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. 2024 Jun 26:14:1322795.
doi: 10.3389/fonc.2024.1322795. eCollection 2024.

GQIcombi application to subdue glioma via differentiation therapy

Varvara Kolesnikova #  1 , Alexander Revishchin  1 , Lika Fab  1 , Anna Alekseeva  1   2 , Anastasia Ryabova  3 , Igor Pronin  4 , Dmitry Y Usachev  4 , Alexey Kopylov  5 , Galina Pavlova #  1   4   6
Affiliations

GQIcombi application to subdue glioma via differentiation therapy

Varvara Kolesnikova et al. Front Oncol. .

Abstract

Current therapy protocols fail to cure high-grade gliomas and prevent recurrence. Therefore, novel approaches need to be developed. A re-programing of glioma cell fate is an alternative attractive way to stop tumor growth. The two-step protocol applies the antiproliferative GQ bi-(AID-1-T) and small molecule inducers with BDNF to trigger neural differentiation into terminally differentiated cells, and it is very effective on GB cell cultures. This original approach is a successful example of the "differentiation therapy". To demonstrate a versatility of this approach, in this publication we have extended a palette of cell cultures to gliomas of II, III and IV Grades, and proved an applicability of that version of differential therapy for a variety of tumor cells. We have justified a sequential mode of adding of GQIcombi components to the glioma cells. We have shown a significant retardation of tumor growth after a direct injection of GQIcombi into the tumor in rat brain, model 101/8. Thus, the proposed strategy of influencing on cancer cell growth is applicable to be further translated for therapy use.

Keywords: G-quadruplex oligonucleotides; antiproliferative activity; cancer stem cells; differentiation therapy; glioma; small molecule inducers.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Transcriptomic analysis of target genes upon GQIcombi (bi-(AID-1-T) + SB431542, LDN-193189, purmorphamine, and BDNF) exposure. Transcriptomic analysis of G01 glioma cell culture after exposure to GQIcombi. (A) Alteration of stem cells associated genes. (B) Alteration of genes associated with proliferation. (C) Alteration of genes associated with migration and invasion. (D) Alteration of ADAMT genes. (E) Alteration of growth factors genes. (F) Alteration of genes responsible for stem cell maintaining.
Figure 2
Figure 2
GQIcombi (bi-(AID-1-T) + SB431542, LDN-193189, purmorphamine, and BDNF) influences proliferation features of IV Grade glioma cell cultures Bl, Sh\fP3, G01, Sus, 40 and Rozh. (A, B) MTT assay for Bl and Sh\fP3 cell cultures in 10 days after the exposure to GQIcombi. Statistically significant differences between the control and the treatment groups are indicated by asterisks (One-Way ANOVA, Bonferroni’s multiple comparisons test, *= p<0.05). (C–H) Plot of normalized cell index versus time of Bl, Sh\fP3, G01, Sus, 40 and Rozh cell cultures in 10 days after the exposure to GQIcombi. Data are represented as mean ± SD; n = 2 for each group.
Figure 3
Figure 3
GQIcombi (bi-(AID-1-T) + SB431542, LDN-193189, purmorphamine, and BDNF) influences proliferation features of III Grade glioma cell cultures 22, G11, 42 and II Grade glioma cell culture G13. (A, B, E, F) MTT assay for 22, G11, 42 and G13 cell cultures in 10 days after the exposure to GQIcombi. Statistically significant differences between the control and the treatment groups are indicated by asterisks (One-Way ANOVA, Bonferroni’s multiple comparisons test, *= p<0.05, ** = p<0.01). (C, D, G, H) Plot of normalized cell index versus time of 22, g11, 42 and g13 cell cultures in 10 days after the exposure to GQIcombi. Data are represented as mean ± SD; n = 2 for each group.
Figure 4
Figure 4
GQIcombi (bi-(AID-1-T) + SB431542, LDN-193189, purmorphamine, and BDNF) influences stemness features of IV Grade glioma cell cultures G01, Sus, Bl, Sh\fP3, 40 and Rozh. (A–C, J–L) The expression of neural stem cells’ genes in G01, Sus, Bl, Sh\fP3, 40 and Rozh cell cultures cultures in 10 days after the exposure to GQIcombi. Data are represented as mean ± SD; n = 3 for each group. Statistically significant differences between the control and the treatment groups are indicated by asterisks (multiple unpaired t test, *= p<0.05, ** = p<0.01, *** = p<0.001, **** = p<0.0001). (D–F, G–I) Micrographs of immunocytochemical staining of G01, Sus, Bl, Sh\fP3, 40 and Rozh cell cultures with anti-CD133, anti-CD44, anti-L1CAM, anti-ki67, anti-bIII tubulin and anti-NeuN antibodies before (contr) and after (exp) exposure to GQIcombi. Scale bar is 50 μm.
Figure 5
Figure 5
GQIcombi (bi-(AID-1-T) + SB431542, LDN-193189, purmorphamine, and BDNF) influences stemness features of III Grade glioma cell cultures 22, G11, 42 and II Grade glioma cell culture G13. (A, B, E, F) The expression of neural stem cells’ genes in 22, G11, 42 and G13 cell cultures in 10 days after the exposure to GQIcombi. Data are represented as mean ± SD; n = 3 for each group. Statistically significant differences between the control and the treatment groups are indicated by asterisks (multiple unpaired t test, *= p<0.05, ** = p<0.01, *** = p<0.001, **** = p<0.0001). (C, D, G, H) Micrographs of immunocytochemical staining of 22, g11, 42 and g13 cell cultures with anti-CD133, anti-CD44, anti-L1CAM, anti-ki67, anti-bIIItubulin and anti-NeuN antibodies before (contr) and after (exp) exposure to GQIcombi. Scale bar is 50 μm.
Figure 6
Figure 6
Apoptosis of G01 cells upon GQIcombi (bi-(AID-1-T) + SB431542, LDN-193189, purmorphamine, and BDNF) exposure bi-(AID-1-T) and biHD1 exposure regimes. Staining of glioblastoma cell culture G01 for apoptosis upon exposure to GQIcombi (caspase-3- red, bisbenzimide - blue). Induction of apoptosis in control cells (A), in 8 days (B), 15 days (C), 21 days (D) and 30 days (E) after the beginning of the experiment. Changing in proliferative rate of G01 and Sus glioma cell cultures by sequential and simultaneous addition of bi-(AID-1-T) (F) or biHD1 (G) and small molecules. Data are represented as mean ± SD. n=3 for each group. Statistically significant differences between the control and the treatment groups are indicated by asterisks (Two-Way ANOVA, Bonferroni’s multiple comparisons test, ** = p<0.01, *** = p<0.001, **** = p<0.0001). GQ – G-quadruplex, SB - SB431542, LDN - LDN-193189, PRM – purmorphamine.
Figure 7
Figure 7
Inhibition of 101/8 tumor growth in rat glioma models upon GQIcombi (bi-(AID-1-T) + SB431542, LDN-193189, purmorphamine, and BDNF) exposure. (A) MRI scans of the 7th and 14th days’ (T1-weighted images using Gadovist) animals with implanted glioblastoma 101/8 in the control and experimental groups. (B) Accumulation of bi-(AID-1-T)-FAM in a 101/8 tumor in 15 minutes after the injection into the rat tail vein (FAM - green, bisbenzimide - blue).
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Ministry of Science and Higher Education of the Russian Federation, grant number 075–15-2024–561.

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