Limits...
Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation.

Luan Z, He Y, He F, Chen Z - Mol Med Rep (2014)

Bottom Line: Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated.Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation.Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
The enhancement of apoptosis is a therapeutic strategy used in the treatment of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, hepatocellular carcinoma (HCC) cells exhibit marked resistance to the induction of cell death by TRAIL. The present study investigated whether rocaglamide, a naturally occurring product isolated from the genus Aglaia, is able to sensitize resistant HCC cells to TRAIL-mediated apoptosis. Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated. The in vivo efficacy of rocaglamide was determined in TRAIL-resistant Huh-7-derived tumor xenografts. Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation. Furthermore, rocaglamide markedly inhibited tumor growth from Huh-7 cells propagated in severe combined immunodeficient mice, suggesting that chemosentization also occurred in vivo. These data suggest that rocaglamide acted synergistically with TRAIL against the TRAIL-resistant HCC cells. Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

Show MeSH

Related in: MedlinePlus

Effect of rocaglamide treatment on the growth of tumors from Huh-7 cells implanted in SCID mice. Huh-7 cell tumors established subcutaneously in SCID mice were treated with vehicle (5% DMSO in olive oil; n=5) or rocaglamide (2.5 mg/kg; n=5) via daily intraperitoneal injection into the mice for 32 days. (A) Tumor volume and (B) body weight were monitored. (C) Histological analysis of apoptosis in xenografted HCC tumors from the mice were performed using H&E, TUNEL and cleaved caspase-3 staining (magnification, ×200). (D) Quantitation of the TUNEL and cleaved caspase-3 staining in rocaglamide-treated tumors compared with vehicle-treated tumors. Data are expressed as the mean ± standard deviation. *P<0.01 compared with vehicle. Data are representative of three experiments. SCID, severe combined immunodeficient; DMSO, dimethyl sulfoxide; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4237083&req=5

f5-mmr-11-01-0203: Effect of rocaglamide treatment on the growth of tumors from Huh-7 cells implanted in SCID mice. Huh-7 cell tumors established subcutaneously in SCID mice were treated with vehicle (5% DMSO in olive oil; n=5) or rocaglamide (2.5 mg/kg; n=5) via daily intraperitoneal injection into the mice for 32 days. (A) Tumor volume and (B) body weight were monitored. (C) Histological analysis of apoptosis in xenografted HCC tumors from the mice were performed using H&E, TUNEL and cleaved caspase-3 staining (magnification, ×200). (D) Quantitation of the TUNEL and cleaved caspase-3 staining in rocaglamide-treated tumors compared with vehicle-treated tumors. Data are expressed as the mean ± standard deviation. *P<0.01 compared with vehicle. Data are representative of three experiments. SCID, severe combined immunodeficient; DMSO, dimethyl sulfoxide; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.

Mentions: To confirm whether the synergistic effect of rocaglamide and TRAIL in resistant cell lines had potentially relevant clinical implications, the present study investigated the in vivo effect of rocaglamide and TRAIL on the growth of HCC xenograft tumors. As natural killer cells produce TRAIL in vivo (26,27), rocaglamide alone was administered in the in vivo study. The Huh-7 cells were subcutaneously injected into the right flanks of SCID mice and, when tumors were visible, the mice were matched for tumor volumes and were assigned to a control group and a rocaglamide-treated group. Tumor volumes in the rocaglamide-treated group were ~45±12% compared with the control group (Fig. 5A). Rocaglamide significantly suppressed tumor growth compared with that in the control group. Notably, treatment with rocaglamide did not lead to any reduction in body weight and no apparent signs of toxicity were observed in the mice during the treatment (Fig. 5B), suggesting that rocaglamide is generally tolerated well in vivo.


Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation.

Luan Z, He Y, He F, Chen Z - Mol Med Rep (2014)

Effect of rocaglamide treatment on the growth of tumors from Huh-7 cells implanted in SCID mice. Huh-7 cell tumors established subcutaneously in SCID mice were treated with vehicle (5% DMSO in olive oil; n=5) or rocaglamide (2.5 mg/kg; n=5) via daily intraperitoneal injection into the mice for 32 days. (A) Tumor volume and (B) body weight were monitored. (C) Histological analysis of apoptosis in xenografted HCC tumors from the mice were performed using H&E, TUNEL and cleaved caspase-3 staining (magnification, ×200). (D) Quantitation of the TUNEL and cleaved caspase-3 staining in rocaglamide-treated tumors compared with vehicle-treated tumors. Data are expressed as the mean ± standard deviation. *P<0.01 compared with vehicle. Data are representative of three experiments. SCID, severe combined immunodeficient; DMSO, dimethyl sulfoxide; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4237083&req=5

f5-mmr-11-01-0203: Effect of rocaglamide treatment on the growth of tumors from Huh-7 cells implanted in SCID mice. Huh-7 cell tumors established subcutaneously in SCID mice were treated with vehicle (5% DMSO in olive oil; n=5) or rocaglamide (2.5 mg/kg; n=5) via daily intraperitoneal injection into the mice for 32 days. (A) Tumor volume and (B) body weight were monitored. (C) Histological analysis of apoptosis in xenografted HCC tumors from the mice were performed using H&E, TUNEL and cleaved caspase-3 staining (magnification, ×200). (D) Quantitation of the TUNEL and cleaved caspase-3 staining in rocaglamide-treated tumors compared with vehicle-treated tumors. Data are expressed as the mean ± standard deviation. *P<0.01 compared with vehicle. Data are representative of three experiments. SCID, severe combined immunodeficient; DMSO, dimethyl sulfoxide; H&E, hematoxylin and eosin; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling.
Mentions: To confirm whether the synergistic effect of rocaglamide and TRAIL in resistant cell lines had potentially relevant clinical implications, the present study investigated the in vivo effect of rocaglamide and TRAIL on the growth of HCC xenograft tumors. As natural killer cells produce TRAIL in vivo (26,27), rocaglamide alone was administered in the in vivo study. The Huh-7 cells were subcutaneously injected into the right flanks of SCID mice and, when tumors were visible, the mice were matched for tumor volumes and were assigned to a control group and a rocaglamide-treated group. Tumor volumes in the rocaglamide-treated group were ~45±12% compared with the control group (Fig. 5A). Rocaglamide significantly suppressed tumor growth compared with that in the control group. Notably, treatment with rocaglamide did not lead to any reduction in body weight and no apparent signs of toxicity were observed in the mice during the treatment (Fig. 5B), suggesting that rocaglamide is generally tolerated well in vivo.

Bottom Line: Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated.Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation.Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
The enhancement of apoptosis is a therapeutic strategy used in the treatment of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, hepatocellular carcinoma (HCC) cells exhibit marked resistance to the induction of cell death by TRAIL. The present study investigated whether rocaglamide, a naturally occurring product isolated from the genus Aglaia, is able to sensitize resistant HCC cells to TRAIL-mediated apoptosis. Two HCC cell lines, HepG2 and Huh-7, were treated with rocaglamide and/or TRAIL and the induction of apoptosis and effects on the TRAIL signaling pathway were investigated. The in vivo efficacy of rocaglamide was determined in TRAIL-resistant Huh-7-derived tumor xenografts. Rocaglamide significantly sensitized the TRAIL-resistant HCC cells to apoptosis by TRAIL, which resulted from the rocaglamide-mediated downregulation of cellular FLICE-like inhibitory protein and subsequent caspase-8 activation. Furthermore, rocaglamide markedly inhibited tumor growth from Huh-7 cells propagated in severe combined immunodeficient mice, suggesting that chemosentization also occurred in vivo. These data suggest that rocaglamide acted synergistically with TRAIL against the TRAIL-resistant HCC cells. Thus, it is concluded that rocaglamide as an adjuvant to TRAIL-based therapy may present a promising therapeutic approach for the treatment of HCC.

Show MeSH
Related in: MedlinePlus