties of independent appear to affect not only adhesive phenomena, but also multiple genetic mutations, a direct association has been observed be- other aspects of tumor cell phenotype as discussed below (3). tween expression of 1-6GIcNAc-branched complex-type car- Interestingly, transformation of cells in tissue culture by bohydrates and malignant potential in these mutant cell lines activated oncogenes in the ras-signaling pathway (i.e., T24 (28, 29). Mutations selected in the highly metastatic MDAY-D2 H-ras, v-src, v-fps, middle T of polyoma virus; Refs. 9, 10, 24, lymphoma cell line are listed in Table 1 in order of increasing and 25) as well as c-mvc (26) has been shown to increase effect on the malignant phenotype. Mutants with minor struc- GIcNAc-TV activity. Thus, up-regulation of this and possibly tural changes in sialic acid showed slower solid tumor growth other enzymes in the pathway may represent mandatory steps in but remained metastatic. In contrast. the deficiency in Golgi the phenotypic expression of some malignancies. UDP-Gal transport activity resulted in loss ofGal and sialic acid Somatic mutant cell lines with defects in the N-linked from both 0- and N-linked oligosaccharides, and clearly had the carbohydrate processing pathway have been selected from most marked effect on solid tumor growth and metastasis (28). Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 1995 American Association for Cancer Research.
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