Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives.

Recently, small compound-based therapies have provided new insights into the treatment of glioblastoma multiforme (GBM) by inducing oxidative impairment. Kinetin riboside (KR) and newly designed derivatives (8-azaKR, 7-deazaKR) selectively affect the molecular pathways crucial for cell growth by interfering with the redox status of cancer cells. Thus, these compounds might serve as potential alternatives in the oxidative therapy of GBM. The increased basal levels of reactive oxygen species (ROS) in GBM support the survival of cancer cells and cause drug resistance. The simplest approach to induce cell death is to achieve the redox threshold and circumvent the antioxidant defense mechanisms. Consequently, cells become more sensitive to oxidative stress (OS) caused by exogenous agents. Here, we investigated the effect of KR and its derivatives on the redox status of T98G cells in 2D and 3D cell culture. The use of spheroids of T98G cells enabled the selection of one derivative-7-deazaKR-with comparable antitumor activity to KR. Both compounds induced ROS generation and genotoxic OS, resulting in lipid peroxidation and leading to apoptosis. Taken together, these results demonstrated that KR and 7-deazaKR modulate the cellular redox environment of T98G cells, and vulnerability of these cells is dependent on their antioxidant capacity

A possible mechanism for 5′ and 3′ end repair in SeMV.

<p>VPg is shown as a small circle at the 5′ end of the (+/−) gRNA, (+/−) sgRNA and primer nucleotides. The 5′ end of the (+) gRNA and (+) sgRNA begins with 5′ACAA3′ sequence. Step1, The VPg-ACAA or VPg-ACA primers could be synthesized by RdRp using unknown internal sequence element (shown as stem-loop) (presence of different VPg forms in the western blots supports this possibility). Step 2, these primers realign at the 3′ end of the (+) gRNA even in the absence of complementarity (Note that initial RNA formed from SeMV icDNA lacks complementarity with the VPg-ACA/VPg-ACAA primer at the 3′ end). Alignment or positioning of primers at the genomic termini could be determined by <i>cis</i> acting elements. The RNA chain could be elongated to synthesize full length negative strand or terminated prematurely to synthesize subgenomic length negative strand (the full length genomic negative strand in replicative form (ds gRNA) and (−) ss sgRNA or ds sgRNA are indeed detected in northern blots). Step 3, the VPg-ACAA/VPg-ACA primers align at the 3′ end of these negative stranded genomic and subgenomic RNAs which could be elongated to synthesize positive stranded genomic and subgenomic RNA respectively.</p