Targeting integrin beta 1 using anti-tumorigenic quinazoline derivative in inhibition of glioblastoma cell invasion and survival: An in vitro preclinical study

Abstract

Objective: Glioblastoma (GBM) is the most common and malignant brain tumor, with a ~14.5 months median survival rate without disease-modifying curative treatment. After surgical resection, radiation, and adjuvant temozolomide (TMZ) chemotherapy is the first-line treatment of GBM with adverse effects, including bone marrow suppression, genotoxicity, and teratogenicity. Here, we report a synthetic quinazoline derivative that inhibits the growth of GBM cells as a new therapeutic approach.
Methods: A potent quinazoline derivative (6-Pyridin-2-yl-5,6-dihydro-benzo[4,5] imidazo[1,2-c] quinazoline) was synthesized by one chemical step with 90% yield, followed by in vitro testing in GBM and neuroblastoma cells.
Results: The in vitro studies showed that the quinazoline derivative is highly specific by decreasing GBM cell invasion while inducing cell death and inhibiting the cellular invasion in the three-dimensional Matrigel matrix. This compound is highly specific to GBM cell death compared with other cells. Synthetic quinazoline derivative is non-toxic to normal non-tumorigenic cells but toxic to cancerous cells. Under these experimental conditions, quinazoline derivatives caused inhibition of beta-1 integrin, which is an important cell adhesion molecule required for tumor cell invasion and metastasis, with extracellular matrix-mediated interactions. Furthermore, a synthetic quinazoline derivative decreases oncogenic PKC-epsilon activity in neuroblastoma cells.
Conclusions: These studies suggest that a synthetic quinazoline derivative may treat GBM effectively alone or combined with other chemotherapeutic/immunotherapeutic agents.

Keywords

Glioblastoma / Integrinβ1 / PKC-epsilon / Quinazoline / Temozolomide

References

[1] Chamberlain MC. Temozolomide: therapeutic limitations in the treatment of adult high-grade gliomas. Expert Rev Neurother. 2010; 10(10): 1537-1544. PMid: 20925470. https://doi.org/10.1586/ern.10.32

[2] Kienast Y, Winkler F. Therapy and prophylaxis of brain metastases. Expert Rev Anticancer Ther. 2010; 10: 1763-1777. PMid: 21080803. https://doi.org/10.1586/era.10.165

[3] Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007; 13: 1253-1259. PMid: 17317837. https://doi.org/10.1158/1078-0432.CCR-06-2309

[4] Uhm JH, Dooley NP, Kyritsis AP, et al. Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. Clin Cancer Res. 1999; 5: 1587-1594.

[5] Carbonell WS, DeLay M, Jahangiri A, et al. β1 integrin target- ing potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Cancer Res. 2013; 73(10): 3145-3154. PMid: 23644530. https://doi.org/10.1158/0008-5472.CAN-13-0011

[6] Sharif TR, Sharif M. Overexpression of protein kinase C epsilon in astroglial brain tumor-derived cell lines and primary tumor samples. Int J Oncol. 1999; 15: 237-43. https://doi.org/10.3892/ijo.15.2.237

[7] Basu A, Sivaprasad U. Protein kinase Cepsilon makes the life and death decision. Cell Signal. 2007; 19: 1633-1642. PMid: 17537614. https://doi.org/10.1016/j.cellsig.2007.04.008

[8] Gorin MA, Pan Q. Protein kinase C epsilon: an oncogene and emerg- ing tumor biomarker. Mol Cancer. 2009; 8: 9-17. PMid: 19228372. https://doi.org/10.1186/1476-4598-8-9

[9] Mehndiratta S, Sapra S, Singh G, et al.Quinazolines as apopto- sis Inducers and Inhibitors: A Review of Patent Literature. Recent Pat Anticancer Drug Discov. 2016; 11: 2-66. PMid: 26681186. https://doi.org/10.2174/1574892811666151218151506

[10] WO1999061428A1: Quinazolines for treating brain tumor.

[11] Peyressatre M, Arama DP, Laure A, et al. Identification of Quinazoli- none Analogs Targeting CDK 5 Kinase Activity and Glioblastoma Cell Proliferation. Front Chem. 2020; 8: 691. PMid: 32974274. https://doi.org/10.3389/fchem.2020.00691

[12] Ravez S, Castillo-Aguilera O, Depreux P, et al. Quinazoline deriva- tives as anticancer drugs: a patent review (2011 - present). Expert Opin Ther Pat. 2015; 25(7): 789-804. PMid: 25910402. https://doi.org/10.1517/13543776.2015.1039512

[13] Sen S, Mukherjee T, Sarkar S, et al. Development of a highly selec- tive cell-permeable ratiometric fluorescent chemosensor for oxorhe- nium(V) ion. Analyst. 2011; 136(22): 4839-4845. PMid: 21971398. https://doi.org/10.1039/c1an15609h

[14] Chirila FV, Khan TK, Alkon DL. Spatiotemporal complexity of fi- broblast networks screens for Alzheimer’s disease. J Alzheimers Dis. 2013. 33(1): 165-76. PMid: 22886026. https://doi.org/10.3233/JAD-2012-120745

[15] Dhruv HD, Roos A, Tomboc PJ, et al. Propentofylline inhibits glioblastoma cell invasion and survival by targeting the TROY signal- ing pathway. J Neurooncol. 2016; 126(3): 397-404. PMid: 26559543. https://doi.org/10.1007/s11060-015-1981-0

[16] Okhrimenko H, Lu W, Xiang C, et al. Protein kinase C-epsilon regulates the necrosis, autophagy, and apoptosis and survival of glioma cells. Cancer Res. 2005; 65(16): 7301-7309. PMid: 16103081. https://doi.org/10.1158/0008-5472.CAN-05-1064

[17] Jacobs VL, Liu Y, De Leo JA. Propentofylline targets TROY, a syn- thetic microglial signaling pathway. PLoS One. 2012; 7(5): e37955. PMid: 22649568. https://doi.org/10.1371/journal.pone.0037955

[18] Grundy TJ, De Leon E, Griffin KR, et al. Differential response of patient-derived primary glioblastoma cells to environmental stiffness. Sci Rep. 2016; 6: 23353. PMid: 26996336. https://doi.org/10.1038/srep23353

[19] Paulus W, Baur I, Beutler AS, et al. Diffuse brain invasion of glioma cells requires β1 integrins. Lab Invest. 1996; 75(6): 819-826. https://doi.org/10.1097/00005072-199605000-00021

[20] Leenders WP, Kusters B, Verrijp K, et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res. 2004; 10: 6222-6230. PMid: 15448011. https://doi.org/10.1158/1078-0432.CCR-04-0823

[21] Azam F, Mehta S, Harris AL. Mechanisms of resistance to anti- angiogenesis therapy. Eur J Cancer. 2010; 46: 1323-1332. PMid: 20236818. https://doi.org/10.1016/j.ejca.2010.02.020

[22] Hou S, Isaji T, Hang Q, et al. Distinct effects of β 1 integrin on cell proliferation and cellular signaling in MDA-MB-231 breast cancer cells. Sci Rep. 2016; 6: 18430. PMid: 26728650. https://doi.org/10.1038/srep18430

[23] Paolillo M, Serra M, Schinelli S. Integrins in glioblastoma: Still an attractive target? Pharmacol Res. 2016; 113(Pt A): 55-61. PMid: 27498157. https://doi.org/10.1016/j.phrs.2016.08.004

[24] Brenner W, Benzing F, Gudejko-Thiel J, et al. Regulation of β1 in- tegrin expression by PKCepsilon in renal cancer cells. Int J Oncol. 2004; 25(4): 1157-63. PMid: 15375568. https://doi.org/10.3892/ijo.25.4.1157

[25] Ramsay AG, Marshall JF, Hart IR. Integrin trafficking and its role in cancer metastasis. Cancer Metastasis Rev. 2007; 26(3-4): 567-78. PMid: 17786537. https://doi.org/10.1007/s10555-007-9078-7

[26] Caccavari F, Valdembri D, Sandri C, et al. Integrin signaling and lung cancer. Cell Adh Migr. 2010; 4(1): 124-9. PMid: 20139694. https://doi.org/10.4161/cam.4.1.10976

[27] Nishioka M, Suehiro Y, Sakai K, et al. TROY is a promising prog- nostic biomarker in patients with colorectal cancer. Oncol Lett. 2018; 15(4): 5989-5994. PMid: 29556315. https://doi.org/10.3892/ol.2018.8079

[28] Deng C, Lin YX, Qi XK, et al. TNFRSF 19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumori- genesis. Cancer Res. 2018. 78(13): 3469-3483. PMid: 29735548. https://doi.org/10.1158/0008-5472.CAN-17-3205

[29] Paulino VM, Yang Z, Kloss J, et al. TROY (TNFRSF19) is over- expressed in advanced glial tumors and promotes glioblastoma cell invasion via Pyk2-Rac1 signaling. Mol Cancer Res. 2010; 8(11): 1558-1567. PMid: 20881009. https://doi.org/10.1158/1541-7786.MCR-10-0334

[30] Malric L, Monferran S, Gilhodes J, et al. Interest of integrins targeting in glioblastoma according to tumor heterogeneity and cancer stem cell paradigm: an update. Oncotarget. 2017; 8(49): 86947-86968. PMid: 29156849. https://doi.org/10.18632/oncotarget.20372