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Characterization of 9-nitrocamptothecin liposomes: anticancer properties and mechanisms on hepatocellular carcinoma in vitro and in vivo.

Zheng S, Chang S, Lu J, Chen Z, Xie L, Nie Y, He B, Zou S, Gu Z - PLoS ONE (2011)

Bottom Line: Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro.Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1.In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.

ABSTRACT

Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with strong anticancer effect. To increase the solubility and stability, we synthesized a novel 9NC loaded liposomes (9NC-LP) via incorporating 9NC into liposomes. In the present study, we determined the effects of 9NC and 9NC-LP on in vitro and in vivo, and the underlying mechanisms.

Methodology/principal findings: We first analyzed the characteristics of 9NC-LP. Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro. We also investigated their anticancer properties in nude mice bearing HCC xenograft in vivo. 9NC-LP has a uniform size (around 190 nm) and zeta potential (∼-11 mV), and exhibited a steady sustained-release pattern profile in vitro. Both 9NC and 9NC-LP could cause cell cycle arrest and apoptosis in a dose-dependent and p53-dependent manner. However, this effect was not ubiquitous in all cell lines. Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1. Furthermore, 9NC-LP exhibited a more potent antiproliferative effect and less side effects in vivo. Western blot analysis of the xenograft tumors in nude mice showed similar changes in protein expression in vivo.

Conclusions/significance: In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.

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Related in: MedlinePlus

Effects of drugs on the expression of proteins related to cell cycle progression and apoptosis in human hepatocellular carcinoma cell line and normal liver cell line.In vitro, HepG2, L02 and Hep3B cells were exposed to the compound (1 µmol/L) for 24 h; then target proteins were examined by western blotting(A). In vivo, compounds were given i.v. at doses of 1.5 mg/kg/d or 2.5 mg/kg/d on a 5/2/5 (5 days on, 2 days off and 5 days on) schedule for 3 weeks. The expression of proteins from tumor homogenates was analyzed by western blotting (B).
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pone-0021064-g005: Effects of drugs on the expression of proteins related to cell cycle progression and apoptosis in human hepatocellular carcinoma cell line and normal liver cell line.In vitro, HepG2, L02 and Hep3B cells were exposed to the compound (1 µmol/L) for 24 h; then target proteins were examined by western blotting(A). In vivo, compounds were given i.v. at doses of 1.5 mg/kg/d or 2.5 mg/kg/d on a 5/2/5 (5 days on, 2 days off and 5 days on) schedule for 3 weeks. The expression of proteins from tumor homogenates was analyzed by western blotting (B).

Mentions: We then investigated the possible mechanisms responsible for the effects of 9NC and 9NC-LP by evaluating its effects on the expression level of various proteins involved in regulating cell cycle progression and apoptosis. In both HepG2 and L02 compounds activated p53; increased the expressions of p21, p27, Bax, Caspase-3, Caspase-8, Caspase-9 and apoptosis-inducing factor, mitochondrion associated 1 (AIFM1); decreased the expressions of Bcl-2, cyclin A, CDK2, cyclin E and cyclin D1. In Hep3B cell, no expression of p53 was detected and effects of compounds on cell cycle-related and apoptosis-related proteins expression is less than HepG2 and L02 cells. Interestingly, the patterns of protein expression in the treated xenograft tumors were similar with those observed in vitro (Fig. 5).


Characterization of 9-nitrocamptothecin liposomes: anticancer properties and mechanisms on hepatocellular carcinoma in vitro and in vivo.

Zheng S, Chang S, Lu J, Chen Z, Xie L, Nie Y, He B, Zou S, Gu Z - PLoS ONE (2011)

Effects of drugs on the expression of proteins related to cell cycle progression and apoptosis in human hepatocellular carcinoma cell line and normal liver cell line.In vitro, HepG2, L02 and Hep3B cells were exposed to the compound (1 µmol/L) for 24 h; then target proteins were examined by western blotting(A). In vivo, compounds were given i.v. at doses of 1.5 mg/kg/d or 2.5 mg/kg/d on a 5/2/5 (5 days on, 2 days off and 5 days on) schedule for 3 weeks. The expression of proteins from tumor homogenates was analyzed by western blotting (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111480&req=5

pone-0021064-g005: Effects of drugs on the expression of proteins related to cell cycle progression and apoptosis in human hepatocellular carcinoma cell line and normal liver cell line.In vitro, HepG2, L02 and Hep3B cells were exposed to the compound (1 µmol/L) for 24 h; then target proteins were examined by western blotting(A). In vivo, compounds were given i.v. at doses of 1.5 mg/kg/d or 2.5 mg/kg/d on a 5/2/5 (5 days on, 2 days off and 5 days on) schedule for 3 weeks. The expression of proteins from tumor homogenates was analyzed by western blotting (B).
Mentions: We then investigated the possible mechanisms responsible for the effects of 9NC and 9NC-LP by evaluating its effects on the expression level of various proteins involved in regulating cell cycle progression and apoptosis. In both HepG2 and L02 compounds activated p53; increased the expressions of p21, p27, Bax, Caspase-3, Caspase-8, Caspase-9 and apoptosis-inducing factor, mitochondrion associated 1 (AIFM1); decreased the expressions of Bcl-2, cyclin A, CDK2, cyclin E and cyclin D1. In Hep3B cell, no expression of p53 was detected and effects of compounds on cell cycle-related and apoptosis-related proteins expression is less than HepG2 and L02 cells. Interestingly, the patterns of protein expression in the treated xenograft tumors were similar with those observed in vitro (Fig. 5).

Bottom Line: Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro.Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1.In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.

ABSTRACT

Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with strong anticancer effect. To increase the solubility and stability, we synthesized a novel 9NC loaded liposomes (9NC-LP) via incorporating 9NC into liposomes. In the present study, we determined the effects of 9NC and 9NC-LP on in vitro and in vivo, and the underlying mechanisms.

Methodology/principal findings: We first analyzed the characteristics of 9NC-LP. Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro. We also investigated their anticancer properties in nude mice bearing HCC xenograft in vivo. 9NC-LP has a uniform size (around 190 nm) and zeta potential (∼-11 mV), and exhibited a steady sustained-release pattern profile in vitro. Both 9NC and 9NC-LP could cause cell cycle arrest and apoptosis in a dose-dependent and p53-dependent manner. However, this effect was not ubiquitous in all cell lines. Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1. Furthermore, 9NC-LP exhibited a more potent antiproliferative effect and less side effects in vivo. Western blot analysis of the xenograft tumors in nude mice showed similar changes in protein expression in vivo.

Conclusions/significance: In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.

Show MeSH
Related in: MedlinePlus