Combination treatment with VPA and MSCs‑TRAIL could increase anti‑tumor effects against intracranial glioma

Park,Soon A.; Han,Hye Rim; Ahn,Stephen; Ryu,Chung Heon; Jeun,Sin‑Soo

doi:10.3892/or.2021.7937

Combination treatment with VPA and MSCs‑TRAIL could increase anti‑tumor effects against intracranial glioma

Authors:
- Soon A. Park
- Hye Rim Han
- Stephen Ahn
- Chung Heon Ryu
- Sin‑Soo Jeun
View Affiliations

Affiliations: Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea, Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea, Department of Clinical Laboratory Science, Daejeon Health Institute of Technology, Daejeon 34504, Republic of Korea
Published online on: January 14, 2021 https://doi.org/10.3892/or.2021.7937
Pages: 869-878
Copyright: © Park 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

Human bone marrow‑derived mesenchymal stem cells secreting tumor necrosis factor‑related apoptosis‑inducing ligand (MSCs‑TRAIL) have demonstrated effective anti‑tumor activity against various tumors including lung, pancreatic and prostate tumors, although several tumor types are not responsive. In such case, other reagents may decrease tumor growth via TRAIL‑mediated cell death. The present study aimed to examine the effectiveness of valproic acid (VPA) in enhancing the efficacy of TRAIL, which was delivered using MSCs. Moreover, the present study examined the induced tumor tropism of MSCs via cell viability and migration assays. Combination treatment with VPA and MSCs‑TRAIL enhanced the glioma therapeutic effect by increasing death receptor 5 and caspase activation. Migration assays identified increased MSC migration in VPA and MSCs‑TRAIL‑treated glioma cells and in the tumor site in glioma‑bearing mice compared with VPA or MSC‑TRAIL treatment alone. In vivo experiments demonstrated that MSC‑based TRAIL gene delivery to VPA‑treated tumors had greater therapeutic efficacy compared with treatment with each agent alone. These findings suggested that VPA treatment increased the therapeutic efficacy of MSC‑TRAIL via TRAIL‑induced apoptosis and enhanced tropism of MSCs, which may offer a useful strategy for tumor gene therapy.

View Figures

View References

1	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
2	Wilson TA, Karajannis MA and Harter DH: Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int. 5:642014. View Article : Google Scholar : PubMed/NCBI
3	Trivedi R and Mishra DP: Trailing TRAIL resistance: Novel targets for TRAIL sensitization in cancer cells. Front Oncol. 5:692015. View Article : Google Scholar : PubMed/NCBI
4	Von Karstedt S, Montinaro A and Walczak H: Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 17:352–366. 2017. View Article : Google Scholar : PubMed/NCBI
5	Hodgkinson CP, Gomez JA, Mirotsou M and Dzau VJ: Genetic engineering of mesenchymal stem cells and its application in human disease therapy. Hum Gene Ther. 21:1513–1526. 2010. View Article : Google Scholar : PubMed/NCBI
6	Müller FJ, Snyder EY and Loring JF: Gene therapy: Can neural stem cells deliver? Nat Rev Neurosci. 7:752006. View Article : Google Scholar : PubMed/NCBI
7	Cheng S, Nethi SK, Rathi S, Layek B and Prabha S: Engineered mesenchymal stem cells for targeting solid tumors: Therapeutic potential beyond regenerative therapy. J Pharmacol Exp Ther. 370:231–241. 2019. View Article : Google Scholar : PubMed/NCBI
8	Xu F and Zhu JH: Stem cells tropism for malignant gliomas. Neurosci Bull. 23:363–369. 2007. View Article : Google Scholar : PubMed/NCBI
9	Menon LG, Picinich S, Koneru R, Gao H, Lin SY, Koneru M, Mayer-Kuckuk P, Glod J and Banerjee D: Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells. Stem Cells. 25:520–528. 2007. View Article : Google Scholar : PubMed/NCBI
10	Menon LG, Kelly K, Yang HW, Kim SK, Black PM and Carroll RS: Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. Stem Cells. 27:2320–2330. 2009. View Article : Google Scholar : PubMed/NCBI
11	Kim SM, Kim DS, Jeong CH, Kim DH, Kim JH, Jeon HB, Kwon SJ, Jeun SS, Yang YS, Oh W and Chang JW: CXC chemokine receptor 1 enhances the ability of human umbilical cord blood-derived mesenchymal stem cells to migrate toward gliomas. Biochem Biophys Res Commun. 407:741–746. 2011. View Article : Google Scholar : PubMed/NCBI
12	Park SA, Ryu CH, Kim SM, Lim JY, Park SI, Jeong CH, Jun J, Oh JH, Park SH, Oh W and Jeun SS: CXCR4-transfected human umbilical cord blood-derived mesenchymal stem cells exhibit enhanced migratory capacity toward gliomas. Int J Oncol. 38:97–103. 2011.PubMed/NCBI
13	Johnstone RW, Frew AJ and Smyth MJ: The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer. 8:782–798. 2008. View Article : Google Scholar : PubMed/NCBI
14	Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A and Ford HL: On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics. Oncogene. 32:1341–1350. 2013. View Article : Google Scholar : PubMed/NCBI
15	Zhang L and Fang B: Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12:228–237. 2005. View Article : Google Scholar : PubMed/NCBI
16	Kim JY, Kim EH, Kim SU, Kwon TK and Choi KS: Capsaicin sensitizes malignant glioma cells to TRAIL-mediated apoptosis via DR5 upregulation and survivin downregulation. Carcinogenesis. 31:367–375. 2009. View Article : Google Scholar : PubMed/NCBI
17	Son YG, Kim EH, Kim JY, Kim SU, Kwon TK, Yoon AR, Yun CO and Choi KS: Silibinin sensitizes human glioma cells to TRAIL-mediated apoptosis via DR5 up-regulation and down-regulation of c-FLIP and survivin. Cancer Res. 67:8274–8284. 2007. View Article : Google Scholar : PubMed/NCBI
18	Kim SM, Oh JH, Park SA, Ryu CH, Lim JY, Kim DS, Chang JW, Oh W and Jeun SS: Irradiation enhances the tumor tropism and therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand-secreting human umbilical cord blood-derived mesenchymal stem cells in glioma therapy. Stem Cells. 28:2217–2228. 2010. View Article : Google Scholar : PubMed/NCBI
19	Fröscher W, Schulz H and Gugler R: Valproic acid in the treatment of epilepsy with special emphasis on serum level determination (author's transl). Fortschr Neurol Psychiatr Grenzgeb. 46:327–341. 1978.(In German). PubMed/NCBI
20	Cipriani A, Reid K, Young AH, Macritchie K and Geddes J: Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 10:CD0031962013.
21	Valiyaveettil D, Malik M, Joseph DM, Ahmed SF, Kothwal SA and Vijayasaradhi M: Effect of valproic acid on survival in glioblastoma: A prospective single-arm study. South Asian J Cancer. 7:159–162. 2018. View Article : Google Scholar : PubMed/NCBI
22	Searles CD, Slesinger PA and Singer HS: Effects of anticonvulsants on cholinergic and GABAergic properties in the neuronal cell clone NG108-15. Neurochem Res. 13:1007–1013. 1988. View Article : Google Scholar : PubMed/NCBI
23	Tarasenko N, Cutts SM, Phillips DR, Berkovitch-Luria G, Bardugo-Nissim E, Weitman M, Nudelman A and Rephaeli A: A novel valproic acid prodrug as an anticancer agent that enhances doxorubicin anticancer activity and protects normal cells against its toxicity in vitro and in vivo. Biochem Pharmacol. 88:158–168. 2014. View Article : Google Scholar : PubMed/NCBI
24	Gotfryd K, Skladchikova G, Lepekhin EA, Berezin V, Bock E and Walmod PS: Cell type specific anti-cancer properties of valproic acid independent effects on HDAC activity and Erk12 phosphorylation. BMC Cancer. 10:3832010. View Article : Google Scholar : PubMed/NCBI
25	Xu W, Parmigiani R and Marks P: Histone deacetylase inhibitors: Molecular mechanisms of action. Oncogene. 26:5541–5552. 2007. View Article : Google Scholar : PubMed/NCBI
26	Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Coco FL, Nervi C, Pelicci PG and Heinzel T: Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20:6969–6978. 2001. View Article : Google Scholar : PubMed/NCBI
27	Chateauvieux S, Morceau F, Dicato M and Diederich M: Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010:4793642010. View Article : Google Scholar : PubMed/NCBI
28	Kim SM, Lim JY, Park SI, Jeong CH, Oh JH, Jeong M, Oh W, Park SH, Sung YC and Jeun SS: Gene therapy using TRAIL-secreting human umbilical cord blood-derived mesenchymal stem cells against intracranial glioma. Cancer Res. 68:9614–9623. 2008. View Article : Google Scholar : PubMed/NCBI
29	Ryu CH, Park SA, Kim SM, Lim JY, Jeong CH, Jun JA, Oh JH, Park SH, Oh WI and Jeun SS: Migration of human umbilical cord blood mesenchymal stem cells mediated by stromal cell-derived factor-1/CXCR4 axis via Akt, ERK, and p38 signal transduction pathways. Biochem Biophys Res Commun. 398:105–110. 2010. View Article : Google Scholar : PubMed/NCBI
30	Kim SM, Woo JS, Jeong CH, Ryu CH, Jang JD and Jeun SS: Potential application of temozolomide in mesenchymal stem cell-based TRAIL gene therapy against malignant glioma. Stem Cells Transl Med. 3:172–182. 2014. View Article : Google Scholar : PubMed/NCBI
31	Janssen CF, Maiello P, Wright MJ Jr, Kracinovsky KB and Newsome JT: Comparison of atipamezole with yohimbine for antagonism of xylazine in mice anesthetized with ketamine and xylazine. J Am Assoc Lab Anim Sci. 56:142–147. 2017.PubMed/NCBI
32	Danneman PJ, Stein S and Walshaw SO: Humane and practical implications of using carbon dioxide mixed with oxygen for anesthesia or euthanasia of rats. Lab Anim Sci. 47:376–385. 1997.PubMed/NCBI
33	Carpenter J and Chris M: Exotic animal formulary. (5th edition). pp4682017.
34	McIlwain DR, Berger T and Mak TW: Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 5:a0086562013. View Article : Google Scholar : PubMed/NCBI
35	Naderi-Meshkin H, Bahrami AR, Bidkhori HR, Mirahmadi M and Ahmadiankia N: Strategies to improve homing of mesenchymal stem cells for greater efficacy in stem cell therapy. Cell Biol Int. 39:23–34. 2015. View Article : Google Scholar : PubMed/NCBI
36	Rosato RR, Almenara JA, Dai Y and Grant S: Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol Cancer Ther. 2:1273–1284. 2003.PubMed/NCBI
37	Frew AJ, Lindemann RK, Martin BP, Clarke CJ, Sharkey J, Anthony DA, Banks K-M, Haynes NM, Gangatirkar P, Stanley K, et al: Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist. Proc Natl Acad Sci USA. 105:11317–11322. 2008. View Article : Google Scholar : PubMed/NCBI
38	Bangert A, Cristofanon S, Eckhardt I, Abhari BA, Kolodziej S, Häcker S, Vellanki SHK, Lausen J, Debatin KM and Fulda S: Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene. 31:4677–4688. 2012. View Article : Google Scholar : PubMed/NCBI
39	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
40	Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, et al: Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 65:3307–3318. 2005. View Article : Google Scholar : PubMed/NCBI
41	Faderl S, O'Brien S, Pui CH, Stock W, Wetzler M, Hoelzer D and Kantarjian HM: Adult acute lymphoblastic leukemia: Concepts and strategies. Cancer. 116:1165–1176. 2010. View Article : Google Scholar : PubMed/NCBI
42	Marquez-Curtis LA and Janowska-Wieczorek A: Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. Biomed Res Int. 2013:5610982013. View Article : Google Scholar : PubMed/NCBI