ENU administration causes genomic instability along with single nucleotide polymorphisms in p53 during gliomagenesis: T11TS administration demonstrated in vivo apoptosis of these genetically altered tumor cells

Abstract

Advancement of molecular analysis of neoplastic cells demonstrated that multiple genetic changes are associated with the development of tumors. Cancer cell must exhibit a mutator phenotype, which is likely to be responsible for the genomic instability found in cancer tissues. The mutator phenotype, such as defective mismatch repair, is known to cause microsatellite instability, which is associated with certain cases of sporadic cancer. Previously many studies have been carried out to determine the relationship between microsatellite instability and human brain tumors. However information on genomic instability in the animal model of brain tumor is still very limited. In the present course of investigations we genetically characterized our ENU induced brain tumor animal model by using PCR based randomly amplified polymorphic DNA (RAPD) analysis and restriction fragment length polymorphism (RFLP) with three microsatellite probes. ENU induced tumors demonstrated genetic instability, including some microsatellite instability. As single nucleotide polymorphisms of the tumor suppressor gene p53 were associated with diverse types of human cancer, we examined the p53 gene of the tumor cells isolated from ENU induced brain tumor animal model, by PCR based RFLP method in p53 exon-2, -3 and -4. In these studies we showed that the restriction site of p53 exon-3 and 4 were mutated in ENU induced brain tumor indicating a genetic defect associated with ENU induced tumorigenesis. In the therapeutic part, we confirmed the anti-tumor property of T11TS/ S-LFA-3 in the ENU induced genetically altered cells. Histological evidences, cytotoxic study, PI-FACS cell-cycle analysis and TUNEL assay confirmed the apoptotic death of glioma cells by T11TS treatment in which p53 is mutated. From the present study we can conclude that ENU administration causes genomic instability along with mutations in p53 during the process of gliomagenesis. Whereas, T11TS/S-LFA3 demonstrated the potential to induce apoptosis of these tumor cells even when p53 is mutated and thus showed its immense potential to be an anti-neoplastic probe against p53 mutated diverse types of tumors.

VEGF Immunopositivity Related to Malignancy Degree, Proliferative Activity and Angiogenesis in ENU-Induced Gliomas

“…Previous studies have reported that ENU affected the expression of genes such as p21-Ras (Engelbergs et al 2000) and p53 (Katayama et al 2005a;Mukherjee et al 2006), closely related to the modulation of morphogenic and The graph shows concentrations of VEGF 165 obtained by ELISA assay for samples with normal blood content (blue box) and for samples of exsanguinated animals after perfusion with saline (green box). The differences between conditions was of p<0.05 and among groups (control, CO classic oligodendroglioma and AO anaplastic oligodendroglioma) of p<0.001.…”

Growth Inhibition and Induction of Apoptosis in SHG‐44 Glioma Cells by Chinese Medicine Formula “Pingliu Keli”

“…The patients with malignant gliomas remain poorly responsive to multimodality therapeutic interventions, including surgery, radiotherapy, and chemotherapy [11, 12]. It has been reported that tumor growth is dependent on not only the rate of cellular proliferation, but also that of cell death [13].…”

The novel-molecule T11TS facilitated arousal of glioma-mediated dormancy of bone-marrow hematopoietic stem-cells

“…Further study in our lab also deciphered that T11TS immunotherapy, mediate functional activation of T cells by rectifying gliomagenic anti-proliferative action on T-cell by correcting CD2-mediated nuclear factor of activated T-cell calcineurin pathway [38] . Some of our previous publications also delineated that T11TS reduces glioma mass simultaneously by accelerating the apoptotic death of brain tumor cells and by decreasing the number of dividing glioma-bearing cells [39,40] .…”