#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15


Autoři: Arjan Mofers aff001;  Paola Perego aff002;  Karthik Selvaraju aff001;  Laura Gatti aff003;  Joachim Gullbo aff004;  Stig Linder aff001;  Padraig D'Arcy aff001
Působiště autorů: Department of Medicine and Health, Linköping University, Linköping, Sweden aff001;  Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy aff002;  Cerebrovascular Unit, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy aff003;  Department of Radiology, Oncology and Radiation Science, Section of Oncology, Uppsala University, Uppsala, Sweden aff004;  Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0223807

Souhrn

Background

b-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) of the 19S proteasome. b-AP15/VLX1570 have been shown to be cytotoxic to cells resistant to bortezomib, raising the possibility that this class of drugs can be used as a second-line therapy for treatment-resistant multiple myeloma. Limited information is available with regard to potential resistance mechanisms to b-AP15/VLX1570.

Results

We found that b-AP15-induced cell death is cell-cycle dependent and that non-cycling tumor cells may evade b-AP15-induced cell death. Such non-cycling cells may re-enter the proliferative state to form colonies of drug-sensitive cells. Long-term selection of cells with b-AP15 resulted in limited drug resistance (~2-fold) that could be reversed by buthionine sulphoximine, implying altered glutathione (GSH) metabolism as a resistance mechanism. In contrast, drug uptake and overexpression of drug efflux transporters were found not to be associated with b-AP15 resistance.

Conclusions

The proteasome DUB inhibitors b-AP15/VLX1570 are cell cycle-active. The slow and incomplete development of resistance towards these compounds is an attractive feature in view of future clinical use.

Klíčová slova:

Cancer treatment – Cell cycle and cell division – Cell cycle inhibitors – Cell death – Drug therapy – Glutathione – Proteasomes


Zdroje

1. Richardson PG, Anderson KC. Bortezomib: a novel therapy approved for multiple myeloma. Clin Adv Hematol Oncol. 2003;1(10):596–600. Epub 2005/11/01. 16258456.

2. Mitsiades CS, Hideshima T, Chauhan D, McMillin DW, Klippel S, Laubach JP, et al. Emerging treatments for multiple myeloma: beyond immunomodulatory drugs and bortezomib. Semin Hematol. 2009;46(2):166–75. Epub 2009/04/25. doi: S0037-1963(09)00031-6 [pii] doi: 10.1053/j.seminhematol.2009.02.003 19389500; PubMed Central PMCID: PMC2746942.

3. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer research. 2007;67(13):6383–91. Epub 2007/07/10. doi: 67/13/6383 [pii] doi: 10.1158/0008-5472.CAN-06-4086 17616698.

4. Kale AJ, Moore BS. Molecular mechanisms of acquired proteasome inhibitor resistance. Journal of medicinal chemistry. 2012;55(23):10317–27. doi: 10.1021/jm300434z 22978849; PubMed Central PMCID: PMC3521846.

5. Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJ, Cloos J. Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy. 2015;18:18–35. doi: 10.1016/j.drup.2014.12.001 25670156.

6. de Wilt LH, Jansen G, Assaraf YG, van Meerloo J, Cloos J, Schimmer AD, et al. Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer. Biochemical pharmacology. 2012;83(2):207–17. doi: 10.1016/j.bcp.2011.10.009 22027222.

7. Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. 2008;112(6):2489–99. Epub 2008/06/21. doi: blood-2007-08-104950 [pii] doi: 10.1182/blood-2007-08-104950 18565852.

8. Franke NE, Niewerth D, Assaraf YG, van Meerloo J, Vojtekova K, van Zantwijk CH, et al. Impaired bortezomib binding to mutant beta5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia. 2011. Epub 2011/09/24. doi: leu2011256 [pii] doi: 10.1038/leu.2011.256 21941364.

9. Suzuki E, Demo S, Deu E, Keats J, Arastu-Kapur S, Bergsagel PL, et al. Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PloS one. 2011;6(12):e27996. doi: 10.1371/journal.pone.0027996 22216088; PubMed Central PMCID: PMC3245226.

10. Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, Ito A, et al. Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. Leukemia. 2010;24(8):1506–12. Epub 2010/06/18. doi: leu2010137 [pii] doi: 10.1038/leu.2010.137 20555361.

11. Rumpold H, Salvador C, Wolf AM, Tilg H, Gastl G, Wolf D. Knockdown of PgP resensitizes leukemic cells to proteasome inhibitors. Biochemical and biophysical research communications. 2007;361(2):549–54. doi: 10.1016/j.bbrc.2007.07.049 17662692.

12. Minderman H, Zhou Y, O'Loughlin KL, Baer MR. Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Cancer chemotherapy and pharmacology. 2007;60(2):245–55. doi: 10.1007/s00280-006-0367-6 17096161.

13. Wiberg K, Carlson K, Aleskog A, Larsson R, Nygren P, Lindhagen E. In vitro activity of bortezomib in cultures of patient tumour cells—potential utility in haematological malignancies. Medical oncology. 2009;26(2):193–201. doi: 10.1007/s12032-008-9107-6 19016012.

14. Verbrugge SE, Assaraf YG, Dijkmans BA, Scheffer GL, Al M, den Uyl D, et al. Inactivating PSMB5 mutations and P-glycoprotein (MDR1/ ABCB1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno) proteasome inhibitors in mononuclear blood cells from rheumatoid arthritis patients. The Journal of pharmacology and experimental therapeutics. 2012. Epub 2012/01/12. doi: jpet.111.187542 [pii] doi: 10.1124/jpet.111.187542 22235146.

15. Hagenbuchner J, Ausserlechner MJ, Porto V, David R, Meister B, Bodner M, et al. The anti-apoptotic protein BCL2L1/Bcl-xL is neutralized by pro-apoptotic PMAIP1/Noxa in neuroblastoma, thereby determining bortezomib sensitivity independent of prosurvival MCL1 expression. The Journal of biological chemistry. 2010;285(10):6904–12. Epub 2010/01/07. doi: M109.038331 [pii] doi: 10.1074/jbc.M109.038331 20051518; PubMed Central PMCID: PMC2844140.

16. Smith AJ, Dai H, Correia C, Takahashi R, Lee SH, Schmitz I, et al. Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. The Journal of biological chemistry. 2011;286(20):17682–92. Epub 2011/04/02. doi: M110.189092 [pii] doi: 10.1074/jbc.M110.189092 21454712; PubMed Central PMCID: PMC3093844.

17. Reuland SN, Goldstein NB, Partyka KA, Smith S, Luo Y, Fujita M, et al. ABT-737 synergizes with Bortezomib to kill melanoma cells. Biology open. 2012;1(2):92–100. doi: 10.1242/bio.2011035 23213401; PubMed Central PMCID: PMC3507205.

18. Kunami N, Katsuya H, Nogami R, Ishitsuka K, Tamura K. Promise of combining a Bcl-2 family inhibitor with bortezomib or SAHA for adult T-cell leukemia/lymphoma. Anticancer research. 2014;34(10):5287–94. 25275021.

19. Johnson-Farley N, Veliz J, Bhagavathi S, Bertino JR. ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in "double hit" lymphoma cells. Leukemia & lymphoma. 2015:1–7. doi: 10.3109/10428194.2014.981172 25373508.

20. Zaal EA, Wu W, Jansen G, Zweegman S, Cloos J, Berkers CR. Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. Cancer & metabolism. 2017;5:7. doi: 10.1186/s40170-017-0169-9 28855983; PubMed Central PMCID: PMC5575874.

21. Tian Z, D'Arcy P, Wang X, Ray A, Tai YT, Hu Y, et al. A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance. Blood. 2014;123(5):706–16. doi: 10.1182/blood-2013-05-500033 24319254; PubMed Central PMCID: PMC3907756.

22. Anchoori RK, Karanam B, Peng S, Wang JW, Jiang R, Tanno T, et al. A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer. Cancer cell. 2013;24(6):791–805. doi: 10.1016/j.ccr.2013.11.001 24332045; PubMed Central PMCID: PMC3881268.

23. Shukla NN, Somwar R, Smith RS, Ambati SR, Munoz S, Merchant MS, et al. Proteasome addiction defined in Ewing's sarcoma is effectively targeted by a novel class of 19S proteasome inhibitors. Cancer research. 2016;76:4525–34. doi: 10.1158/0008-5472.CAN-16-1040 27256563.

24. Chitta K, Paulus A, Akhtar S, Blake MK, Caulfield TR, Novak AJ, et al. Targeted inhibition of the deubiquitinating enzymes, USP14 and UCHL5, induces proteotoxic stress and apoptosis in Waldenstrom macroglobulinaemia tumour cells. British journal of haematology. 2015;169:377–90. Epub Feb 17. doi: 10.1111/bjh.13304 25691154.

25. Kropp KN, Maurer S, Rothfelder K, Schmied BJ, Clar KL, Schmidt M, et al. The novel deubiquitinase inhibitor b-AP15 induces direct and NK cell-mediated antitumor effects in human mantle cell lymphoma. Cancer immunology, immunotherapy: CII. 2018;67:935–47. doi: 10.1007/s00262-018-2151-y 29556699.

26. Ding Y, Chen X, Wang B, Yu B, Ge J. Deubiquitinase inhibitor b-AP15 activates endoplasmic reticulum (ER) stress and inhibits Wnt/Notch1 signaling pathway leading to the reduction of cell survival in hepatocellular carcinoma cells. European journal of pharmacology. 2018;825:10–8. Epub 2018/02/20. doi: 10.1016/j.ejphar.2018.02.020 29454609.

27. Cai J, Xia X, Liao Y, Liu N, Guo Z, Chen J, et al. A novel deubiquitinase inhibitor b-AP15 triggers apoptosis in both androgen receptor-dependent and -independent prostate cancers. Oncotarget. 2017;8(38):63232–46. doi: 10.18632/oncotarget.18774 28968984; PubMed Central PMCID: PMC5609916.

28. Vogel RI, Coughlin K, Scotti A, Iizuka Y, Anchoori R, Roden RB, et al. Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells. Oncotarget. 2015;6(6):4159–70. doi: 10.18632/oncotarget.2904 25784654.

29. Didier R, Mallavialle A, Ben Jouira R, Domdom MA, Tichet M, Auberger P, et al. Targeting the Proteasome-Associated Deubiquitinating Enzyme USP14 Impairs Melanoma Cell Survival and Overcomes Resistance to MAPK-Targeting Therapies. Mol Cancer Ther. 2018;17(7):1416–29. doi: 10.1158/1535-7163.MCT-17-0919 29703842.

30. D'Arcy P, Brnjic S, Olofsson MH, Fryknas M, Lindsten K, De Cesare M, et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nature medicine. 2011;17(12):1636–40. Epub 2011/11/08. doi: 10.1038/nm.2536 22057347.

31. Yu Y, Zhao Y, Fan Y, Chen Z, Li H, Lu J, et al. Inhibition of Ubiquitin-specific protease 14 suppresses cell proliferation and synergizes with chemotherapeutic agents in neuroblastoma. Mol Cancer Ther. 2019. Epub 2019/04/10. doi: 10.1158/1535-7163.MCT-18-0146 30962318.

32. Cersosimo U, Sgorbissa A, Foti C, Drioli S, Angelica R, Tomasella A, et al. Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent. Journal of medicinal chemistry. 2015;58(4):1691–704. doi: 10.1021/jm501336h 25639862.

33. Ciotti S, Sgarra R, Sgorbissa A, Penzo C, Tomasella A, Casarsa F, et al. The binding landscape of a partially-selective isopeptidase inhibitor with potent pro-death activity, based on the bis(arylidene)cyclohexanone scaffold. Cell death & disease. 2018;9(2):184. doi: 10.1038/s41419-017-0259-1 29416018.

34. Wang X, Mazurkiewicz M, Hillert EK, Olofsson MH, Pierrou S, Hillertz P, et al. The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells. Scientific reports. 2016;6:26979. doi: 10.1038/srep26979 27264969; PubMed Central PMCID: PMC4893612.

35. Greene JM, Levy D, Fung KL, Souza PS, Gottesman MM, Lavi O. Modeling intrinsic heterogeneity and growth of cancer cells. Journal of theoretical biology. 2015;367:262–77. doi: 10.1016/j.jtbi.2014.11.017 25457229; PubMed Central PMCID: PMC4308514.

36. Menendez-Benito V, Verhoef LG, Masucci MG, Dantuma NP. Endoplasmic reticulum stress compromises the ubiquitin-proteasome system. Human molecular genetics. 2005;14(19):2787–99. Epub 2005/08/17. doi: ddi312 [pii] doi: 10.1093/hmg/ddi312 16103128.

37. Yin D, Zhou H, Kumagai T, Liu G, Ong JM, Black KL, et al. Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene. 2005;24(3):344–54. Epub 2004/11/09. doi: 1208225 [pii] doi: 10.1038/sj.onc.1208225 15531918.

38. Ozols RF. Pharmacologic reversal of drug resistance in ovarian cancer. Seminars in oncology. 1985;12(3 Suppl 4):7–11. 4048979.

39. Doroshow JH, Akman S, Chu FF, Esworthy S. Role of the glutathione-glutathione peroxidase cycle in the cytotoxicity of the anticancer quinones. Pharmacology & therapeutics. 1990;47(3):359–70. doi: 10.1016/0163-7258(90)90062-7 2290853.

40. Traverso N, Ricciarelli R, Nitti M, Marengo B, Furfaro AL, Pronzato MA, et al. Role of glutathione in cancer progression and chemoresistance. Oxidative medicine and cellular longevity. 2013;2013:972913. doi: 10.1155/2013/972913 23766865; PubMed Central PMCID: PMC3673338.

41. Nielsen D, Maare C, Skovsgaard T. Cellular resistance to anthracyclines. General pharmacology. 1996;27(2):251–5. doi: 10.1016/0306-3623(95)02013-6 8919638.

42. Batist G, Tulpule A, Sinha BK, Katki AG, Myers CE, Cowan KH. Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells. The Journal of biological chemistry. 1986;261(33):15544–9. 3782078.

43. Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer cell. 2004;6(2):129–37. doi: 10.1016/j.ccr.2004.06.026 15324696.

44. Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R, et al. LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology. 2001;120(7):1689–99. doi: 10.1053/gast.2001.24804 11375950.

45. Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM. The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annual review of pharmacology and toxicology. 2008;48:495–535. doi: 10.1146/annurev.pharmtox.48.080907.180426 17937596.

46. Okabe M, Szakacs G, Reimers MA, Suzuki T, Hall MD, Abe T, et al. Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters. Mol Cancer Ther. 2008;7(9):3081–91. doi: 10.1158/1535-7163.MCT-08-0539 18790787; PubMed Central PMCID: PMC2597359.

47. Alvarez M, Paull K, Monks A, Hose C, Lee JS, Weinstein J, et al. Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. The Journal of clinical investigation. 1995;95(5):2205–14. doi: 10.1172/JCI117910 7738186; PubMed Central PMCID: PMC295832.

48. Broggini M, Grandi M, Ubezio P, Geroni C, Giuliani FC, D'Incalci M. Intracellular doxorubicin concentrations and drug-induced DNA damage in a human colon adenocarcinoma cell line and in a drug-resistant subline. Biochemical pharmacology. 1988;37(23):4423–31. doi: 10.1016/0006-2952(88)90656-9 3202888.

49. Perego P, De Cesare M, De Isabella P, Carenini N, Beggiolin G, Pezzoni G, et al. A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line. Cancer research. 2001;61(16):6034–7. 11507048.

50. Beretta GL, Gatti L, Corna E, Carenini N, Zunino F, Perego P. Defining targets of modulation of human tumor cell response to cisplatin. Journal of inorganic biochemistry. 2008;102(7):1406–15. doi: 10.1016/j.jinorgbio.2008.01.002 18279962.

51. Wang X, D'Arcy P, Caulfield TR, Paulus A, Chitta K, Mohanty C, et al. Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chemical biology & drug design. 2015;86(5):1036–48. doi: 10.1111/cbdd.12571 25854145; PubMed Central PMCID: PMC4846425.

52. Wang X, Stafford W, Mazurkiewicz M, Fryknas M, Brjnic S, Zhang X, et al. The 19S Deubiquitinase inhibitor b-AP15 is enriched in cells and elicits rapid commitment to cell death. Molecular pharmacology. 2014;85(6):932–45. doi: 10.1124/mol.113.091322 24714215.

53. Zetterberg A, Larsson O. Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells. Proceedings of the National Academy of Sciences of the United States of America. 1985;82(16):5365–9. doi: 10.1073/pnas.82.16.5365 3860868; PubMed Central PMCID: PMC390569.

54. Schewe DM, Aguirre-Ghiso JA. Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer research. 2009;69(4):1545–52. Epub 2009/02/05. doi: 0008-5472.CAN-08-3858 [pii] doi: 10.1158/0008-5472.CAN-08-3858 19190324; PubMed Central PMCID: PMC2726651.

55. Pajic M, Blatter S, Guyader C, Gonggrijp M, Kersbergen A, Kucukosmanoglu A, et al. Selected Alkylating Agents Can Overcome Drug Tolerance of G0-like Tumor Cells and Eradicate BRCA1-Deficient Mammary Tumors in Mice. Clinical cancer research: an official journal of the American Association for Cancer Research. 2017;23(22):7020–33. Epub 2017/08/20. doi: 10.1158/1078-0432.CCR-17-1279 28821557.

56. Tomasella A, Picco R, Ciotti S, Sgorbissa A, Bianchi E, Manfredini R, et al. The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells. Oncotarget. 2016;7:45429–43. doi: 10.18632/oncotarget.9742 27259251.

57. Beretta GL, Benedetti V, Cossa G, Assaraf YG, Bram E, Gatti L, et al. Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin. Biochemical pharmacology. 2010;79(8):1108–17. Epub 2009/12/17. doi: S0006-2952(09)01059-4 [pii] doi: 10.1016/j.bcp.2009.12.002 20005867.

58. Lindhagen E, Nygren P, Larsson R. The fluorometric microculture cytotoxicity assay. Nature protocols. 2008;3(8):1364–9. Epub 2008/08/21. doi: nprot.2008.114 [pii] doi: 10.1038/nprot.2008.114 18714304.

59. Bedrosian I, Lu KH, Verschraegen C, Keyomarsi K. Cyclin E deregulation alters the biologic properties of ovarian cancer cells. Oncogene. 2004;23(15):2648–57. doi: 10.1038/sj.onc.1207408 15007381.


Článek vyšel v časopise

PLOS One


2019 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

KOST
Koncepce osteologické péče pro gynekology a praktické lékaře
nový kurz
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Svět praktické medicíny 5/2023 (znalostní test z časopisu)

Imunopatologie? … a co my s tím???
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#