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Chloroquine-enhanced efficacy of cisplatin in the treatment of hypopharyngeal carcinoma in xenograft mice.

Zhao XG, Sun RJ, Yang XY, Liu DY, Lei DP, Jin T, Pan XL - PLoS ONE (2015)

Bottom Line: However, resistance to DDP severely impairs the effectiveness of chemotherapy for HSCC.Chloroquine (CQ) has been reported to enhance the effectiveness of chemotherapy and radiotherapy in liver, pancreas, breast, prostate and colon tumors, but it is unclear whether CQ could increase the efficacy of DDP for treating HSCC.Inhibition of autophagy markedly enhanced the DDP-induced antitumor effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.

ABSTRACT
Hypopharyngeal squamous cell carcinoma (HSCC) has the worst prognosis among head and neck cancers. Cisplatin (DDP)-based chemotherapy is an important part of multimodal treatments. However, resistance to DDP severely impairs the effectiveness of chemotherapy for HSCC. Chloroquine (CQ) has been reported to enhance the effectiveness of chemotherapy and radiotherapy in liver, pancreas, breast, prostate and colon tumors, but it is unclear whether CQ could increase the efficacy of DDP for treating HSCC. We inoculated BALB/c nude mice with a subcutaneous injection of human hypopharyngeal FaDu cells to generate our animal model. Mice were randomly divided into 4 groups and treated with vehicle control, CQ (60 mg/kg/day), DDP (5 mg/kg/6 days), or a combination of DDP and CQ. Tumor growth and survival of the mice were monitored. We found that CQ inhibited autophagy and increased DDP-induced apoptosis in the xenograft mouse model. CQ enhanced the efficacy of DDP, resulting in decreased tumor growth and prolonged survival of the mice. To test whether blocking autophagy enhanced the efficacy of DDP, FaDu cells were infected with lentiviral shRNA to Beclin-1 and inoculated into the flanks of nude mice. Inhibition of autophagy markedly enhanced the DDP-induced antitumor effect. Our study suggests that the addition of CQ to DDP-based chemotherapy could be a potential therapeutic strategy for treating HSCC, and the inhibition of autophagy may contribute to chemotherapy sensitization in HSCC.

No MeSH data available.


Related in: MedlinePlus

Addition of CQ to DDP treatment increases apoptosis of the tumor cells in vivo.(A) Representative photographs of Western blot analysis of Bax and Bcl-2 and Bax/Bcl-2 ratio levels by densitometric analysis of the Western blot bands (7 animals per group). (B) Representative TdT-mediated dUTP nick end labeling (TUNEL) staining of tumor tissues, scale bar = 20 μm. (C) The average numbers of TUNEL-positive cells per field in each group. Cells were counted in 10 randomly selected fields in 7 tumor samples from each group. The values represent the mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.
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pone.0126147.g003: Addition of CQ to DDP treatment increases apoptosis of the tumor cells in vivo.(A) Representative photographs of Western blot analysis of Bax and Bcl-2 and Bax/Bcl-2 ratio levels by densitometric analysis of the Western blot bands (7 animals per group). (B) Representative TdT-mediated dUTP nick end labeling (TUNEL) staining of tumor tissues, scale bar = 20 μm. (C) The average numbers of TUNEL-positive cells per field in each group. Cells were counted in 10 randomly selected fields in 7 tumor samples from each group. The values represent the mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.

Mentions: Bcl-2 family proteins are the main regulators of the mitochondrial pathway of apoptosis. Bax is pro-apoptotic and Bcl-2 is anti-apoptotic [29]. To assess the effect of CQ on tumor cell apoptosis, we performed Western blot analysis of Bax and Bcl-2, and the Bax/Bcl-2 ratio was calculated. A TUNEL assay was also performed to evaluate apoptosis (Fig 3). As expected, DDP treatment caused marked apoptosis of tumor cells (p<0.05 relative to the control). CQ alone did not have a pro-apoptosis effect. However, the addition of CQ significantly increased the apoptosis of tumor cells induced by DDP compared with that of DDP alone (p<0.001).


Chloroquine-enhanced efficacy of cisplatin in the treatment of hypopharyngeal carcinoma in xenograft mice.

Zhao XG, Sun RJ, Yang XY, Liu DY, Lei DP, Jin T, Pan XL - PLoS ONE (2015)

Addition of CQ to DDP treatment increases apoptosis of the tumor cells in vivo.(A) Representative photographs of Western blot analysis of Bax and Bcl-2 and Bax/Bcl-2 ratio levels by densitometric analysis of the Western blot bands (7 animals per group). (B) Representative TdT-mediated dUTP nick end labeling (TUNEL) staining of tumor tissues, scale bar = 20 μm. (C) The average numbers of TUNEL-positive cells per field in each group. Cells were counted in 10 randomly selected fields in 7 tumor samples from each group. The values represent the mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4414471&req=5

pone.0126147.g003: Addition of CQ to DDP treatment increases apoptosis of the tumor cells in vivo.(A) Representative photographs of Western blot analysis of Bax and Bcl-2 and Bax/Bcl-2 ratio levels by densitometric analysis of the Western blot bands (7 animals per group). (B) Representative TdT-mediated dUTP nick end labeling (TUNEL) staining of tumor tissues, scale bar = 20 μm. (C) The average numbers of TUNEL-positive cells per field in each group. Cells were counted in 10 randomly selected fields in 7 tumor samples from each group. The values represent the mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.
Mentions: Bcl-2 family proteins are the main regulators of the mitochondrial pathway of apoptosis. Bax is pro-apoptotic and Bcl-2 is anti-apoptotic [29]. To assess the effect of CQ on tumor cell apoptosis, we performed Western blot analysis of Bax and Bcl-2, and the Bax/Bcl-2 ratio was calculated. A TUNEL assay was also performed to evaluate apoptosis (Fig 3). As expected, DDP treatment caused marked apoptosis of tumor cells (p<0.05 relative to the control). CQ alone did not have a pro-apoptosis effect. However, the addition of CQ significantly increased the apoptosis of tumor cells induced by DDP compared with that of DDP alone (p<0.001).

Bottom Line: However, resistance to DDP severely impairs the effectiveness of chemotherapy for HSCC.Chloroquine (CQ) has been reported to enhance the effectiveness of chemotherapy and radiotherapy in liver, pancreas, breast, prostate and colon tumors, but it is unclear whether CQ could increase the efficacy of DDP for treating HSCC.Inhibition of autophagy markedly enhanced the DDP-induced antitumor effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.

ABSTRACT
Hypopharyngeal squamous cell carcinoma (HSCC) has the worst prognosis among head and neck cancers. Cisplatin (DDP)-based chemotherapy is an important part of multimodal treatments. However, resistance to DDP severely impairs the effectiveness of chemotherapy for HSCC. Chloroquine (CQ) has been reported to enhance the effectiveness of chemotherapy and radiotherapy in liver, pancreas, breast, prostate and colon tumors, but it is unclear whether CQ could increase the efficacy of DDP for treating HSCC. We inoculated BALB/c nude mice with a subcutaneous injection of human hypopharyngeal FaDu cells to generate our animal model. Mice were randomly divided into 4 groups and treated with vehicle control, CQ (60 mg/kg/day), DDP (5 mg/kg/6 days), or a combination of DDP and CQ. Tumor growth and survival of the mice were monitored. We found that CQ inhibited autophagy and increased DDP-induced apoptosis in the xenograft mouse model. CQ enhanced the efficacy of DDP, resulting in decreased tumor growth and prolonged survival of the mice. To test whether blocking autophagy enhanced the efficacy of DDP, FaDu cells were infected with lentiviral shRNA to Beclin-1 and inoculated into the flanks of nude mice. Inhibition of autophagy markedly enhanced the DDP-induced antitumor effect. Our study suggests that the addition of CQ to DDP-based chemotherapy could be a potential therapeutic strategy for treating HSCC, and the inhibition of autophagy may contribute to chemotherapy sensitization in HSCC.

No MeSH data available.


Related in: MedlinePlus