Abstract
BackgroundAntisense oligonucleotides against hTR (As-ODN-hTR) have shown promising results as treatment strategies for various human malignancies. All-trans retinoic acid (ATRA) is a signalling molecule with important roles in differentiation and apoptosis. Biological responses to ATRA are currently used therapeutically in various human cancers. The aim of this study was to evaluate the anti-tumor effects of As-ODN-hTR combined with ATRA in vivo.MethodsIn situ human oral squamous cell carcinoma (OSCC) models were established by subcutaneous injection of Tca8113 cells. Mice were treated with sense oligonucleotides against hTR(S-ODN-hTR) alone, As-ODN-hTR alone, ATRA alone, As-ODN-hTR plus ATRA, or S-ODN-hTR plus ATRA. Tumor size and weight were assessed in the mice. Telomerase activity was detected by a TRAP assay, apoptotic cells were evaluated with a Tunel assay, the expression of apoptosis-related proteins (Bcl-2 and Bax) was evaluated by immunohistochemistry and ultrastructural morphological changes in the tumor specimen were examined.ResultsBoth As-ODN-hTR and ATRA can significantly inhibit tumor growth in this OSCC xenograft solid-tumor model, and the combination of the two agents had a synergistic anti-tumorogenic effect. We also demonstrated that this anti-tumor effect correlated with inhibition of telomerase activity. Furthermore, significant increases in the number of apoptotic cells, typical apoptotic morphology and a downregulation of the anti-apoptotic protein, bcl-2 were observed in the treated tissues.ConclusionThe combination of As-ODN-hTR and ATRA has a synergistic anti-tumor effect. This anti-tumor effect can be mainly attributed to apoptosis induced by a decrease in telomerase activity. Bcl-2 plays an important role in this process. Therefore, combining As-ODN-hTR and ATRA may be an approach for the treatment of human oral squamous cell carcinoma.
Highlights
Antisense oligonucleotides against human telomerase RNA template subunit (hTR) (As-ODN-hTR) have shown promising results as treatment strategies for various human malignancies
We have previously reported that the combination of oligonucleotide As-ODN-hTR treatment with All-trans retinoic acid (ATRA) had a cytotoxic effect on oral squamous cell carcinoma (Tca8113) in vitro, in a synergistic manner [11]
Tumor volume and tumor weight in the control group were 796.2 ± 133.7 mm3 and 0.522 ± 0.109 g, respectively. Both As-ODN and ATRA treatment resulted in a Treatment of mice with a combination of As-ODN and ATRA resulted in a significant enhancement of the reduction in tumor growth when compared with therapy with either As-ODN (P < 0.01) or ATRA alone (P < 0.01)
Summary
Antisense oligonucleotides against hTR (As-ODN-hTR) have shown promising results as treatment strategies for various human malignancies. The aim of this study was to evaluate the anti-tumor effects of As-ODN-hTR combined with ATRA in vivo. The human telomerase holoenzyme consists of the human telomerase RNA template subunit (hTR), the human telomerase reverse transcriptase (hTERT) and a number of associated proteins. Both the telomerase RNA component hTR and hTERT are essential for telomerase function, these components may be good candidates for targeted therapy of malignant tumors [2]. Strategies using antisense oligonucleotides (As-ODN) against hTR (As-ODNhTR) have shown promising results as treatment strategies for various human malignancies [3,4]. Since antisense therapy was unable to completely inhibit telomerase activity and directly kill tumor cells in vivo, it was suggested that this strategy would have to be combined with another approach in order to provide an adequate level of therapy
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