The dual HDAC and PI3K inhibitor, CUDC‑907, inhibits tumor growth and stem‑like properties by suppressing PTX3 in neuroblastoma

Li,Mengzhen; Hu,Yang; Wang,Juan; Xu,Yanjie; Hong,Ye; Zhang,Li; Luo,Qiuyun; Zhen,Zijun; Lu,Suying; Huang,Junting; Zhu,Jia; Zhang,Yizhuo; Que,Yi; Sun,Feifei

doi:10.3892/ijo.2023.5602

The dual HDAC and PI3K inhibitor, CUDC‑907, inhibits tumor growth and stem‑like properties by suppressing PTX3 in neuroblastoma

Authors:
- Mengzhen Li
- Yang Hu
- Juan Wang
- Yanjie Xu
- Ye Hong
- Li Zhang
- Qiuyun Luo
- Zijun Zhen
- Suying Lu
- Junting Huang
- Jia Zhu
- Yizhuo Zhang
- Yi Que
- Feifei Sun
View Affiliations

Affiliations: Department of Pediatric Oncology, Sun Yat‑sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
Published online on: December 8, 2023 https://doi.org/10.3892/ijo.2023.5602
Article Number: 14
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Neuroblastoma (NB) is one of the common solid tumors in childhood and poses a threat to the lives of children. Patients with advanced‑stage or recurrent NB have a poor prognosis. CUDC‑907, as a novel dual‑target inhibitor of histone deacetylase (HDAC) and phosphatidylinositol‑3‑kinase (PI3K), has been proven to play an antitumor role in several types of tumors. However, the exact role of CUDC‑907 in NB remains unclear. In the present study, in vivo and in vitro assays were performed to investigate the anti‑NB activity of CUDC‑907. Pentraxin 3 (PTX3) small interfering RNA (siRNA) and PTX3 overexpression plasmid were transfected into cells to define the underlying mechanisms of CUDC‑907. Tumor tissues and clinical information were collected and immunohistochemistry (IHC) was conducted to analyze the association between the expression of HDAC1, HDAC2, HDAC3 and CD44, and the prognosis of patients with NB. The results indicated that CUDC‑907 significantly inhibited the proliferation and migration, and induced the apoptosis of NB cells, downregulating the expression level of MYCN, and suppressing the PI3K/AKT and MAPK/ERK pathways. Furthermore, CUDC‑907 suppressed the stem‑like properties of NB cells by inhibiting PTX3, a ligand and upstream protein of CD44. IHC revealed that the high expression of HDAC1, 2, 3 and CD44 was associated with a poor prognosis of patients with NB. On the whole, these findings indicate that CUDC‑907 may be developed into a possible therapeutic approach for patients with NB.

View Figures

View References

1	Maris JM, Hogarty MD, Bagatell R and Cohn SL: Neuroblastoma. Lancet. 369:2106–2120. 2007.
2	Whittle SB, Smith V, Doherty E, Zhao S, McCarty S and Zage PE: Overview and recent advances in the treatment of neuroblastoma. Expert Rev Anticancer Ther. 17:369–386. 2017.
3	Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, et al: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 363:1324–1334. 2010.
4	McGinty L and Kolesar J: Dinutuximab for maintenance therapy in pediatric neuroblastoma. Am J Health Syst Pharm. 74:563–567. 2017.
5	Schramm A, Köster J, Assenov Y, Althoff K, Peifer M, Mahlow E, Odersky A, Beisser D, Ernst C, Henssen AG, et al: Mutational dynamics between primary and relapse neuroblastomas. Nat Genet. 47:872–877. 2015.
6	Mohammad HP, Barbash O and Creasy CL: Targeting epigenetic modifications in cancer therapy: Erasing the roadmap to cancer. Nat Med. 25:403–418. 2019.
7	Witt O, Deubzer HE, Lodrini M, Milde T and Oehme I: Targeting histone deacetylases in neuroblastoma. Curr Pharm Des. 15:436–447. 2009.
8	Robey RW, Chakraborty AR, Basseville A, Luchenko V, Bahr J, Zhan Z and Bates SE: Histone deacetylase inhibitors: Emerging mechanisms of resistance. Mol Pharm. 8:2021–2031. 2011.
9	Yin L, Liu Y, Peng Y, Peng Y, Yu X, Gao Y, Yuan B, Zhu Q, Cao T, He L, et al: PARP inhibitor veliparib and HDAC inhibitor SAHA synergistically co-target the UHRF1/BRCA1 DNA damage repair complex in prostate cancer cells. J Exp Clin Cancer Res. 37:1532018.
10	McClure JJ, Li X and Chou CJ: Advances and challenges of HDAC inhibitors in cancer therapeutics. Adv Cancer Res. 138:183–211. 2018.
11	Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M, et al: Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin Cancer Res. 18:4104–4113. 2012.
12	Guo H, Zeng D, Zhang H, Bell T, Yao J, Liu Y, Huang S, Li CJ, Lorence E, Zhou S, et al: Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma. Oncogene. 38:1802–1814. 2019.
13	Li X, Su Y, Madlambayan G, Edwards H, Polin L, Kushner J, Dzinic SH, White K, Ma J, Knight T, et al: Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia. Haematologica. 104:2225–2240. 2019.
14	Chen Y, Peubez C, Smith V, Xiong S, Kocsis-Fodor G, Kennedy B, Wagner S, Balotis C, Jayne S, Dyer MJ and Macip S: CUDC-907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL. J Cell Mol Med. 23:340–348. 2019.
15	Fu XH, Zhang X, Yang H, Xu XW, Hu ZL, Yan J, Zheng XL, Wei RR, Zhang ZQ, Tang SR, et al: CUDC-907 displays potent antitumor activity against human pancreatic adenocarcinoma in vitro and in vivo through inhibition of HDAC6 to downregulate c-Myc expression. Acta Pharmacol Sin. 40:677–688. 2019.
16	Pal S, Kozono D, Yang X, Fendler W, Fitts W, Ni J, Alberta JA, Zhao J, Liu KX, Bian J, et al: Dual HDAC and PI3K inhibition abrogates NF kappa B- and FOXM1-mediated DNA damage response to radiosensitize pediatric high-grade gliomas. Cancer Res. 78:4007–4021. 2018.
17	Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, Kelly KR, Copeland AR, Akins A, Clancy MS, et al: Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: An open-label, dose-escalation, phase 1 trial. Lancet Oncol. 17:622–631. 2016.
18	Oki Y, Kelly KR, Flinn I, Patel MR, Gharavi R, Ma A, Parker J, Hafeez A, Tuck D and Younes A: CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: Results from an expanded phase I trial. Haematologica. 102:1923–1930. 2017.
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.
20	Li M, Sun C, Bu X, Que Y, Zhang L, Zhang Y, Zhang L, Lu S, Huang J, Zhu J, et al: ISL1 promoted tumorigenesis and EMT via Aurora kinase A-induced activation of PI3K/AKT signaling pathway in neuroblastoma. Cell Death Dis. 12:6202021.
21	Hickman DL: Minimal exposure times for irreversible euthanasia with carbon dioxide in mice and rats. J Am Assoc Lab Anim Sci. 61:283–286. 2022.
22	Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L and Weiss WA: Neuroblastoma. Nat Rev Dis Primers. 2:160782016.
23	Eleveld TF, Oldridge DA, Bernard V, Koster J, Colmet DL, Diskin SJ, Schild L, Bentahar NB, Bellini A, Chicard M, et al: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 47:864–871. 2015.
24	Mlakar V, Morel E, Mlakar SJ, Ansari M and Gumy-Pause F: A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma. J Exp Clin Cancer Res. 40:1892021.
25	Veschi V, Verona F and Thiele CJ: Cancer stem cells and neuroblastoma: Characteristics and therapeutic targeting options. Front Endocrinol (Lausanne). 10:7822019.
26	Aravindan N, Somasundaram DB, Herman TS and Aravindan S: Significance of hematopoietic surface antigen CD34 in neuroblastoma prognosis and the genetic landscape of CD34-expressing neuroblastoma CSCs. Cell Biol Toxicol. 37:461–478. 2021.
27	Mehrazma M, Madjd Z, Kalantari E, Panahi M, Hendi A and Shariftabrizi A: Expression of stem cell markers, CD133 and CD44, in pediatric solid tumors: a study using tissue microarray. Fetal Pediatr Pathol. 32:192–204. 2013.
28	Mesrati MH, Syafruddin SE, Mohtar MA and Syahir A: CD44: A multifunctional mediator of cancer progression. Biomolecules. 11:18502021.
29	Gomez KE, Wu F, Keysar SB, Morton JJ, Miller B, Chimed TS, Le PN, Nieto C, Chowdhury FN, Tyagi A, et al: Cancer cell CD44 mediates macrophage/monocyte-driven regulation of head and neck cancer stem cells. Cancer Res. 80:4185–4198. 2020.
30	Hsiao YW, Chi JY, Li CF, Chen LY, Chen YT, Liang HY, Lo YC, Hong JY, Chuu CP, Hung LY, et al: Disruption of the pentraxin 3/CD44 interaction as an efficient therapy for triple-negative breast cancers. Clin Transl Med. 12:e7242022.
31	Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F, Foster J, Zhou J and Zhang R: Molecular targeting therapies for neuroblastoma: Progress and challenges. Med Res Rev. 41:961–1021. 2021.
32	Westhoff MA, Karpel-Massler G, Brühl O, Enzenmuller S, La Ferla-Bruhl K, Siegelin MD, Nonnenmacher L and Debatin KM: A critical evaluation of PI3K inhibition in glioblastoma and neuroblastoma therapy. Mol Cell Ther. 2:322014.
33	Li Z and Thiele CJ: Targeting Akt to increase the sensitivity of neuroblastoma to chemotherapy: Lessons learned from the brain-derived neurotrophic factor/TrkB signal transduction pathway. Expert Opin Ther Targets. 11:1611–1621. 2007.
34	Boller D, Schramm A, Doepfner KT, Shalaby T, von Bueren AO, Eggert A, Grotzer MA and Arcaro A: Targeting the phosphoinositide 3-kinase isoform p110delta impairs growth and survival in neuroblastoma cells. Clin Cancer Res. 14:1172–1181. 2008.
35	Iwamoto M, Friedman EJ, Sandhu P, Agrawal NG, Rubin EH and Wagner JA: Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor. Cancer Chemother Pharmacol. 72:493–508. 2013.
36	Zorzi AP, Bernstein M, Samson Y, Wall DA, Desai S, Nicksy D, Nancy W, Elizabeth E and Sylvain B: A phase I study of histone deacetylase inhibitor, pracinostat (SB939), in pediatric patients with refractory solid tumors: IND203 a trial of the NCIC IND pro-gram/C17 pediatric phase I consortium. Pediatr Blood Cancer. 60:1868–1874. 2013.
37	Yang J, Nie J, Ma X, Wei Y, Peng Y and Wei X: Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol Cancer. 18:262019.
38	Chilamakuri R and Agarwal S: Dual targeting of PI3K and HDAC by CUDC-907 inhibits pediatric neuroblastoma growth. Cancers (Basel). 14:10672022.
39	Mondello P, Derenzini E, Asgari Z, Philip J, Brea EJ, Seshan V, Hendrickson RC, de Stanchina E, Scheinberg DA and Younes A: Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma. Oncotarget. 8:14017–14028. 2017.
40	Vega FM, Colmenero-Repiso A, Gomez-Munoz MA, Rodriguez-Prieto I, Aguilar-Morante D, Ramirez G, Marquez C, Cabello R and Pardal R: CD44-high neural crest stem-like cells are associated with tumour aggressiveness and poor survival in neuroblastoma tumours. EBioMedicine. 49:82–95. 2019.
41	Fabian J, Lodrini M, Oehme I, Schier MC, Thole TM, Hielscher T, Kopp-Schneider A, Opitz L, Capper D, von Deimling A, et al: GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3. Cancer Res. 74:2604–2616. 2014.
42	Fabian J, Opitz D, Althoff K, Lodrini M, Hero B, Volland R, Beckers A, de Preter K, Decock A, Patil N, et al: MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma. Oncotarget. 7:66344–66359. 2016.
43	Chesler L, Schlieve C, Goldenberg DD, Kenney A, Kim G, McMillan A, Matthay KK, Rowitch D and Weiss WA: Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Cancer Res. 66:8139–8146. 2006.
44	Smith JR, Moreno L, Heaton SP, Chesler L, Pearson AD and Garrett MD: Novel pharmacodynamic biomarkers for MYCN protein and PI3K/AKT/mTOR pathwaysignaling in children with neuroblastoma. Mol Oncol. 10:538–552. 2016.
45	Valencia-Sama I, Ladumor Y, Kee L, Adderley T, Christopher G, Robinson CM, Kano Y, Ohh M and Irwin MS: NRAS status determines sensitivity to SHP2 inhibitor combination therapies targeting the RAS-MAPK pathway in neuroblastoma. Cancer Res. 80:3413–3423. 2020.
46	Chakrabarti L, Abou-Antoun T, Vukmanovic S and Sandler AD: Reversible adaptive plasticity: A mechanism for neuroblastoma cell heterogeneity and chemo-resistance. Front Oncol. 2:822012.
47	Nassar D and Blanpain C: Cancer stem cells: Basic concepts and therapeutic implications. Annu Rev Pathol. 11:47–76. 2016.
48	Ross RA, Walton JD, Han D, Guo HF and Cheung NK: A distinct gene expression signature characterizes human neuroblastoma cancer stem cells. Stem Cell Res. 15:419–426. 2015.
49	Dong W, Xu X, Luo Y, Yang C, He Y, Dong X and Wang J: PTX3 promotes osteogenic differentiation by triggering HA/CD44/FAK/AKT positive feedback loop in an inflammatory environment. Bone. 154:1162312022.
50	Zhang H, Brown RL, Wei Y, Zhao P, Liu S, Liu X, Deng Y, Hu X, Zhang J, Gao XD, et al: CD44 splice isoform switching determines breast cancer stem cell state. Genes Dev. 33:166–179. 2019.
51	Louhichi T, Ziadi S, Saad H, Dhiab MB, Mestiri S and Trimeche M: Clinicopathological significance of cancer stem cell markers CD44 and ALDH1 expression in breast cancer. Breast Cancer. 25:698–705. 2018.
52	Elkashty OA, Elghanam GA, Su X, Liu Y, Chauvin PJ and Tran SD: Cancer stem cells enrichment with surface markers CD271 and CD44 in human head and neck squamous cell carcinomas. Carcinogenesis. 41:458–466. 2020.
53	Chen F, Chen X, Ren Y, Weng G, Keng PC, Chen Y and Lee SO: Radiation-induced glucocorticoid receptor promotes CD44+ prostate cancer stem cell growth through activation of SGK1-Wnt/beta-catenin signaling. J Mol Med (Berl). 97:1169–1182. 2019.
54	Tomizawa F, Jang MK, Mashima T and Seimiya H: c-KIT regulates stability of cancer stemness in CD44-positive colorectal cancer cells. Biochem Biophys Res Commun. 527:1014–1020. 2020.
55	Sadeghi A, Roudi R, Mirzaei A, Zare MA, Madjd Z and Abolhasani M: CD44 epithelial isoform inversely associates with invasive characteristics of colorectal cancer. Biomark Med. 13:419–426. 2019.
56	Kumazoe M, Takai M, Bae J, Hiroi S, Huang Y, Takamatsu K, Won Y, Yamashita M, Hidaka S, Yamashita S, et al: FOXO3 is essential for CD44 expression in pancreatic cancer cells. Oncogene. 36:2643–2654. 2017.
57	Cai HY, Yu B, Feng ZC, Qi X and Wei XJ: Clinical significance of CD44 expression in children with hepatoblastoma. Genet Mol Res. 14:13203–13207. 2015.
58	Ghanem MA, Van Steenbrugge GJ, Van Der Kwast TH, Sudaryo MK, Noordzij MA and Nijman RJ: Expression and prognostic value Of CD44 isoforms in nephroblastoma (Wilms tumor). J Urol. 168:681–686. 2002.
59	Amirghofran Z, Asiaee E and Kamazani FM: Soluble CD44 and CD44v6 and prognosis in children with B-cell acute lymphoblastic leukemia. Asia Pac J Clin Oncol. 12:e375–e382. 2016.
60	Legras S, Gunthert U, Stauder R, Curt F, Oliferenko S, Kluin-Nelemans HC, Marie JP, Proctor S, Jasmin C and Smadja-Joffe F: A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia. Blood. 91:3401–3413. 1998.