MGCD0103 induces apoptosis and simultaneously increases the expression of NF‑κB and PD‑L1 in classical Hodgkin's lymphoma

Huang,Renhong; Zhang,Xiaowei; Min,Zhijun; Shadia,Abdelbari Sophia; Yang,Shun'e; Liu,Xiaojian

doi:10.3892/etm.2018.6677

MGCD0103 induces apoptosis and simultaneously increases the expression of NF‑κB and PD‑L1 in classical Hodgkin's lymphoma

Authors:
- Renhong Huang
- Xiaowei Zhang
- Zhijun Min
- Abdelbari Sophia Shadia
- Shun'e Yang
- Xiaojian Liu
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Affiliations: Department of Gastrointestinal Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China, Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200031, P.R. China, Department of Lymphoma, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
Published online on: September 3, 2018 https://doi.org/10.3892/etm.2018.6677
Pages: 3827-3834
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

At present there is no consensus on the treatment of classical Hodgkin's lymphoma (CHL) following relapse. The aim of the present study was to access the class I‑selective histone deacetylase (HDAC) inhibitor (HDACI) MGCD0103 on the expression levels of Bcl‑2, nuclear factor (NF)‑κB and programmed death‑ligand 1 (PD‑L1) in CHL, to explore the possible therapeutic value of MGCD0103 in combined relative target drugs for patients with CHL. In L1236 and L428 cell lines, apoptosis and cell cycle stage were identified using flow cytometry, and the effects of HDACI on CHL were assessed in terms of Bcl‑2, NF‑κB and PD‑L1 expression levels, which were detected by western blotting and co‑focusing experiments. The results demonstrated that MGCD0103 could induce cell apoptosis and cell cycle arrest, down‑regulate Bcl‑2 and increase NF‑κB and PD‑L1 expression levels in L1236 and L428 cell lines. MGCD0103 decreases Bcl‑2 levels and upregulates PD‑L1, which indicates that the combined use of HDACIs and a PD‑L1 inhibitor in theory may improve treatment outcomes in patients with CHL. MGCD0103 may also up‑regulate NF‑κB, which seems to induce resistance towards anti‑apoptotic drugs. Clinical trials combining HDACIs with NF‑κB and/or PD‑L1 inhibitors should be designed to further improve treatment outcomes for patients with CHL.

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1	Gobbi PG, Ferreri AJ, Ponzoni M and Levis A: Hodgkin lymphoma. Crit Rev Oncol Hematol. 85:216–237. 2013. View Article : Google Scholar : PubMed/NCBI
2	Venkataraman G, Mirza MK, Eichenauer DA and Diehl V: Current status of prognostication in classical Hodgkin lymphoma. Br J Haematol. 165:287–299. 2014. View Article : Google Scholar : PubMed/NCBI
3	Küppers R: The biology of Hodgkin's lymphoma. Nat Rev Cancer. 9:15–27. 2009. View Article : Google Scholar : PubMed/NCBI
4	Jalali A, Ha FJ, Chong G, Grigg A, Mckendrick J, Schwarer AP, Doig R, Hamid A and Hawkes EA: Hodgkin lymphoma: An Australian experience of ABVD chemotherapy in the modern era. Ann Hematol. 95:809–816. 2016. View Article : Google Scholar : PubMed/NCBI
5	Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN, Horning SJ, Dar AR, Shustik C, Stewart DA, et al: ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med. 366:399–408. 2012. View Article : Google Scholar : PubMed/NCBI
6	Morales CR, Li DL, Pedrozo Z, May HI, Jiang N, Kyrychenko V, Cho GW, Kim SY, Wang ZV, Rotter D, et al: Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repression. Sci Signal. 9:ra342016. View Article : Google Scholar : PubMed/NCBI
7	Falkenberg KJ and Johnstone RW: Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov. 13:673–691. 2014. View Article : Google Scholar : PubMed/NCBI
8	Phelps MP, Bailey JN, Vleeshouwer-Neumann T and Chen EY: CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma. Proc Natl Acad Sci USA. 113:15090–15095. 2016. View Article : Google Scholar : PubMed/NCBI
9	Locatelli SL, Cleris L, Stirparo GG, Tartari S, Saba E, Pierdominici M, Malorni W, Carbone A, Anichini A and Carlo-Stella C: BIM upregulation and ROS-dependent necroptosis mediate the antitumor effects of the HDACi Givinostat and Sorafenib in Hodgkin lymphoma cell line xenografts. Leukemia. 28:1861–1871. 2014. View Article : Google Scholar : PubMed/NCBI
10	Bolden JE, Peart MJ and Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 5:769–784. 2006. View Article : Google Scholar : PubMed/NCBI
11	Minucci S and Pelicci PG: Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 6:38–51. 2006. View Article : Google Scholar : PubMed/NCBI
12	Zagni C, Floresta G, Monciino G and Rescifina A: The search for potent, small-molecule HDACIs in cancer treatment: A decade after vorinostat. Med Res Rev. 37:1373–1428. 2017. View Article : Google Scholar : PubMed/NCBI
13	Lin TY, Fenger J, Murahari S, Bear MD, Kulp SK, Wang D, Chen CS, Kisseberth WC and London CA: AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. Blood. 115:4217–4225. 2010. View Article : Google Scholar : PubMed/NCBI
14	Peart MJ, Smyth GK, van Laar RK, Bowtell DD, Richon VM, Marks PA, Holloway AJ and Johnstone RW: Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA. 102:3697–3702. 2005. View Article : Google Scholar : PubMed/NCBI
15	Batlevi CL, Crump M, Andreadis C, Rizzieri D, Assouline SE, Fox S, van der Jagt RHC, Copeland A, Potvin D, Chao R and Younes A: A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br J Haematol. 178:434–441. 2017. View Article : Google Scholar : PubMed/NCBI
16	Jude JG, Spencer GJ, Huang X, Somerville TDD, Jones DR, Divecha N and Somervaille TCP: A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival. Oncogene. 34:1253–1262. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kirschbaum MH: Histone deacetylase inhibitors and Hodgkin's lymphoma. Lancet Oncol. 12:1178–1179. 2011. View Article : Google Scholar : PubMed/NCBI
18	Zagni C, Floresta G, Monciino G and Rescifina A: The search for potent, small-molecule HDACIs in cancer treatment: A decade after vorinostat. Med Res Rev. 37:1373–1428. 2017. View Article : Google Scholar : PubMed/NCBI
19	Rosenquist R and Stamatopoulos K: B-cell malignancies: All roads lead to NF-κB activation. Semin Cancer Biol. 39:1–2. 2016. View Article : Google Scholar : PubMed/NCBI
20	Weniger MA and Küppers R: NF-κB deregulation in Hodgkin lymphoma. Semin Cancer Biol. 39:32–39. 2016. View Article : Google Scholar : PubMed/NCBI
21	Roemer MGM, Redd R and Cader F: Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic hodgkin lymphoma. J Clin Oncol. 36:942–950. 2018. View Article : Google Scholar : PubMed/NCBI
22	Tanaka Y, Maeshima AM, Nomoto J, Makita S, Fukuhara S, Munakata W, Maruyama D, Tobinai K and Kobayashi Y: Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. Eur J Haematol. 100:511–517. 2018. View Article : Google Scholar : PubMed/NCBI
23	Pianko MJ, Moskowitz AJ and Lesokhin AM: Immunotherapy of lymphoma and myeloma: Facts and hopes. Clin Cancer Res. 24:1002–1010. 2018. View Article : Google Scholar : PubMed/NCBI
24	Alinari L and Blum K: How I treat relapsed classical Hodgkin lymphoma after autologous stem cell transplant. Blood. 127:287–295. 2016. View Article : Google Scholar : PubMed/NCBI
25	Villasboas JC and Ansell S: Checkpoint inhibition: programmed cell death 1 and programmed cell death 1 ligand inhibitors in Hodgkin lymphoma. Cancer J. 22:17–22. 2016. View Article : Google Scholar : PubMed/NCBI
26	Huang R, Zhang X, Sophia S, Min Z and Liu X: Clinicopathological features and prediction values of HDAC1, HDAC2, HDAC3, and HDAC11 in classical Hodgkin lymphoma. Anticancer Drugs. 29:364–370. 2018. View Article : Google Scholar : PubMed/NCBI
27	Delbridge A, Grabow S, Strasser A and Vaux DL: Thirty years of BCL-2: Translating cell death discoveries into novel cancer therapies. Nat Rev Cancer. 16:99–109. 2016. View Article : Google Scholar : PubMed/NCBI
28	Karube K and Campo E: MYC alterations in diffuse large B-cell lymphomas. Semin Hematol. 52:97–106. 2015. View Article : Google Scholar : PubMed/NCBI
29	Richmond A: Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol. 2:664–674. 2002. View Article : Google Scholar : PubMed/NCBI
30	Wang Y, Tang P, Chen Y, Chen J, Ma R and Sun L: Overexpression of microRNA-125b inhibits human acute myeloid leukemia cells invasion, proliferation and promotes cells apoptosis by targeting NF-κB signaling pathway. Biochem Biophys Res Commun. 488:60–66. 2017. View Article : Google Scholar : PubMed/NCBI
31	Lee SJ, Jung YH, Song EJ, Jang KK, Choi SH and Han HJ: Vibrio vulnificus VvpE stimulates IL-1β production by the hypomethylation of the IL-1β promoter and NF-κB activation via lipid raft-dependent ANXA2 recruitment and reactive oxygen species signaling in intestinal epithelial cells. J Immunol. 195:2282–2293. 2015. View Article : Google Scholar : PubMed/NCBI
32	de Oliveira KA, Kaergel E, Heinig M, Fontaine JF, Patone G, Muro EM, Mathas S, Hummel M, Andrade-Navarro MA, Hübner N and Scheidereit C: A roadmap of constitutive NF-κB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses. Genome Med. 8:282016. View Article : Google Scholar : PubMed/NCBI
33	Buglio D, Mamidipudi V, Khaskhely NM, Brady H, Heise C, Besterman J, Martell RE, MacBeth K and Younes A: The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism. Br J Haematol. 151:387–396. 2010. View Article : Google Scholar : PubMed/NCBI
34	Zhang YH, Tian M, Tang MX, Liu ZZ and Liao AH: Recent insight into the role of the PD-1/PD-L1 pathway in feto-maternal tolerance and pregnancy. Am J Reprod Immunol. 74:201–208. 2015. View Article : Google Scholar : PubMed/NCBI
35	Le Burel S, Champiat S, Routier E, Aspeslagh S, Albiges L, Szwebel TA, Michot JM, Chretien P, Mariette X, Voisin AL and Lambotte O: Onset of connective tissue disease following anti-PD1/PD-L1 cancer immunotherapy. Ann Rheum Dis. 77:468–470. 2018. View Article : Google Scholar : PubMed/NCBI
36	Seko Y, Yagita H, Okumura K, Azuma M and Nagai R: Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3. Cardiovasc Res. 75:158–167. 2007. View Article : Google Scholar : PubMed/NCBI
37	Topalian SL, Taube JM, Anders RA and Pardoll DM: Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 16:275–287. 2016. View Article : Google Scholar : PubMed/NCBI
38	McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, Fong L, Joseph RW, Pal SK, Reeves JA, et al: Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 24:749–757. 2018. View Article : Google Scholar : PubMed/NCBI
39	Chen XY, Zhang J, Hou LD, Zhang R, Chen W, Fan HN, Huang YX, Liu H and Zhu JS: Upregulation of PD-L1 predicts poor prognosis and is associated with miR-191-5p dysregulation in colon adenocarcinoma. Int J Immunopathol Pharmacol. 32:20587384187903182018. View Article : Google Scholar : PubMed/NCBI
40	Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Eder JP, Golan T, Le DT, Burtness B, et al: Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): A multicentre, open-label, phase 1b trial. Lancet Oncol. 17:717–726. 2016. View Article : Google Scholar : PubMed/NCBI
41	Keir ME, Butte MJ, Freeman GJ and Sharpe AH: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 26:677–704. 2008. View Article : Google Scholar : PubMed/NCBI
42	Ravi R, Noonan KA, Pham V, Bedi R, Zhavoronkov A, Ozerov IV, Makarev E, Artemov V A, Wysocki PT, Mehra R, et al: Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun. 9:7412018. View Article : Google Scholar : PubMed/NCBI
43	Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF and Bluestone JA: Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol. 10:1185–1192. 2009. View Article : Google Scholar : PubMed/NCBI
44	Lau J, Cheung J, Navarro A, Lianoglou S, Haley B, Totpal K, Sanders L, Koeppen H, Caplazi P, McBride J, et al: Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice. Nat Commun. 8:145722017. View Article : Google Scholar : PubMed/NCBI
45	Gravelle P, Burroni B, Péricart S, Rossi C, Bezombes C, Tosolini M, Damotte D, Brousset P, Fournié JJ and Laurent C: Mechanisms of PD-1/PD-L1 expression and prognostic relevance in non-Hodgkin lymphoma: A summary of immunohistochemical studies. Oncotarget. 8:44960–44975. 2017. View Article : Google Scholar : PubMed/NCBI
46	Buglio D, Mamidipudi V, Khaskhely NM, Brady H, Heise C, Besterman J, Martell RE, MacBeth K and Younes A: The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism. Br J Haematol. 151:387–396. 2010. View Article : Google Scholar : PubMed/NCBI
47	Booth L, Roberts J, Poklepovic A, Kirkwood J and Dent P: HDAC inhibitors enhance the immunotherapy response of melanoma cells. Oncotarget. 8:83155–83170. 2017. View Article : Google Scholar : PubMed/NCBI
48	Woods DM, Sodré AL, Villagra A, Sarnaik A, Sotomayor EM and Weber J: HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res. 3:1375–1385. 2015. View Article : Google Scholar : PubMed/NCBI
49	Briere D, Sudhakar N, Woods DM, Hallin J, Engstrom LD, Aranda R, Chiang H, Sodré AL, Olson P, Weber JS and Christensen JG: The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy. Cancer Immunol Immunother. 67:381–392. 2018. View Article : Google Scholar : PubMed/NCBI
50	Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, Connelly CF, Sun HH, Daadi SE, Freeman GJ, et al: PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 34:2690–2697. 2016. View Article : Google Scholar : PubMed/NCBI