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STAT3 Decoy Oligodeoxynucleotides-Loaded Solid Lipid Nanoparticles Induce Cell Death and Inhibit Invasion in Ovarian Cancer Cells.

Ma Y, Zhang X, Xu X, Shen L, Yao Y, Yang Z, Liu P - PLoS ONE (2015)

Bottom Line: Blockage of the STAT3 pathway by SLN-STAT3 decoy ODN complexes resulted in an evident induction of cell death, including apoptotic and autophagic death.The mechanism involved the increased expression of cleaved caspase 3, Bax, Beclin-1 and LC3-II and reduced expression of Bcl-2, pro-caspase 3, Survivin, p-Akt and p-mTOR.We propose that SLN represent a potential approach for targeted gene delivery in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, China.

ABSTRACT
Recent advances in the synthesis of multi-functional nanoparticles have opened up tremendous opportunities for the targeted delivery of genes of interest. Cationic solid lipid nanoparticles (SLN) can efficiently bind nucleic acid molecules and transfect genes in vitro. Few reports have combined SLN with therapy using decoy oligodeoxynucleotides (ODN). In the present study, we prepared SLN to encapsulate STAT3 decoy ODN; then, the properties and in vitro behavior of SLN-STAT3 decoy ODN complexes were investigated. SLN-STAT3 decoy ODN complexes were efficiently taken up by human ovarian cancer cells and significantly suppressed cell growth. Blockage of the STAT3 pathway by SLN-STAT3 decoy ODN complexes resulted in an evident induction of cell death, including apoptotic and autophagic death. The mechanism involved the increased expression of cleaved caspase 3, Bax, Beclin-1 and LC3-II and reduced expression of Bcl-2, pro-caspase 3, Survivin, p-Akt and p-mTOR. In addition, SLN-STAT3 decoy ODN complexes inhibited cell invasion by up-regulating E-cadherin expression and down-regulating Snail and MMP-9 expression. These findings confirmed that SLN as STAT3 decoy ODN carriers can induce cell death and inhibit invasion of ovarian cancer cells. We propose that SLN represent a potential approach for targeted gene delivery in cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Cell viability of ODN formulations by MTT assay.SKOV3 (A) and A2780 (B) cells were treated with negative agents (negative control, NC), SLN-decoy ODN complexes, SLN-scrambled ODN complexes, naked ODN, Lipofectamine 2000-decoy ODN complexes (Lipo-decoy ODN), SLN and Lipofectamine 2000 at different concentrations (12.5, 25 and 50 nmol/L). At 48 hours after treatment, an MTT assay was performed. SKOV3 (C) and A2780 (D) cells were transfected with serial concentrations of SLN-decoy ODN complexes (12.5, 25 and 50 nmol/L), and cell viability was assessed at 24, 48 and 72 hours. The data are expressed as the means ± SD of three independent experiments, * P < 0.05, ** P < 0.01 compared with NC.
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pone.0124924.g002: Cell viability of ODN formulations by MTT assay.SKOV3 (A) and A2780 (B) cells were treated with negative agents (negative control, NC), SLN-decoy ODN complexes, SLN-scrambled ODN complexes, naked ODN, Lipofectamine 2000-decoy ODN complexes (Lipo-decoy ODN), SLN and Lipofectamine 2000 at different concentrations (12.5, 25 and 50 nmol/L). At 48 hours after treatment, an MTT assay was performed. SKOV3 (C) and A2780 (D) cells were transfected with serial concentrations of SLN-decoy ODN complexes (12.5, 25 and 50 nmol/L), and cell viability was assessed at 24, 48 and 72 hours. The data are expressed as the means ± SD of three independent experiments, * P < 0.05, ** P < 0.01 compared with NC.

Mentions: Our previous study showed that Lipofectamine 2000-STAT3 decoy ODN (Lipo-decoy ODN) can suppress the growth of SKOV3 and OVCAR3 cells. To explore whether SLN-decoy ODN have a similar effect on tumor suppression as Lipo-decoy ODN, SKOV3 and A2780 cells were treated with different concentrations of SLN-decoy ODN and Lipo-decoy ODN. STAT3 scrambled ODN were used to test the sequence specificity of the decoy ODN. Negative control (NC), naked decoy ODN, SLN, and Lipofectamine 2000 groups were used as controls. Cell growth was notably suppressed by the SLN-decoy ODN and Lipo-decoy ODN (P < 0.05), although the SLN did not induce a marked growth suppression effect compared with the NC or Lipo groups at each investigated concentration at 48 hours after treatment. The growth suppression of the SLN-decoy ODN showed no significant difference from that of the Lipo-decoy ODN at each dose after treatment for 48 hours. SLN-scrambled ODN complexes and naked decoy ODN indicated no effects on cell proliferation compared with the NC group at each concentration (Fig 2A and 2B; P > 0.05). SLN-decoy ODN complexes inhibited cell growth in a time- and dose-dependent manner (Fig 2C and 2D). Considering the cytotoxicity of CTAB, we chose a concentration of 25 nmol/L for the following experiments. These data suggested that both the SLN-decoy ODN and the Lipo-decoy ODN could clearly suppress the growth of ovarian cancer cells. The data also suggested that the suppression effect of SLN-decoy ODN was not due to the nanoparticle carrier because SLN did not show any suppression effect in vitro.


STAT3 Decoy Oligodeoxynucleotides-Loaded Solid Lipid Nanoparticles Induce Cell Death and Inhibit Invasion in Ovarian Cancer Cells.

Ma Y, Zhang X, Xu X, Shen L, Yao Y, Yang Z, Liu P - PLoS ONE (2015)

Cell viability of ODN formulations by MTT assay.SKOV3 (A) and A2780 (B) cells were treated with negative agents (negative control, NC), SLN-decoy ODN complexes, SLN-scrambled ODN complexes, naked ODN, Lipofectamine 2000-decoy ODN complexes (Lipo-decoy ODN), SLN and Lipofectamine 2000 at different concentrations (12.5, 25 and 50 nmol/L). At 48 hours after treatment, an MTT assay was performed. SKOV3 (C) and A2780 (D) cells were transfected with serial concentrations of SLN-decoy ODN complexes (12.5, 25 and 50 nmol/L), and cell viability was assessed at 24, 48 and 72 hours. The data are expressed as the means ± SD of three independent experiments, * P < 0.05, ** P < 0.01 compared with NC.
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Related In: Results  -  Collection

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pone.0124924.g002: Cell viability of ODN formulations by MTT assay.SKOV3 (A) and A2780 (B) cells were treated with negative agents (negative control, NC), SLN-decoy ODN complexes, SLN-scrambled ODN complexes, naked ODN, Lipofectamine 2000-decoy ODN complexes (Lipo-decoy ODN), SLN and Lipofectamine 2000 at different concentrations (12.5, 25 and 50 nmol/L). At 48 hours after treatment, an MTT assay was performed. SKOV3 (C) and A2780 (D) cells were transfected with serial concentrations of SLN-decoy ODN complexes (12.5, 25 and 50 nmol/L), and cell viability was assessed at 24, 48 and 72 hours. The data are expressed as the means ± SD of three independent experiments, * P < 0.05, ** P < 0.01 compared with NC.
Mentions: Our previous study showed that Lipofectamine 2000-STAT3 decoy ODN (Lipo-decoy ODN) can suppress the growth of SKOV3 and OVCAR3 cells. To explore whether SLN-decoy ODN have a similar effect on tumor suppression as Lipo-decoy ODN, SKOV3 and A2780 cells were treated with different concentrations of SLN-decoy ODN and Lipo-decoy ODN. STAT3 scrambled ODN were used to test the sequence specificity of the decoy ODN. Negative control (NC), naked decoy ODN, SLN, and Lipofectamine 2000 groups were used as controls. Cell growth was notably suppressed by the SLN-decoy ODN and Lipo-decoy ODN (P < 0.05), although the SLN did not induce a marked growth suppression effect compared with the NC or Lipo groups at each investigated concentration at 48 hours after treatment. The growth suppression of the SLN-decoy ODN showed no significant difference from that of the Lipo-decoy ODN at each dose after treatment for 48 hours. SLN-scrambled ODN complexes and naked decoy ODN indicated no effects on cell proliferation compared with the NC group at each concentration (Fig 2A and 2B; P > 0.05). SLN-decoy ODN complexes inhibited cell growth in a time- and dose-dependent manner (Fig 2C and 2D). Considering the cytotoxicity of CTAB, we chose a concentration of 25 nmol/L for the following experiments. These data suggested that both the SLN-decoy ODN and the Lipo-decoy ODN could clearly suppress the growth of ovarian cancer cells. The data also suggested that the suppression effect of SLN-decoy ODN was not due to the nanoparticle carrier because SLN did not show any suppression effect in vitro.

Bottom Line: Blockage of the STAT3 pathway by SLN-STAT3 decoy ODN complexes resulted in an evident induction of cell death, including apoptotic and autophagic death.The mechanism involved the increased expression of cleaved caspase 3, Bax, Beclin-1 and LC3-II and reduced expression of Bcl-2, pro-caspase 3, Survivin, p-Akt and p-mTOR.We propose that SLN represent a potential approach for targeted gene delivery in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, China.

ABSTRACT
Recent advances in the synthesis of multi-functional nanoparticles have opened up tremendous opportunities for the targeted delivery of genes of interest. Cationic solid lipid nanoparticles (SLN) can efficiently bind nucleic acid molecules and transfect genes in vitro. Few reports have combined SLN with therapy using decoy oligodeoxynucleotides (ODN). In the present study, we prepared SLN to encapsulate STAT3 decoy ODN; then, the properties and in vitro behavior of SLN-STAT3 decoy ODN complexes were investigated. SLN-STAT3 decoy ODN complexes were efficiently taken up by human ovarian cancer cells and significantly suppressed cell growth. Blockage of the STAT3 pathway by SLN-STAT3 decoy ODN complexes resulted in an evident induction of cell death, including apoptotic and autophagic death. The mechanism involved the increased expression of cleaved caspase 3, Bax, Beclin-1 and LC3-II and reduced expression of Bcl-2, pro-caspase 3, Survivin, p-Akt and p-mTOR. In addition, SLN-STAT3 decoy ODN complexes inhibited cell invasion by up-regulating E-cadherin expression and down-regulating Snail and MMP-9 expression. These findings confirmed that SLN as STAT3 decoy ODN carriers can induce cell death and inhibit invasion of ovarian cancer cells. We propose that SLN represent a potential approach for targeted gene delivery in cancer therapy.

No MeSH data available.


Related in: MedlinePlus