Are off-target effects of imatinib the key to improving beta-cell function in diabetes?
Keywords:
Pancreatic beta-cells, type 1 diabetes, type 2 diabetes, imatinib, tyrosine kinase inhibitor, mitochondria
Abstract
The small tyrosine kinase (TK) inhibitor imatinib mesylate (Gleevec, STI571) protects against both type 1 and type 2 diabetes, but as it inhibits many TKs and other proteins, it is not clear by which mechanisms it acts. This present review will focus on the possibility that imatinib acts, at least in part, by improving beta-cell function and survival via off-target effects on beta-cell signaling/metabolic flow events. Particular attention will be given to the possibility that imatinib and other TK inhibitors function as inhibitors of mitochondrial respiration. A better understanding of how imatinib counteracts diabetes will possibly help to clarify the pathogenic role of beta-cell signaling events and mitochondrial function, and hopefully leading to improved treatment of the disease.
Downloads
Download data is not yet available.
References
1. Manley P, Cowan-Jacob S, Mestan J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim Biophys Acta 2005;1754:3–13. doi: 10.1016/j.bbapap.2005.07.040
2. Hägerkvist R, Makeeva N, Elliman S, Welsh N. Imatinib mesylate (Gleevec) protects against streptozotocin-induced diabetes and islet cell death in vitro. Cell Biol Int 2006 Dec;30:1013–17. doi: 10.1016/j.cellbi.2006.08.006
3. Hägerkvist R, Sandler S, Mokhtari D, Welsh N. Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J 2007 Feb;21(2):618–28. doi: 10.1096/fj.06-6910com
4. Hägerkvist R, Jansson L, Welsh N. Imatinib mesylate improves insulin sensitivity and glucose disposal rates in rats fed a high-fat diet. Clin Sci (Lond) 2008 Jan;114:65–71. doi: 10.1042/CS20070122
5. Han MS, Chung KW, Cheon HG, Rhee SD, Yoon CH, Lee MK, et al. Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice. Diabetes 2009 Feb;58:329–36. doi: 10.2337/db08-0080
6. Louvet C, Szot GL, Lang J, Lee MR, Martinier N, Bollag G, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A 2008 Dec 2;105:18895–900. doi: 10.1073/pnas.0810246105
7. Gur S, Kadowitz PJ, Hellstrom WJ. A protein tyrosine kinase inhibitor, imatinib mesylate (Gleevec), improves erectile and vascular function secondary to a reduction of hyperglycemia in diabetic rats. J Sex Med 2010 Oct;7:3341–50. doi: 10.1111/j.1743-6109.2010.01922.x
8. Lau J, Zhou Q, Sutton SE, Herman AE, Schmedt C, Glynne R. Inhibition of c-Kit is not required for reversal of hyperglycemia by imatinib in NOD mice. PLoS One 2014 Jan 15;9:e84900. doi: 10.1371/journal.pone.0084900
9. Wilson CS, Spaeth JM, Karp J, Stocks BT, Hoopes EM, Stein RW, et al. B lymphocytes protect islet β cells in diabetes prone NOD mice treated with imatinib. JCI Insight 2019 Apr 9;5:e125317. doi: 10.1172/jci.insight.125317
10. Samaha MM, Said E, Salem HA. Modulatory role of imatinib mesylate on pancreatic β-cells’ secretory functions in an STZ rat model of diabetes mellitus. Chem Biol Interact 2020 Sep 1;328:109197. doi: 10.1016/j.cbi.2020.109197
11. Breccia M, Muscaritoli M, Aversa Z, Mandelli F, Alimena G. Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment. J Clin Oncol 2004 Nov 15;22:4653–5. doi: 10.1200/JCO.2004.04.217
12. Gómez-Sámano MÁ, Baquerizo-Burgos JE, Coronel MFC, Wong-Campoverde BD, Villanueva-Martinez F, Molina-Botello D, et al. Effect of imatinib on plasma glucose concentration in subjects with chronic myeloid leukemia and gastrointestinal stromal tumor. BMC Endocr Disord 2018 Nov 3;18:77. doi: 10.1186/s12902-018-0303-x
13. Gitelman SE, Bundy BN, Ferrannini E, Lim N, Blanchfield JL, DiMeglio LA, et al. Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol 2021 Aug;9:502–14. doi: 10.1016/S2213-8587(21)00139-X
14. Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma 2008 Apr;49:615–19. doi: 10.1080/10428190801896103
15. Wolf D, Tilg H, Rumpold H, Gastl G, Wolf AM. The kinase inhibitor imatinib – an immunosuppressive drug? Curr Cancer Drug Targets 2007 May;7:251–8. doi: 10.2174/156800907780618293
16. Bellora F, Dondero A, Corrias MV, Casu B, Regis S, Caliendo F, et al. Imatinib and nilotinib off-target effects on human NK cells, monocytes, and M2 macrophages. J Immunol 2017 Aug 15;199:1516–25. doi: 10.4049/jimmunol.1601695
17. Zitvogel L, Rusakiewicz S, Routy B, Ayyoub M, Kroemer G. Immunological off-target effects of imatinib. Nat Rev Clin Oncol 2016 Jul;13:431–46. doi: 10.1038/nrclinonc.2016.41
18. Tsutsui Y, Deredge D, Wintrode PL, Hays FA. Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy. Sci Rep 2016 Aug 2;6:30832. doi: 10.1038/srep30832
19. Fröbom R, Berglund E, Aspinwall CA, Lui WO, Nilsson IL, Larsson C, et al. Direct interaction of the ATP-sensitive K+channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib. Biochem Biophys Res Commun 2021 Jun 11;557:14–19. doi: 10.1016/j.bbrc.2021.03.166
20. Lee SJ, Wang JY. Exploiting the promiscuity of imatinib. J Biol 2009;8:30. doi: 10.1186/jbiol134
21. Choi SS, Kim ES, Jung JE, Marciano DP, Jo A, Koo JY, et al. PPARγ antagonist gleevec improves insulin sensitivity and promotes the browning of white adipose tissue. Diabetes 2016 Apr;65:829–39. doi: 10.2337/db15-1382
22. Azizi G, Mirshafiey A. Imatinib mesylate: an innovation in treatment of autoimmune diseases. Recent Pat Inflamm Allergy Drug Discov 2013 Sep;7:259–67. doi: 10.2174/1872213x113079990021
23. Alton G, Schwamborn K, Satoh Y, Westwick JK. Therapeutic modulation of inflammatory gene transcription by kinase inhibitors. Expert Opin Biol Ther 2002 Aug;2:621–32. doi: 10.1517/14712598.2.6.621
24. Marselli L, Bugliani M, Suleiman M, Olimpico F, Masini M, Petrini M, et al. β-Cell inflammation in human type 2 diabetes and the role of autophagy. Diabetes Obes Metab 2013 Sep;15:130–6. doi: 10.1111/dom.12152
25. Lim YM, Lim H, Hur KY, Quan W, Lee HY, Cheon H, et al. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat Commun 2014 Sep 26;5:4934. doi: 10.1038/ncomms5934
26. Welsh N. Does the small tyrosine kinase inhibitor Imatinib mesylate counteract diabetes by affecting pancreatic islet amyloidosis and fibrosis? Expert Opin Investig Drugs 2012 Nov;21:1743–50. doi: 10.1517/13543784.2012.724398
27. Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004 May;24:935–42. doi: 10.1161/01.ATV.0000124105.39900.db
28. Mokhtari D, Al-Amin A, Turpaev K, Li T, Idevall-Hagren O, Li J, et al. Imatinib mesilate-induced phosphatidylinositol 3-kinase signalling and improved survival in insulin-producing cells: role of Src homology 2-containing inositol 5’-phosphatase interaction with c-Abl. Diabetologia 2013 Jun;56:1327–38. doi: 10.1007/s00125-013-2868-2
29. Xia CQ, Zhang P, Li S, Yuan L, Xia T, Xie C, et al. C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2. PLoS One 2014 May 16;9:e97694. doi: 10.1371/journal.pone.0097694
30. Fred RG, Boddeti SK, Lundberg M, Welsh N. Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells. Clin Sci (Lond) 2015 Jan;128:17–28. doi: 10.1042/CS20130560
31. King AJ, Griffiths LA, Persaud SJ, Jones PM, Howell SL, Welsh N. Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome. Ups J Med Sci 2016 May;121:140–5. doi: 10.3109/03009734.2016.1151090
32. Morita S, Villalta SA, Feldman HC, Register AC, Rosenthal W, Hoffmann-Petersen IT, et al. Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes. Cell Metab 2017 Apr 4;25:883–97.e8. doi: 10.1016/j.cmet.2017.03.018
33. Elksnis A, Schiffer TA, Palm F, Wang Y, Cen J, Turpaev K, et al. Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK. Clin Sci (Lond) 2021 Oct 14;135:2243–63. doi: 10.1042/CS20210604
34. Wang JY. The capable ABL: what is its biological function? Mol Cell Biol 2014 Apr;34:1188–97. doi: 10.1128/MCB.01454-13
35. Kharbanda S, Ren R, Pandey P, Shafman TD, Feller SM, Weichselbaum RR, et al. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 1995 Aug 31;376:785–8. doi: 10.1038/376785a0
36. Sun X, Majumder P, Shioya H, Wu F, Kumar S, Weichselbaum R, et al. Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species. J Biol Chem 2000 Jun 9;275:17237–40. doi: 10.1074/jbc.C000099200
37. Raina D, Mishra N, Kumar S, Kharbanda S, Saxena S, Kufe D. Inhibition of c-Abl with STI571 attenuates stress-activated protein kinase activation and apoptosis in the cellular response to 1-beta-D-arabinofuranosylcytosine. Mol Pharmacol 2002 Jun;61:1489–95. doi: 10.1124/mol.61.6.1489
38. Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T, et al. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 1997 May 29;387:520–3. doi: 10.1038/387520a0
39. Jiang Z, Kamath R, Jin S, Balasubramani M, Pandita TK, Rajasekaran B. Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl. Mol Cancer 2011 Jul 22;10:88. doi: 10.1186/1476-4598-10-88
40. Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci U S A 2010 Sep 21;107:16691–6. doi: 10.1073/pnas.1006083107
41. Cong F, Goff SP. c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation. Proc Natl Acad Sci U S A 1999 Nov 23;96:13819–24. doi: 10.1073/pnas.96.24.13819
42. Sionov RV, Coen S, Goldberg Z, Berger M, Bercovich B, Ben-Neriah Y, et al. c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Mol Cell Biol 2001 Sep;21:5869–78. doi: 10.1128/MCB.21.17.5869-5878.2001
43. Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M, et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 1999 Jun 24;399:806–9. doi: 10.1038/21690
44. Kawai H, Nie L, Yuan ZM. Inactivation of NF-kappaB-dependent cell survival, a novel mechanism for the proapoptotic function of c-Abl. Mol Cell Biol 2002 Sep;22:6079–88. doi: 10.1128/MCB.22.17.6079-6088.2002
45. Ito Y, Pandey P, Mishra N, Kumar S, Narula N, Kharbanda S, et al. Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis. Mol Cell Biol 2001 Sep;21:6233–42. doi: 10.1128/MCB.21.18.6233-6242.2001
46. Hägerkvist R, Mokhtari D, Myers JW, Tengholm A, Welsh N. siRNA produced by recombinant dicer mediates efficient gene silencing in islet cells. Ann N Y Acad Sci 2005 Apr;1040:114–22. doi: 10.1196/annals.1327.014
47. Karunakaran U, Elumalai S, Moon JS, Won KC. c-Abl tyrosine kinase inhibition attenuate oxidative stress-induced pancreatic β-cell dysfunction via glutathione antioxidant system. Transl Res 2022. doi: 10.1016/j.trsl.2022.06.007
48. Ikushima YM, Awazawa M, Kobayashi N, Osonoi S, Takemiya S, Kobayashi H, et al. MEK/ERK signaling in β-cells bifunctionally regulates β-cell mass and glucose-stimulated insulin secretion response to maintain glucose homeostasis. Diabetes 2021 Jul;70:1519–35. doi: 10.2337/db20-1295
49. Hu W, Lu S, McAlpine I, Jamieson JD, Lee DU, Marroquin LD, et al. Mechanistic investigation of imatinib-induced cardiac toxicity and the involvement of c-Abl kinase. Toxicol Sci 2012 Sep;129:188–99. doi: 10.1093/toxsci/kfs192
50. Dufey E, Bravo-San Pedro JM, Eggers C, González-Quiroz M, Urra H, Sagredo AI, et al. Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response. Nat Commun 2020 May 14;11:2401. doi: 10.1038/s41467-020-15694-y
51. Zhang J, Salminen A, Yang X, Luo Y, Wu Q, White M, et al. Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria. Arch Toxicol 2017 Aug;91:2921–38. doi: 10.1007/s00204-016-1918-1
52. Bouitbir J, Alshaikhali A, Panajatovic MV, Abegg VF, Paech F, Krähenbühl S. Mitochondrial oxidative stress plays a critical role in the cardiotoxicity of sunitinib: running title: sunitinib and oxidative stress in hearts. Toxicology 2019 Oct 1;426:152281. doi: 10.1016/j.tox.2019.152281
53. Paech F, Abegg VF, Duthaler U, Terracciano L, Bouitbir J, Krähenbühl S. Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice. Toxicology 2018 Nov 1;409:13–23. doi: 10.1016/j.tox.2018.07.009
54. Ross FA, Hawley SA, Auciello FR, Gowans GJ, Atrih A, Lamont DJ, et al. Mechanisms of paradoxical activation of AMPK by the kinase inhibitors SU6656 and sorafenib. Cell Chem Biol 2017 Jul 20;24:813–24.e4. doi: 10.1016/j.chembiol.2017.05.021
55. Villanueva-Paz M, Cotán D, Garrido-Maraver J, Oropesa-Ávila M, de la Mata M, Delgado-Pavón A, et al. AMPK regulation of cell growth, apoptosis, autophagy, and bioenergetics. Exp Suppl 2016;107:45–71. doi: 10.1007/978-3-319-43589-3_3
56. Fred RG, Kappe C, Ameur A, Cen J, Bergsten P, Ravassard P, et al. Role of the AMP kinase in cytokine-induced human EndoC-βH1 cell death. Mol Cell Endocrinol 2015 Oct 15;414:53–63. doi: 10.1016/j.mce.2015.07.015
57. Shalev A. Minireview: thioredoxin-interacting protein: regulation and function in the pancreatic β-cell. Mol Endocrinol 2014 Aug;28:1211–20. doi: 10.1210/me.2014-1095
58. Costa DB, Huberman MS. Improvement of type 2 diabetes in a lung cancer patient treated with Erlotinib. Diabetes Care 2006 Jul;29:1711. doi: 10.2337/dc06-0558
59. Breccia M, Muscaritoli M, Cannella L, Stefanizzi C, Frustaci A, Alimena G. Fasting glucose improvement under dasatinib treatment in an accelerated phase chronic myeloid leukemia patient unresponsive to imatinib and nilotinib. Leuk Res 2008 Oct;32:1626–8. doi: 10.1016/j.leukres.2008.01.015
60. Templeton A, Brändle M, Cerny T, Gillessen S. Remission of diabetes while on sunitinib treatment for renal cell carcinoma. Ann Oncol 2008 Apr;19:824–5. doi: 10.1093/annonc/mdn047
61. Agostino NM, Chinchilli VM, Lynch CJ, Koszyk-Szewczyk A, Gingrich R, Sivik J, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and non-diabetic patients in general clinical practice. J Oncol Pharm Pract 2011 Sep;17:197–202. doi: 10.1177/1078155210378913
62. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 2018 Aug;24:1246–56. doi: 10.1038/s41591-018-0092-9
63. Salaami O, Kuo CL, Drake MT, Kuchel GA, Kirkland JL, Pignolo RJ. Antidiabetic effects of the senolytic agent dasatinib. Mayo Clin Proc 2021 Dec;96:3021–9. doi: 10.1016/j.mayocp.2021.06.025
64. Bouitbir J, Panajatovic MV, Frechard T, Roos NJ, Krähenbühl S. Imatinib and dasatinib provoke mitochondrial dysfunction leading to oxidative stress in C2C12 myotubes and human RD cells. Front Pharmacol 2020 Jul 23;11:1106. doi: 10.3389/fphar.2020.01106
65. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia 2013 Sep;56:1898–906. doi: 10.1007/s00125-013-2991-0
66. Sandler S, Andersson AK, Larsson J, Makeeva N, Olsen T, Arkhammar POG, et al. Possible role of an ischemic preconditioning-like response mechanism in KATP channel opener-mediated protection against streptozotocin-induced suppression of rat pancreatic islet function. Biochem Pharmacol 2008;76:1748–56. doi: 10.1016/j.bcp.2008.09.004
2. Hägerkvist R, Makeeva N, Elliman S, Welsh N. Imatinib mesylate (Gleevec) protects against streptozotocin-induced diabetes and islet cell death in vitro. Cell Biol Int 2006 Dec;30:1013–17. doi: 10.1016/j.cellbi.2006.08.006
3. Hägerkvist R, Sandler S, Mokhtari D, Welsh N. Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J 2007 Feb;21(2):618–28. doi: 10.1096/fj.06-6910com
4. Hägerkvist R, Jansson L, Welsh N. Imatinib mesylate improves insulin sensitivity and glucose disposal rates in rats fed a high-fat diet. Clin Sci (Lond) 2008 Jan;114:65–71. doi: 10.1042/CS20070122
5. Han MS, Chung KW, Cheon HG, Rhee SD, Yoon CH, Lee MK, et al. Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice. Diabetes 2009 Feb;58:329–36. doi: 10.2337/db08-0080
6. Louvet C, Szot GL, Lang J, Lee MR, Martinier N, Bollag G, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A 2008 Dec 2;105:18895–900. doi: 10.1073/pnas.0810246105
7. Gur S, Kadowitz PJ, Hellstrom WJ. A protein tyrosine kinase inhibitor, imatinib mesylate (Gleevec), improves erectile and vascular function secondary to a reduction of hyperglycemia in diabetic rats. J Sex Med 2010 Oct;7:3341–50. doi: 10.1111/j.1743-6109.2010.01922.x
8. Lau J, Zhou Q, Sutton SE, Herman AE, Schmedt C, Glynne R. Inhibition of c-Kit is not required for reversal of hyperglycemia by imatinib in NOD mice. PLoS One 2014 Jan 15;9:e84900. doi: 10.1371/journal.pone.0084900
9. Wilson CS, Spaeth JM, Karp J, Stocks BT, Hoopes EM, Stein RW, et al. B lymphocytes protect islet β cells in diabetes prone NOD mice treated with imatinib. JCI Insight 2019 Apr 9;5:e125317. doi: 10.1172/jci.insight.125317
10. Samaha MM, Said E, Salem HA. Modulatory role of imatinib mesylate on pancreatic β-cells’ secretory functions in an STZ rat model of diabetes mellitus. Chem Biol Interact 2020 Sep 1;328:109197. doi: 10.1016/j.cbi.2020.109197
11. Breccia M, Muscaritoli M, Aversa Z, Mandelli F, Alimena G. Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment. J Clin Oncol 2004 Nov 15;22:4653–5. doi: 10.1200/JCO.2004.04.217
12. Gómez-Sámano MÁ, Baquerizo-Burgos JE, Coronel MFC, Wong-Campoverde BD, Villanueva-Martinez F, Molina-Botello D, et al. Effect of imatinib on plasma glucose concentration in subjects with chronic myeloid leukemia and gastrointestinal stromal tumor. BMC Endocr Disord 2018 Nov 3;18:77. doi: 10.1186/s12902-018-0303-x
13. Gitelman SE, Bundy BN, Ferrannini E, Lim N, Blanchfield JL, DiMeglio LA, et al. Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol 2021 Aug;9:502–14. doi: 10.1016/S2213-8587(21)00139-X
14. Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma 2008 Apr;49:615–19. doi: 10.1080/10428190801896103
15. Wolf D, Tilg H, Rumpold H, Gastl G, Wolf AM. The kinase inhibitor imatinib – an immunosuppressive drug? Curr Cancer Drug Targets 2007 May;7:251–8. doi: 10.2174/156800907780618293
16. Bellora F, Dondero A, Corrias MV, Casu B, Regis S, Caliendo F, et al. Imatinib and nilotinib off-target effects on human NK cells, monocytes, and M2 macrophages. J Immunol 2017 Aug 15;199:1516–25. doi: 10.4049/jimmunol.1601695
17. Zitvogel L, Rusakiewicz S, Routy B, Ayyoub M, Kroemer G. Immunological off-target effects of imatinib. Nat Rev Clin Oncol 2016 Jul;13:431–46. doi: 10.1038/nrclinonc.2016.41
18. Tsutsui Y, Deredge D, Wintrode PL, Hays FA. Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy. Sci Rep 2016 Aug 2;6:30832. doi: 10.1038/srep30832
19. Fröbom R, Berglund E, Aspinwall CA, Lui WO, Nilsson IL, Larsson C, et al. Direct interaction of the ATP-sensitive K+channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib. Biochem Biophys Res Commun 2021 Jun 11;557:14–19. doi: 10.1016/j.bbrc.2021.03.166
20. Lee SJ, Wang JY. Exploiting the promiscuity of imatinib. J Biol 2009;8:30. doi: 10.1186/jbiol134
21. Choi SS, Kim ES, Jung JE, Marciano DP, Jo A, Koo JY, et al. PPARγ antagonist gleevec improves insulin sensitivity and promotes the browning of white adipose tissue. Diabetes 2016 Apr;65:829–39. doi: 10.2337/db15-1382
22. Azizi G, Mirshafiey A. Imatinib mesylate: an innovation in treatment of autoimmune diseases. Recent Pat Inflamm Allergy Drug Discov 2013 Sep;7:259–67. doi: 10.2174/1872213x113079990021
23. Alton G, Schwamborn K, Satoh Y, Westwick JK. Therapeutic modulation of inflammatory gene transcription by kinase inhibitors. Expert Opin Biol Ther 2002 Aug;2:621–32. doi: 10.1517/14712598.2.6.621
24. Marselli L, Bugliani M, Suleiman M, Olimpico F, Masini M, Petrini M, et al. β-Cell inflammation in human type 2 diabetes and the role of autophagy. Diabetes Obes Metab 2013 Sep;15:130–6. doi: 10.1111/dom.12152
25. Lim YM, Lim H, Hur KY, Quan W, Lee HY, Cheon H, et al. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat Commun 2014 Sep 26;5:4934. doi: 10.1038/ncomms5934
26. Welsh N. Does the small tyrosine kinase inhibitor Imatinib mesylate counteract diabetes by affecting pancreatic islet amyloidosis and fibrosis? Expert Opin Investig Drugs 2012 Nov;21:1743–50. doi: 10.1517/13543784.2012.724398
27. Lassila M, Allen TJ, Cao Z, Thallas V, Jandeleit-Dahm KA, Candido R, et al. Imatinib attenuates diabetes-associated atherosclerosis. Arterioscler Thromb Vasc Biol 2004 May;24:935–42. doi: 10.1161/01.ATV.0000124105.39900.db
28. Mokhtari D, Al-Amin A, Turpaev K, Li T, Idevall-Hagren O, Li J, et al. Imatinib mesilate-induced phosphatidylinositol 3-kinase signalling and improved survival in insulin-producing cells: role of Src homology 2-containing inositol 5’-phosphatase interaction with c-Abl. Diabetologia 2013 Jun;56:1327–38. doi: 10.1007/s00125-013-2868-2
29. Xia CQ, Zhang P, Li S, Yuan L, Xia T, Xie C, et al. C-Abl inhibitor imatinib enhances insulin production by β cells: c-Abl negatively regulates insulin production via interfering with the expression of NKx2.2 and GLUT-2. PLoS One 2014 May 16;9:e97694. doi: 10.1371/journal.pone.0097694
30. Fred RG, Boddeti SK, Lundberg M, Welsh N. Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells. Clin Sci (Lond) 2015 Jan;128:17–28. doi: 10.1042/CS20130560
31. King AJ, Griffiths LA, Persaud SJ, Jones PM, Howell SL, Welsh N. Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome. Ups J Med Sci 2016 May;121:140–5. doi: 10.3109/03009734.2016.1151090
32. Morita S, Villalta SA, Feldman HC, Register AC, Rosenthal W, Hoffmann-Petersen IT, et al. Targeting ABL-IRE1α signaling spares ER-stressed pancreatic β cells to reverse autoimmune diabetes. Cell Metab 2017 Apr 4;25:883–97.e8. doi: 10.1016/j.cmet.2017.03.018
33. Elksnis A, Schiffer TA, Palm F, Wang Y, Cen J, Turpaev K, et al. Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK. Clin Sci (Lond) 2021 Oct 14;135:2243–63. doi: 10.1042/CS20210604
34. Wang JY. The capable ABL: what is its biological function? Mol Cell Biol 2014 Apr;34:1188–97. doi: 10.1128/MCB.01454-13
35. Kharbanda S, Ren R, Pandey P, Shafman TD, Feller SM, Weichselbaum RR, et al. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 1995 Aug 31;376:785–8. doi: 10.1038/376785a0
36. Sun X, Majumder P, Shioya H, Wu F, Kumar S, Weichselbaum R, et al. Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species. J Biol Chem 2000 Jun 9;275:17237–40. doi: 10.1074/jbc.C000099200
37. Raina D, Mishra N, Kumar S, Kharbanda S, Saxena S, Kufe D. Inhibition of c-Abl with STI571 attenuates stress-activated protein kinase activation and apoptosis in the cellular response to 1-beta-D-arabinofuranosylcytosine. Mol Pharmacol 2002 Jun;61:1489–95. doi: 10.1124/mol.61.6.1489
38. Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T, et al. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 1997 May 29;387:520–3. doi: 10.1038/387520a0
39. Jiang Z, Kamath R, Jin S, Balasubramani M, Pandita TK, Rajasekaran B. Tip60-mediated acetylation activates transcription independent apoptotic activity of Abl. Mol Cancer 2011 Jul 22;10:88. doi: 10.1186/1476-4598-10-88
40. Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc Natl Acad Sci U S A 2010 Sep 21;107:16691–6. doi: 10.1073/pnas.1006083107
41. Cong F, Goff SP. c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation. Proc Natl Acad Sci U S A 1999 Nov 23;96:13819–24. doi: 10.1073/pnas.96.24.13819
42. Sionov RV, Coen S, Goldberg Z, Berger M, Bercovich B, Ben-Neriah Y, et al. c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Mol Cell Biol 2001 Sep;21:5869–78. doi: 10.1128/MCB.21.17.5869-5878.2001
43. Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M, et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 1999 Jun 24;399:806–9. doi: 10.1038/21690
44. Kawai H, Nie L, Yuan ZM. Inactivation of NF-kappaB-dependent cell survival, a novel mechanism for the proapoptotic function of c-Abl. Mol Cell Biol 2002 Sep;22:6079–88. doi: 10.1128/MCB.22.17.6079-6088.2002
45. Ito Y, Pandey P, Mishra N, Kumar S, Narula N, Kharbanda S, et al. Targeting of the c-Abl tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis. Mol Cell Biol 2001 Sep;21:6233–42. doi: 10.1128/MCB.21.18.6233-6242.2001
46. Hägerkvist R, Mokhtari D, Myers JW, Tengholm A, Welsh N. siRNA produced by recombinant dicer mediates efficient gene silencing in islet cells. Ann N Y Acad Sci 2005 Apr;1040:114–22. doi: 10.1196/annals.1327.014
47. Karunakaran U, Elumalai S, Moon JS, Won KC. c-Abl tyrosine kinase inhibition attenuate oxidative stress-induced pancreatic β-cell dysfunction via glutathione antioxidant system. Transl Res 2022. doi: 10.1016/j.trsl.2022.06.007
48. Ikushima YM, Awazawa M, Kobayashi N, Osonoi S, Takemiya S, Kobayashi H, et al. MEK/ERK signaling in β-cells bifunctionally regulates β-cell mass and glucose-stimulated insulin secretion response to maintain glucose homeostasis. Diabetes 2021 Jul;70:1519–35. doi: 10.2337/db20-1295
49. Hu W, Lu S, McAlpine I, Jamieson JD, Lee DU, Marroquin LD, et al. Mechanistic investigation of imatinib-induced cardiac toxicity and the involvement of c-Abl kinase. Toxicol Sci 2012 Sep;129:188–99. doi: 10.1093/toxsci/kfs192
50. Dufey E, Bravo-San Pedro JM, Eggers C, González-Quiroz M, Urra H, Sagredo AI, et al. Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response. Nat Commun 2020 May 14;11:2401. doi: 10.1038/s41467-020-15694-y
51. Zhang J, Salminen A, Yang X, Luo Y, Wu Q, White M, et al. Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria. Arch Toxicol 2017 Aug;91:2921–38. doi: 10.1007/s00204-016-1918-1
52. Bouitbir J, Alshaikhali A, Panajatovic MV, Abegg VF, Paech F, Krähenbühl S. Mitochondrial oxidative stress plays a critical role in the cardiotoxicity of sunitinib: running title: sunitinib and oxidative stress in hearts. Toxicology 2019 Oct 1;426:152281. doi: 10.1016/j.tox.2019.152281
53. Paech F, Abegg VF, Duthaler U, Terracciano L, Bouitbir J, Krähenbühl S. Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice. Toxicology 2018 Nov 1;409:13–23. doi: 10.1016/j.tox.2018.07.009
54. Ross FA, Hawley SA, Auciello FR, Gowans GJ, Atrih A, Lamont DJ, et al. Mechanisms of paradoxical activation of AMPK by the kinase inhibitors SU6656 and sorafenib. Cell Chem Biol 2017 Jul 20;24:813–24.e4. doi: 10.1016/j.chembiol.2017.05.021
55. Villanueva-Paz M, Cotán D, Garrido-Maraver J, Oropesa-Ávila M, de la Mata M, Delgado-Pavón A, et al. AMPK regulation of cell growth, apoptosis, autophagy, and bioenergetics. Exp Suppl 2016;107:45–71. doi: 10.1007/978-3-319-43589-3_3
56. Fred RG, Kappe C, Ameur A, Cen J, Bergsten P, Ravassard P, et al. Role of the AMP kinase in cytokine-induced human EndoC-βH1 cell death. Mol Cell Endocrinol 2015 Oct 15;414:53–63. doi: 10.1016/j.mce.2015.07.015
57. Shalev A. Minireview: thioredoxin-interacting protein: regulation and function in the pancreatic β-cell. Mol Endocrinol 2014 Aug;28:1211–20. doi: 10.1210/me.2014-1095
58. Costa DB, Huberman MS. Improvement of type 2 diabetes in a lung cancer patient treated with Erlotinib. Diabetes Care 2006 Jul;29:1711. doi: 10.2337/dc06-0558
59. Breccia M, Muscaritoli M, Cannella L, Stefanizzi C, Frustaci A, Alimena G. Fasting glucose improvement under dasatinib treatment in an accelerated phase chronic myeloid leukemia patient unresponsive to imatinib and nilotinib. Leuk Res 2008 Oct;32:1626–8. doi: 10.1016/j.leukres.2008.01.015
60. Templeton A, Brändle M, Cerny T, Gillessen S. Remission of diabetes while on sunitinib treatment for renal cell carcinoma. Ann Oncol 2008 Apr;19:824–5. doi: 10.1093/annonc/mdn047
61. Agostino NM, Chinchilli VM, Lynch CJ, Koszyk-Szewczyk A, Gingrich R, Sivik J, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and non-diabetic patients in general clinical practice. J Oncol Pharm Pract 2011 Sep;17:197–202. doi: 10.1177/1078155210378913
62. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 2018 Aug;24:1246–56. doi: 10.1038/s41591-018-0092-9
63. Salaami O, Kuo CL, Drake MT, Kuchel GA, Kirkland JL, Pignolo RJ. Antidiabetic effects of the senolytic agent dasatinib. Mayo Clin Proc 2021 Dec;96:3021–9. doi: 10.1016/j.mayocp.2021.06.025
64. Bouitbir J, Panajatovic MV, Frechard T, Roos NJ, Krähenbühl S. Imatinib and dasatinib provoke mitochondrial dysfunction leading to oxidative stress in C2C12 myotubes and human RD cells. Front Pharmacol 2020 Jul 23;11:1106. doi: 10.3389/fphar.2020.01106
65. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia 2013 Sep;56:1898–906. doi: 10.1007/s00125-013-2991-0
66. Sandler S, Andersson AK, Larsson J, Makeeva N, Olsen T, Arkhammar POG, et al. Possible role of an ischemic preconditioning-like response mechanism in KATP channel opener-mediated protection against streptozotocin-induced suppression of rat pancreatic islet function. Biochem Pharmacol 2008;76:1748–56. doi: 10.1016/j.bcp.2008.09.004
Published
2022-09-14
How to Cite
Welsh N. (2022). Are off-target effects of imatinib the key to improving beta-cell function in diabetes?. Upsala Journal of Medical Sciences, 127(1). https://doi.org/10.48101/ujms.v127.8841
Section
Review Articles
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain copyright of their work, with first publication rights granted to Upsala Medical Society. Read the full Copyright- and Licensing Statement.
