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The cooperative effect of p53 and Rb in local nanotherapy in a rabbit VX2 model of hepatocellular carcinoma.

Dong S, Tang Q, Long M, Guan J, Ye L, Li G - Int J Nanomedicine (2013)

Bottom Line: The administration procedure proved safe for the rabbits' liver function, the p53 plus Rb LNT showed significantly better antitumoral effect and lower expression of malignant genes than the p53 or Rb LNT, although no significant difference was observed in animal survival when the p53 plus Rb LNT was compared with the p53 LNT.Rb works synergistically with p53 in combined therapy mediated by a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex to augment the antitumoral effect through the downregulated expression of important genes related to apoptosis, necrosis, growth, differentiation and multidrug resistance of tumor cells.LNT with p53 and Rb is potentially an effective antitumor therapy for hepatocellular carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Department of general surgery, The second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi Province, People's Republic of China.

ABSTRACT

Background/aim: A local nanotherapy (LNT) combining the therapeutic efficacy of trans-arterial embolization, nanoparticles, and p53 gene therapy has been previously presented. The study presented here aimed to further improve the incomplete tumor eradication and limited survival enhancement and to elucidate the molecular mechanism of the LNT.

Methods: In a tumor-targeting manner, recombinant expressing plasmids harboring wild-type p53 and Rb were either co-transferred or transferred separately to rabbit hepatic VX2 tumors in a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex and Lipiodol® (Guerbet, Villepinte, France) emulsion via the hepatic artery. Subsequent co-expression of p53 and Rb proteins within the treated tumors was investigated by Western blotting and in situ analysis by laser-scanning confocal microscopy. The therapeutic effect was evaluated by the tumor growth velocity, apoptosis and necrosis rates, their sensitivity to Adriamycin® (ADM), mitomycin C, and fluorouracil, the microvessel density of tumor tissue, and the survival time of animals. Eventually, real-time polymerase chain reaction and enhanced chemiluminescence Western blotting were used to investigate the expressive changes of important genes related to the therapy.

Results: The administration procedure proved safe for the rabbits' liver function, the p53 plus Rb LNT showed significantly better antitumoral effect and lower expression of malignant genes than the p53 or Rb LNT, although no significant difference was observed in animal survival when the p53 plus Rb LNT was compared with the p53 LNT.

Conclusion: Rb works synergistically with p53 in combined therapy mediated by a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex to augment the antitumoral effect through the downregulated expression of important genes related to apoptosis, necrosis, growth, differentiation and multidrug resistance of tumor cells. LNT with p53 and Rb is potentially an effective antitumor therapy for hepatocellular carcinoma.

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Relative quantitative real-time polymerase chain reaction analysis of messenger RNA (mRNA) expression of each gene in tumors from ten rabbits in each group: Lipiodol® (Guerbet, Villepinte, France) (Group A), nanoplex/Lipiodol (Group B), nanoplex-p53/Lipiodol (Group C), nanoplex-Rb/Lipiodol (Group D), and nanoplex-(p53+Rb)/Lipiodol (Group E).Notes: * Δ, ▲, and ✰ represent significant difference from Groups A, B, C, and D, respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.Abbreviations: BCRP, breast cancer resistance protein; CD34, cluster of differentiation 34; P-gp, P-glycoprotein 1; VEGF, vascular endothelial growth factor.
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f8-ijn-8-3757: Relative quantitative real-time polymerase chain reaction analysis of messenger RNA (mRNA) expression of each gene in tumors from ten rabbits in each group: Lipiodol® (Guerbet, Villepinte, France) (Group A), nanoplex/Lipiodol (Group B), nanoplex-p53/Lipiodol (Group C), nanoplex-Rb/Lipiodol (Group D), and nanoplex-(p53+Rb)/Lipiodol (Group E).Notes: * Δ, ▲, and ✰ represent significant difference from Groups A, B, C, and D, respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.Abbreviations: BCRP, breast cancer resistance protein; CD34, cluster of differentiation 34; P-gp, P-glycoprotein 1; VEGF, vascular endothelial growth factor.

Mentions: Relative quantitative analysis of the 2-ddCt method showed that the mRNA level of gene expression in the Lipiodol alone and nanoplex/Lipiodol groups was not significantly different. The nanoplex-p53/Lipiodol system significantly decreased the mRNA expression of mutant p53, VEGF, P-gp, and BCRP, while the nanoplex-Rb/Lipiodol system significantly decreased the mRNA expression of CD34, VEGF, P-gp, and BCRP. The nanoplex-(p53+Rb)/Lipiodol system lowered the expression of mRNA of p53, CD34, VEGF, Twist, P-gp, and BCRP the most, and was significantly different to the other two polyplexes for some genes in this regard (Figure 8).


The cooperative effect of p53 and Rb in local nanotherapy in a rabbit VX2 model of hepatocellular carcinoma.

Dong S, Tang Q, Long M, Guan J, Ye L, Li G - Int J Nanomedicine (2013)

Relative quantitative real-time polymerase chain reaction analysis of messenger RNA (mRNA) expression of each gene in tumors from ten rabbits in each group: Lipiodol® (Guerbet, Villepinte, France) (Group A), nanoplex/Lipiodol (Group B), nanoplex-p53/Lipiodol (Group C), nanoplex-Rb/Lipiodol (Group D), and nanoplex-(p53+Rb)/Lipiodol (Group E).Notes: * Δ, ▲, and ✰ represent significant difference from Groups A, B, C, and D, respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.Abbreviations: BCRP, breast cancer resistance protein; CD34, cluster of differentiation 34; P-gp, P-glycoprotein 1; VEGF, vascular endothelial growth factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3794986&req=5

f8-ijn-8-3757: Relative quantitative real-time polymerase chain reaction analysis of messenger RNA (mRNA) expression of each gene in tumors from ten rabbits in each group: Lipiodol® (Guerbet, Villepinte, France) (Group A), nanoplex/Lipiodol (Group B), nanoplex-p53/Lipiodol (Group C), nanoplex-Rb/Lipiodol (Group D), and nanoplex-(p53+Rb)/Lipiodol (Group E).Notes: * Δ, ▲, and ✰ represent significant difference from Groups A, B, C, and D, respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.Abbreviations: BCRP, breast cancer resistance protein; CD34, cluster of differentiation 34; P-gp, P-glycoprotein 1; VEGF, vascular endothelial growth factor.
Mentions: Relative quantitative analysis of the 2-ddCt method showed that the mRNA level of gene expression in the Lipiodol alone and nanoplex/Lipiodol groups was not significantly different. The nanoplex-p53/Lipiodol system significantly decreased the mRNA expression of mutant p53, VEGF, P-gp, and BCRP, while the nanoplex-Rb/Lipiodol system significantly decreased the mRNA expression of CD34, VEGF, P-gp, and BCRP. The nanoplex-(p53+Rb)/Lipiodol system lowered the expression of mRNA of p53, CD34, VEGF, Twist, P-gp, and BCRP the most, and was significantly different to the other two polyplexes for some genes in this regard (Figure 8).

Bottom Line: The administration procedure proved safe for the rabbits' liver function, the p53 plus Rb LNT showed significantly better antitumoral effect and lower expression of malignant genes than the p53 or Rb LNT, although no significant difference was observed in animal survival when the p53 plus Rb LNT was compared with the p53 LNT.Rb works synergistically with p53 in combined therapy mediated by a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex to augment the antitumoral effect through the downregulated expression of important genes related to apoptosis, necrosis, growth, differentiation and multidrug resistance of tumor cells.LNT with p53 and Rb is potentially an effective antitumor therapy for hepatocellular carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Department of general surgery, The second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, Shanxi Province, People's Republic of China.

ABSTRACT

Background/aim: A local nanotherapy (LNT) combining the therapeutic efficacy of trans-arterial embolization, nanoparticles, and p53 gene therapy has been previously presented. The study presented here aimed to further improve the incomplete tumor eradication and limited survival enhancement and to elucidate the molecular mechanism of the LNT.

Methods: In a tumor-targeting manner, recombinant expressing plasmids harboring wild-type p53 and Rb were either co-transferred or transferred separately to rabbit hepatic VX2 tumors in a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex and Lipiodol® (Guerbet, Villepinte, France) emulsion via the hepatic artery. Subsequent co-expression of p53 and Rb proteins within the treated tumors was investigated by Western blotting and in situ analysis by laser-scanning confocal microscopy. The therapeutic effect was evaluated by the tumor growth velocity, apoptosis and necrosis rates, their sensitivity to Adriamycin® (ADM), mitomycin C, and fluorouracil, the microvessel density of tumor tissue, and the survival time of animals. Eventually, real-time polymerase chain reaction and enhanced chemiluminescence Western blotting were used to investigate the expressive changes of important genes related to the therapy.

Results: The administration procedure proved safe for the rabbits' liver function, the p53 plus Rb LNT showed significantly better antitumoral effect and lower expression of malignant genes than the p53 or Rb LNT, although no significant difference was observed in animal survival when the p53 plus Rb LNT was compared with the p53 LNT.

Conclusion: Rb works synergistically with p53 in combined therapy mediated by a poly-L-lysine-modified hydroxyapatite nanoparticle nanoplex to augment the antitumoral effect through the downregulated expression of important genes related to apoptosis, necrosis, growth, differentiation and multidrug resistance of tumor cells. LNT with p53 and Rb is potentially an effective antitumor therapy for hepatocellular carcinoma.

Show MeSH
Related in: MedlinePlus