The effects Metformin/Irinotecan-loaded PLGA nanoparticles on glutamate re-uptake time and alteration EAAT1 gene expression level in vitro

Document Type: Research Paper

Authors

1 Department of Pharmacology and Toxicology, Faculty of Veterinary, Ataturk University, Erzurum, 25240, Turkey

2 Department of Medical Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, 25240, Turkey

3 Department of Pharmaceutical Technology, Faculty of Pharmacy, Ataturk University, Erzurum, 25240, Turkey

Abstract

Objective(s): The present study was designed to evaluate of Metformin/Irinotecan-loaded poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) effects on glutamate re-uptake time and receptor expression status in both glioblastoma multiforme (GBM) and cortex neuron cultures. The study was performed on glioblastoma cell line and primer cortex neuron.
Materials and Methods: The re-uptake time and gene expression status of pure drugs and MET- or IRI-loaded-PLGA NPs on healthy neuron cells and U-87 MG cell line were investigated by using glutamate specific voltammetry electrodes technique and real time PCR.
Results: Both MET and MET-PLGA NPs (1 and 2 mM) exhibited significant cytotoxicity on both U87MG and neuron cells. MET and MET-PLGA NPs (0.5 mM) showed lower cytotoxic effects on both cells. IRI and IRI-PLGA NPs (100 µM) had significant cytotoxic effects on both cell lines.
Conclusion: All drug-loaded NPs caused a significant reduction in glutamate reuptake time compared with free drugs, blank NPs and cancer cells control groups. Consequently, MET- and IRI-loaded PLGA NPs may be a promising approach to treat GBM.

Keywords


1.Anjum K, Shagufta BI, Abbas SQ, Patel S, Khan I, Shah SAA. Current status and future therapeutic perspectives of glioblastoma multiforme (GBM) therapy: A review. Biomed Pharmacother. 2018; 101: 820.
2.Taghizadehghalehjoughi A, Hacimuftuoglu A, Cetin M, Ugur AB, Galateanu B, Mezhuev Y. Effect of metformin/irinotecan-loaded poly-lactic-co-glycolic acid nanoparticles on glioblastoma: in vitro and in vivo studies. Nanomedicine-Uk. 2018; 13(13): 1595-1606.
3.Das A, Learn J, Le MT, Yu J, Pikul B, Black K. Treatment of recurrent anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) with the glutamate antagonist riluzole. Neuro-Oncology. 2004; 6(4): 373.
4.Curry RJ, Peng K, Lu Y. Neurotransmitter- and Release-Mode-Specific Modulation of Inhibitory Transmission by Group I Metabotropic Glutamate Receptors in Central Auditory Neurons of the Mouse. J Neurosci. 2018; 38(38): 81887-81899.
5.Dar NJ, Satti NK, Dutt P, Hamid A, Ahmad M. Attenuation of Glutamate-Induced Excitotoxicity by Withanolide-A in Neuron-Like Cells: Role for PI3K/Akt/MAPK Signaling Pathway. Mol Neurobiol. 2018; 55(4): 2725-2739.
6.Sheahan TD, Valtcheva MV, Mcllvried LA, Pullen MY, Baranger DAA, Gereau RW. Metabotropic Glutamate Receptor 2/3 (mGluR2/3) Activation Suppresses TRPV1 Sensitization in Mouse, But Not Human, Sensory Neurons. Eneuro. 2018; 5(2).
7.Xu Y, Kim CS, Saylor DM, Koo D. Polymer degradation and drug delivery in PLGA-based drug-polymer applications: A review of experiments and theories. Journal of biomedical materials research Part B, Applied biomaterials. [Review Research Support, Non-U.S. Gov’t]. 2017; 105(6): 1692-1716.
8.Park J, Pham HV, Mogensen K, Solling TI, Vad Bennetzen M, Houk KN. Hydrocarbon Binding by Proteins: Structures of Protein Binding Sites for >/=C Linear Alkanes or Long-Chain Alkyl and Alkenyl Groups. The Journal of organic chemistry. 2015.
9.Morales DR, Morris AD. Metformin in cancer treatment and prevention. Annual review of medicine. 2015; 66:17-29.
10.Chiang CF, Chao TT, Su YF, Hsu CC, Chien CY, Chiu KC, et al. Metformin-treated cancer cells modulate macrophage polarization through AMPK-NF-kappa B signaling. Oncotarget. 2017; 8(13): 20706-20718.
11.Greenhill C. Gastric cancer: Metformin improves survival and recurrence rate in patients with diabetes and gastric cancer. Nature reviews Gastroenterology & hepatology. 2015.
12.Reddi A, Powers MA, Dellavalle RP. Therapeutic potential of the anti-diabetic agent metformin in targeting the skin cancer stem cell diaspora. Experimental dermatology. 2014; 23(5): 345-346.
13.Orecchioni S, Reggiani F, Talarico G, Mancuso P, Calleri A, Gregato G, et al. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int J Cancer. 2015; 136(6): 534-544.
14.Ucbek A, Ozunal ZG, Uzun O, Gepdiremen A. Effect of metformin on the human T98G glioblastoma multiforme cell line. Exp Ther Med. 2014; 7(5): 1285-1290.
15.Chang TC, Shiah HS, Yang CH, Yeh KH, Cheng AL, Shen BN. Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients. Cancer chemotherapy and pharmacology. 2015.
16.Sendur MA, Ozdemir N, Ozatli T, Yazici O, Aksoy S, Ekinci AS. Comparison the efficacy of second-line modified EOX (epirubicin, oxaliplatin, and capecitabine) and irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) regimens in metastatic gastric cancer patients that progressed on first-line modified docetaxel and cisplatin plus fluorouracil (DCF) regimen. Medical oncology. 2014; 31(9): 153.
17.Yoshino K, Nakamura K, Terajima Y, Kurita A, Matsuzaki T, Yamashita K. Comparative studies of irinotecan-loaded polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Bba-Biomembranes. 2012; 1818(11): 2901-2907.
18.Sepehri N, Rouhani H, Tavassolian F, Montazeri H, Khoshayand MR, Ghahremani MH. SN38 polymeric nanoparticles: in vitro cytotoxicity and in vivo antitumor efficacy in xenograft balb/c model with breast cancer versus irinotecan. International journal of pharmaceutics. 2014; 471(1-2): 485-497.
19.Kuroda J, Kuratsu J, Yasunaga M, Koga Y, Kenmotsu H, Sugino T. Antitumor effect of NK012, a 7-ethyl-10-hydroxycamptothecin-incorporating polymeric micelle, on U87MG orthotopic glioblastoma in mice compared with irinotecan hydrochloride in combination with bevacizumab. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010; 16(2): 521-529.
20.Cetin D, Hacimuftuoglu A, Aricioglu F, Okkay U, Ozcan H. The importance of the re-uptake time of glutamate in the neurobiology of depression and anxiety. Eur Neuropsychopharm. 2014; 24: S252-S.
21.Hacimuftuoglu A, Tatar A, Cetin D, Taspinar N, Saruhan F, Okkay U. Astrocyte/neuron ratio and its importance on glutamate toxicity: an in vitro voltammetric study. Cytotechnology. 2016; 68(4): 1425-1433.
22.Taghizadehghalehjoughi A, Hacimuftuoglu A, Cetin M, Ugur AB, Galateanu B, Mezhuev Y. Effect of metformin/irinotecan-loaded poly-lactic-co-glycolic acid nanoparticles on glioblastoma: in vitro and in vivo studies. Nanomedicine (Lond). [Research Support, Non-U.S. Gov’t]. 2018; 13(13): 1595-1606.
23.Kamalak H, Kamalak A, Taghizadehghalehjoughi A, Hacimuftuoglu A, Nalci KA. Cytotoxic and biological effects of bulk fill composites on rat cortical neuron cells. Odontology. 2018; 106(4): 377-388.
24.Yesilyurt F, Taghizadehghalehjoughi A, Hacimuftuoglu A. ACTH and Amlodipine Effects on Neuroblastoma and Cortical Neurons. Neuroendocrinology. 2018; 107: 19.
25.Gepdiremen A, Duzenli S, Hacimuftuoglu A, Bulucu D, Suleyman H. The effects of melatonin in glutamate-induced neurotoxicity of rat cerebellar granular cell culture. Jpn J Pharmacol. 2000; 84(4): 467-469.
26.Gepdiremen A, Hacimuftuoglu A, Duzenli S, Oztas S, Suleyman H. Effects of salicylic acid in glutamate- and kainic acid-induced neurotoxicity in cerebellar granular cell culture of rats. Pharmacol Res. 2000; 42(6): 547-551.
27.Deng B, Wang WH, Deng LL, Yao SX, Ming J, Zeng KF. Comparative RNA-seq analysis of citrus fruit in response to infection with three major postharvest fungi. Postharvest Biol Tec. 2018; 146: 134-46.
28.Capeloa T, Caramelo F, Fontes-Ribeiro C, Gomes C, Silva AP. Role of Methamphetamine on Glioblastoma Cytotoxicity Induced by Doxorubicin and Methotrexate. Neurotox Res. 2014; 26(3): 216-27.
29.Chaudhary SC, Kurundkar D, Elmets CA, Kopelovich L, Athar M. Metformin, an Antidiabetic Agent Reduces Growth of Cutaneous Squamous Cell Carcinoma by Targeting mTOR Signaling Pathway. Photochem Photobiol. 2012; 88(5): 1149-1156.
30.Beckner ME, Gobbel GT, Abounader R, Burovic F, Agostino NR, Laterra J. Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis. Lab Invest. 2005; 85(12): 1457-70.
31.Pare L, Baiget M. Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes (vol 15, pg 1788, 2008). Clin Cancer Res. 2009 Dec 1;15(23):7449-.
32.Tadokoro J, Kakihata K, Shimazaki M, Shiozawa T, Masatani S, Yamaguchi F. Post-marketing Surveillance (PMS) of all Patients Treated with Irinotecan in Japan: Clinical Experience and ADR Profile of 13 935 Patients. Jpn J Clin Oncol. 2011; 41(9): 1101-1111.
33.Rothenberg ML. Irinotecan (CPT-11): Recent developments and future directions-colorectal cancer and beyond. Oncologist. 2001; 6(1): 66-80.
34.Patel VJ, Elion GB, Houghton PJ, Keir S, Pegg AE, Johnson SP. Schedule-dependent activity of temozolomide plus CPT-11 against a human central nervous system tumor-derived xenograft. Clin Cancer Res. 2000; 6(10): 4154-4157.
35.Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999; 17(5): 1516-1525.