A Combined Effect of G-Quadruplex and Neuro-Inducers as an Alternative Approach to Human Glioblastoma Therapy

Abstract

Cancer cell reprogramming based on treatment with G-quadruplex, having antiproliferative power, along with small molecules able to develop iPSCs into neurons, could create a novel approach to diminish the chance of glioblastoma recurrence and circumvent tumor resistance to conventional therapy. In this research, we have tested several combinations of factors to affect both total cell cultures, derived from tumor tissue of patients after surgical resection and two subfractions of this cell culture after dividing them into CD133-enriched and CD133-depleted populations (assuming CD133 to be a marker of glioblastoma stem-like cells). CD133+ and CD133− cells exhibit different responses to the same combinations of factors; CD133+ cells have stem-like properties and are more resistant. Therefore, the ability to affect CD133+ cells provides a possibility to circumvent resistance to conventional therapy and to build a promising strategy for translation to improve the treatment of patients with glioblastoma.

GQIcombi application to subdue glioma via differentiation therapy

“…Characterization of glioma cell cultures of Grades IV, III, and II employed MTT assay, XCelligence Real-Time Cell Analyzer, ICH, and RT-qPCR. MTT assay was conducted on day 10, excluding G01, Sus, 40, Rozh (previously reported ( 24 ),). XCelligence RTCA S16 involved six analysis time points, including factor additions at 24-hour intervals, with a key impact observed upon bi-(AID-1-T) addition ( Figures 2C–H , 3C, D, G, H ).…”

“…In this way the very proliferation potential of cells is blocked ( 39 , 40 ). This approach allows to avoid the cytotoxic effect and to target the tumor cells of all stages of differentiation including cancer stem cells ( 24 ). The application of GQIcombi for the differential therapy of human glioblastoma proved itself as a promising approach ( 24 ).…”

“…bi-(AID-1-T) appeared to be an apt agent to cytotoxically stop the cell division cycle. After that we applied to combination of small molecules, namely, SB431542, LDN-193189, purmorphamine, and BDNF ( 24 ). SB431542 (SB) is capable to specifically interact with the ATP-binding domains of activin receptor-like kinases ALK5, ALK4, and ALK7, thus it inhibits Smad2/3 activation and blocks TGF-β signal transduction, which affects gene expression ( 41 ).…”

“…Cell cultures G01, Sus (Sus\fP2), Bl (G23), Rozh (G22), 40, Sh\fP3 (N1) (IV Grade), 22, 42, G11 (III Grade), G13 (II Grade) were obtained from human glioma tissues after tumor resection. Upon tumor resection cells were treated as it is previously described ( 24 ).…”

“…In our previous study, we had demonstrated a retardation of proliferation of glioblastoma cell cultures, Grade IV, after GQIcombi treatment: cytostatic G-quadruplex bi-(AID-1-T) oligonucleotide ( 21 ), SB431542 (SB), purmorphamine (PRM), LDN-193189 (LDN), and Brain-Derived Neurotrophic Factor (BDNF) ( 24 ). SB431542 acts as a competitive inhibitor of the ATP-binding sites of activin receptor-like kinases 4 (ALK4), ALK5, and ALK7, which are type 1 receptors in the TGF-β pathway, thereby specifically blocking Smad2/3-mediated signal transduction ( 25 , 26 ).…”