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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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Apoptosis and necrosis rate of tumor cells from different groups.Notes: * Δ, ▲, and ✰ represent significant difference from Lipiodol® (Guerbet, Villepinte, France) (Group A, n = 10), nanoplex/Lipiodol (Group B, n = 10), nanoplex-p53/Lipiodol (Group C, n = 10), and nanoplex-Rb/Lipiodol (Group D, n = 10), respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.
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f7-ijn-8-3757: Apoptosis and necrosis rate of tumor cells from different groups.Notes: * Δ, ▲, and ✰ represent significant difference from Lipiodol® (Guerbet, Villepinte, France) (Group A, n = 10), nanoplex/Lipiodol (Group B, n = 10), nanoplex-p53/Lipiodol (Group C, n = 10), and nanoplex-Rb/Lipiodol (Group D, n = 10), respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.

Mentions: The apoptosis results showed that the nanoplexes could induce cancer cell apoptosis and that antitumoral effects could be enhanced further by the polyplexes (P < 0.05). There was no significant difference in this regard between the three polyplex emulsions. The nanoplex/Lipiodol system induced more necrosis than Lipiodol alone, and this effect was greater with the nanoplex-p53/Lipiodol and nanoplex-(p53+Rb)/Lipiodol systems, but not with the nanoplex-Rb/Lipiodol system. There was no significant difference between the p53 and (p53+Rb) systems (Figure 7).


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)

Apoptosis and necrosis rate of tumor cells from different groups.Notes: * Δ, ▲, and ✰ represent significant difference from Lipiodol® (Guerbet, Villepinte, France) (Group A, n = 10), nanoplex/Lipiodol (Group B, n = 10), nanoplex-p53/Lipiodol (Group C, n = 10), and nanoplex-Rb/Lipiodol (Group D, n = 10), respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.
© Copyright Policy
Related In: Results  -  Collection

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

f7-ijn-8-3757: Apoptosis and necrosis rate of tumor cells from different groups.Notes: * Δ, ▲, and ✰ represent significant difference from Lipiodol® (Guerbet, Villepinte, France) (Group A, n = 10), nanoplex/Lipiodol (Group B, n = 10), nanoplex-p53/Lipiodol (Group C, n = 10), and nanoplex-Rb/Lipiodol (Group D, n = 10), respectively, as calculated with one-way analysis of variance and Fisher’s least significant difference multiple comparison test.
Mentions: The apoptosis results showed that the nanoplexes could induce cancer cell apoptosis and that antitumoral effects could be enhanced further by the polyplexes (P < 0.05). There was no significant difference in this regard between the three polyplex emulsions. The nanoplex/Lipiodol system induced more necrosis than Lipiodol alone, and this effect was greater with the nanoplex-p53/Lipiodol and nanoplex-(p53+Rb)/Lipiodol systems, but not with the nanoplex-Rb/Lipiodol system. There was no significant difference between the p53 and (p53+Rb) systems (Figure 7).

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