Osteosarcoma growth suppression by riluzole delivery via iron oxide nanocage in nude mice

Raghubir,Marian; Rahman,Chowdhury   Nowshin; Fang,Justin; Matsui,Hiroshi; Mahajan,Shahana   Sultana

doi:10.3892/or.2019.7420

Osteosarcoma growth suppression by riluzole delivery via iron oxide nanocage in nude mice

Authors:
- Marian Raghubir
- Chowdhury Nowshin Rahman
- Justin Fang
- Hiroshi Matsui
- Shahana Sultana Mahajan
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Affiliations: Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, NY 10065, USA, Department of Chemistry, Hunter College, City University of New York, New York, NY 10065, USA
Published online on: November 28, 2019 https://doi.org/10.3892/or.2019.7420
Pages: 169-176
Copyright: © Raghubir et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteosarcomas are the most commonly occurring malignant bone cancer in young individuals. The survival rate of patients with metastatic osteosarcoma is low and has been stagnant for over two decades. We previously demonstrated that the glutamate release inhibitor, riluzole inhibits osteosarcoma cell growth. Towards the development of more effective therapy, we investigated the delivery of riluzole in human metastatic osteosarcoma xenografts in mice. We compared the efficacy of riluzole delivery by intraperitoneally injecting either free riluzole or riluzole released via two different shapes of iron oxide nanoparticles (nanocage or nanosphere) of size 15±2.5 nm. We monitored tumor size using Vernier calipers and bioluminescence assay and found a significant reduction in tumor size in the riluzole‑treated groups when injected, either in free form or via nanoparticles, compared to the control groups (PBS, nanosphere or nanocage). Importantly, nanocage‑delivered riluzole was most effective in reducing tumor size in the xenograft nude mice. While riluzole delivery induced apoptosis in tumor tissues in all three groups of riluzole‑treated animals, it was highest in tumors from the nanocage‑delivered riluzole group. Therefore, we conclude that riluzole is an effective drug to reduce tumor size in osteosarcoma and the efficacy of riluzole as a apoptotic and tumor‑reducing drug is enhanced when delivered via nanocage.

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1	Dorfman HD and Czerniak B: Bone cancers. Cancer. 75:203–210. 1995. View Article : Google Scholar : PubMed/NCBI
2	Whelan JS: Osteosarcoma. Eur J Cancer. 33:1611–1618. 1997. View Article : Google Scholar : PubMed/NCBI
3	Kaste SC, Pratt CB, Cain AM, Jones-Wallace DJ and Rao BN: Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis: Imaging features. Cancer. 86:1602–1608. 1999. View Article : Google Scholar : PubMed/NCBI
4	Mialou V, Philip T, Kalifa C, Perol D, Gentet JC, Marec-Berard P, Pacquement H, Chastagner P, Defaschelles AS and Hartmann O: Metastatic osteosarcoma at diagnosis: Prognostic factors and long-term outcome-the french pediatric experience. Cancer. 104:1100–1109. 2005. View Article : Google Scholar : PubMed/NCBI
5	Berner K, Johannesen TB, Berner A, Haugland HK, Bjerkehagen B, Bohler PJ and Bruland OS: Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma. Acta Oncol. 54:25–33. 2015. View Article : Google Scholar : PubMed/NCBI
6	Mirabello L, Troisi RJ and Savage SA: Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the surveillance, epidemiology, and end results program. Cancer. 115:1531–1543. 2009. View Article : Google Scholar : PubMed/NCBI
7	Geller DS and Gorlick R: Osteosarcoma: A review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 8:705–718. 2010.PubMed/NCBI
8	Lindsey BA, Markel JE and Kleinerman ES: Osteosarcoma overview. Rheumatol Ther. 4:25–43. 2017. View Article : Google Scholar : PubMed/NCBI
9	Morrow JJ and Khanna C: Osteosarcoma genetics and epigenetics: Emerging biology and candidate therapies. Crit Rev Oncog. 20:173–197. 2015. View Article : Google Scholar : PubMed/NCBI
10	Martin GS: Cell signaling and cancer. Cancer Cell. 4:167–174. 2003. View Article : Google Scholar : PubMed/NCBI
11	Stepulak A, Luksch H, Gebhardt C, Uckermann O, Marzahn J, Sifringer M, Rzeski W, Staufner C, Brocke KS, Turski L and Ikonomidou C: Expression of glutamate receptor subunits in human cancers. Histochem Cell Biol. 132:435–445. 2009. View Article : Google Scholar : PubMed/NCBI
12	Stepulak A, Rola R, Polberg K and Ikonomidou C: Glutamate and its receptors in cancer. J Neural Transm (Vienna). 121:933–944. 2014. View Article : Google Scholar : PubMed/NCBI
13	Koochekpour S: Glutamate, a metabolic biomarker of aggressiveness and a potential therapeutic target for prostate cancer. Asian J Androl. 15:212–213. 2013. View Article : Google Scholar : PubMed/NCBI
14	Pollock PM, Cohen-Solal K, Sood R, Namkoong J, Martino JJ, Koganti A, Zhu H, Robbins C, Makalowska I, Shin SS, et al: Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet. 34:108–112. 2003. View Article : Google Scholar : PubMed/NCBI
15	Willard SS and Koochekpour S: Glutamate signaling in benign and malignant disorders: Current status, future perspectives, and therapeutic implications. Int J Biol Sci. 9:728–742. 2013. View Article : Google Scholar : PubMed/NCBI
16	Willard SS and Koochekpour S: Glutamate, glutamate receptors, and downstream signaling pathways. Int J Biol Sci. 9:948–959. 2013. View Article : Google Scholar : PubMed/NCBI
17	Yu LJ, Wall BA, Wangari-Talbot J and Chen S: Metabotropic glutamate receptors in cancer. Neuropharmacology. 15:193–202. 2016.
18	Savage SA, Mirabello L, Wang Z, Gastier-Foster JM, Gorlick R, Khanna C, Flanagan AM, Tirabosco R, Andrulis IL, Wunder JS, et al: Genome-Wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet. 45:799–803. 2013. View Article : Google Scholar : PubMed/NCBI
19	Kalariti NP, Lembessis P and Koutsilieris M: Characterization of the glutametergic system in MG-63 osteoblast-like osteosarcoma cells. Anticancer Res. 24:3923–3929. 2004.PubMed/NCBI
20	Martin D, Thompson MA and Nadler JV: The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1. Eur J Pharmacol. 250:473–476. 1993. View Article : Google Scholar : PubMed/NCBI
21	Doble A: The pharmacology and mechanism of action of riluzole. Neurology. 47 (Suppl 4):S233–S241. 1996. View Article : Google Scholar : PubMed/NCBI
22	Hubert JP, Delumeau JC, Glowinski J, Premont J and Doble A: Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rat cultured granule cells: Evidence for a dual mechanism of action. Br J Pharmacol. 113:261–267. 1994. View Article : Google Scholar : PubMed/NCBI
23	Jan CR, Lu YC, Jiann BP, Chang HT and Huang JK: Effect of riluzole on cytosolic Ca²⁺ increase in human osteosarcoma cells. Pharmacology. 66:120–127. 2002. View Article : Google Scholar : PubMed/NCBI
24	Liu J and Wang LN: The efficacy and safety of riluzole for neurodegenerative movement disorders: A systematic review with meta-analysis. Drug Deliv. 25:43–48. 2018. View Article : Google Scholar : PubMed/NCBI
25	Speyer CL, Smith JS, Banda M, DeVries JA, Mekani T and Gorski DH: Metabotropic glutamate receptor-1: A potential therapeutic target for the treatment of breast cancer. Breast Cancer Res Treat. 132:565–573. 2012. View Article : Google Scholar : PubMed/NCBI
26	Akamatsu K, Shibata MA, Ito Y, Sohma Y, Azuma H and Otsuki Y: Riluzole induces apoptotic cell death in human prostate cancer cells via endoplasmic reticulum stress. Anticancer Res. 29:2195–2204. 2009.PubMed/NCBI
27	Le MN, Chan JL, Rosenberg SA, Nabatian AS, Merrigan KT, Cohen-Solal KA and Goydos JS: The glutamate release inhibitor Riluzole decreases migration, invasion, and proliferation of melanoma cells. J Invest Dermatol. 130:2240–2249. 2010. View Article : Google Scholar : PubMed/NCBI
28	Liao S, Ruiz Y, Gulzar H, Yelskaya Z, Ait Taouit L, Houssou M, Jaikaran T, Schvarts Y, Kozlitina K, Basu-Roy K, et al: Osteosarcoma cell proliferation and survival requires mGluR5 receptor activity and is blocked by riluzole. PLoS One. 12:e01712562017. View Article : Google Scholar : PubMed/NCBI
29	Sperling ST, Aung S, Martin V, Rohde V and Ninkovic M: Riluzole: A potential therapeutic intervention in human brain tumor stem-like cells. Oncotarget. 8:96697–96709. 2017. View Article : Google Scholar : PubMed/NCBI
30	Yelskaya Z, Carrillo E, Dubisz E, Gulzar H, Morgan D and Mahajan SS: Synergistic inhibition of survival, proliferation, and migration of U87 cells with a combination of LY341495 and iressa. PLoS One. 8:e645882013. View Article : Google Scholar : PubMed/NCBI
31	Zhang C, Yuan XR, Li HY, Zhao ZJ, Liao YW, Wang XY, Su J, Sang SS and Liu Q: Anti-cancer effect of metabotropic glutamate receptor 1 inhibition in human glioma U87 cells: Involvement of PI3K/Akt/mTOR pathway. Cell Physiol Biochem. 35:419–432. 2015. View Article : Google Scholar : PubMed/NCBI
32	Yip D, Le MN, Chan JL, Lee JH, Mehnert JA, Yudd A, Kempf J, Shih WJ, Chen S and Goydos JS: A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma. Clin Cancer Res. 15:3896–3902. 2009. View Article : Google Scholar : PubMed/NCBI
33	Mehnert JM, Silk AW, Wen Y, Lee JH, Dudek L, Jeong BS, Li J, Schenkel JM, Sadimin E, Kane M, et al: A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma. Pigment Cell Melanoma Res. 31:534–540. 2018. View Article : Google Scholar : PubMed/NCBI
34	Jia SF, Worth LL and Kleinerman ES: A nude mouse model of human osteosarcoma lung metastases for evaluating new therapeutic strategies. Clin Exp Metastasis. 17:501–506. 1999. View Article : Google Scholar : PubMed/NCBI
35	Caldorera-Moore M, Guimard N, Shi L and Roy K: Designer nanoparticles: Incorporating size, shape and triggered release into nanoscale drug carriers. Expert Opin Drug Deliv. 7:479–495. 2010. View Article : Google Scholar : PubMed/NCBI
36	Tomuleasa C, Braicu C, Irimie A, Craciun L and Berindan- Neagoe I: Nanopharmacology in translational hematology and oncology. Int J Nanomedicine. 9:3465–3479. 2014.PubMed/NCBI
37	Dadwal A, Baldi A and Kumar Narang R: Nanoparticles as carriers for drug delivery in cancer. Artif Cells Nanomed Biotechnol. 46:295–305. 2018. View Article : Google Scholar : PubMed/NCBI
38	Sykes EA, Chen J, Zheng G and Chan WC: Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano. 8:5696–5706. 2014. View Article : Google Scholar : PubMed/NCBI
39	Moghimi SM and Szebeni J: Stealth liposomes and long circulating nanoparticles: Critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res. 42:463–478. 2003. View Article : Google Scholar : PubMed/NCBI
40	Gao Y, Xie J, Chen H, Gu S, Zhao R, Shao J and Jia L: Nanotechnology-Based intelligent drug design for cancer metastasis treatment. Biotechnol Adv. 32:761–777. 2014. View Article : Google Scholar : PubMed/NCBI
41	Kim PS, Djazayeri S and Zeineldin R: Novel nanotechnology approaches to diagnosis and therapy of ovarian cancer. Gynecol Oncol. 120:393–403. 2011. View Article : Google Scholar : PubMed/NCBI
42	Champion JA, Katare YK and Mitragotri S: Particle shape: A new design parameter for micro- and nanoscale drug delivery carriers. J Control Release. 121:3–9. 2007. View Article : Google Scholar : PubMed/NCBI
43	Toy R, Peiris PM, Ghaghada KB and Karathanasis E: Shaping cancer nanomedicine: The effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine (Lond). 9:121–134. 2014. View Article : Google Scholar : PubMed/NCBI
44	Truong NP, Whittaker MR, Mak CW and Davis TP: The importance of nanoparticle shape in cancer drug delivery. Expert Opin Drug Deliv. 12:129–142. 2015. View Article : Google Scholar : PubMed/NCBI
45	Rampersaud S, Fang J, Wei Z, Fabijanic K, Silver S, Jaikaran T, Ruiz Y, Houssou M, Yin Z, Zheng S, et al: The effect of cage shape on nanoparticle-based drug carriers: Anticancer drug release and efficacy via receptor blockade using dextran-coated iron oxide nanocages. Nano Lett. 16:7357–7363. 2016. View Article : Google Scholar : PubMed/NCBI
46	Oh MH, Yu T, Yu SH, Lim B, Ko KT, Willinger MG, Seo DH, Kim BH, Cho MG, Park JH, et al: Galvanic replacement reactions in metal oxide nanocrystals. Science. 340:964–968. 2013. View Article : Google Scholar : PubMed/NCBI
47	Liu Y, Chen T, Wu C, Qiu L, Hu R, Li J, Cansiz S, Zhang L, Cui C, Zhu G, et al: Facile surface functionalization of hydrophobic magnetic nanoparticles. J Am Chem Soc. 136:12552–12555. 2014. View Article : Google Scholar : PubMed/NCBI
48	Ray P, Wu AM and Gambhir SS: Optical bioluminescence and positron emission tomography imaging of a novel fusion reporter gene in tumor xenografts of living mice. Cancer Res. 63:1160–1165. 2003.PubMed/NCBI
49	Steckiewicz KP, Barcinska E, Malankowska A, Zauszkiewicz- Pawlak A, Nowaczyk G, Zaleska-Medynska A and Inkielewicz-Stepniak I: Impact of gold nanoparticles shape on their cytotoxicity against human osteoblast and osteosarcoma in in vitro model. Evaluation of the safety of use and anti-cancer potential. J Mater Sci Mater Med. 30:222019. View Article : Google Scholar : PubMed/NCBI
50	Groeneveld GJ, Van Kan HJ, Kalmijn S, Veldink JH, Guchelaar HJ, Wokke JH and Van den Berg LH: Riluzole serum concentrations in patients with ALS: Associations with side effects and symptoms. Neurology. 61:1141–1143. 2003. View Article : Google Scholar : PubMed/NCBI
51	Groeneveld GJ, van Kan HJ, Lie AHL, Guchelaar HJ and van den Berg LH: An association study of riluzole serum concentration and survival and disease progression in patients with ALS. Clin Pharmacol Ther. 83:718–722. 2008. View Article : Google Scholar : PubMed/NCBI
52	Bondi ML, Craparo EF, Giammona G and Drago F: Brain-targeted solid lipid nanoparticles containing riluzole: Preparation, characterization and biodistribution. Nanomedicine (Lond). 5:25–32. 2010. View Article : Google Scholar : PubMed/NCBI