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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

Inhibition of autophagy by CQ and induction of autophagy by DDP in vivo.Tumor tissues were harvested for autophagy analysis after treatment for 18 days. (A) Western blot analysis of autophagy markers LC3 and p62. (B) Representative micrographs of tumor sections: hematoxylin and eosin (H&E) stain (upper panel) and immunohistochemistry (IHC) for LC3 (middle panel) and p62 (lower panel). Scale bar = 20 μm. (C) Quantification of LC3 expression (left) and p62 expression (right) according to the Integrated Optical Density (IOD) (**p<0.01, ***p<0.001).
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pone.0126147.g002: Inhibition of autophagy by CQ and induction of autophagy by DDP in vivo.Tumor tissues were harvested for autophagy analysis after treatment for 18 days. (A) Western blot analysis of autophagy markers LC3 and p62. (B) Representative micrographs of tumor sections: hematoxylin and eosin (H&E) stain (upper panel) and immunohistochemistry (IHC) for LC3 (middle panel) and p62 (lower panel). Scale bar = 20 μm. (C) Quantification of LC3 expression (left) and p62 expression (right) according to the Integrated Optical Density (IOD) (**p<0.01, ***p<0.001).

Mentions: We used LC3 and p62 as markers of autophagy induction and inhibition. Groups of mice were sacrificed and tumor tissues were collected after 18 days of treatment, and the expression levels of LC3 and p62 were examined by Western blot and IHC (Fig 2, S2 Fig). (1) In the mono-CQ treated group, the levels of LC3 and p62 were substantially increased compared with that of control, suggesting a blockade of the autophagy flux by CQ administration. (2) In the mono-DDP treated group, the levels of LC3 were increased whereas accumulation of p62 was decreased relative to control, which suggested that DDP, as a classical anti-tumor agent, caused autophagy induction in the tumors. (3) In the CQ+DDP treated group, a further increase of LC3 levels was observed compared with the mono-DDP treated group.


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)

Inhibition of autophagy by CQ and induction of autophagy by DDP in vivo.Tumor tissues were harvested for autophagy analysis after treatment for 18 days. (A) Western blot analysis of autophagy markers LC3 and p62. (B) Representative micrographs of tumor sections: hematoxylin and eosin (H&E) stain (upper panel) and immunohistochemistry (IHC) for LC3 (middle panel) and p62 (lower panel). Scale bar = 20 μm. (C) Quantification of LC3 expression (left) and p62 expression (right) according to the Integrated Optical Density (IOD) (**p<0.01, ***p<0.001).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0126147.g002: Inhibition of autophagy by CQ and induction of autophagy by DDP in vivo.Tumor tissues were harvested for autophagy analysis after treatment for 18 days. (A) Western blot analysis of autophagy markers LC3 and p62. (B) Representative micrographs of tumor sections: hematoxylin and eosin (H&E) stain (upper panel) and immunohistochemistry (IHC) for LC3 (middle panel) and p62 (lower panel). Scale bar = 20 μm. (C) Quantification of LC3 expression (left) and p62 expression (right) according to the Integrated Optical Density (IOD) (**p<0.01, ***p<0.001).
Mentions: We used LC3 and p62 as markers of autophagy induction and inhibition. Groups of mice were sacrificed and tumor tissues were collected after 18 days of treatment, and the expression levels of LC3 and p62 were examined by Western blot and IHC (Fig 2, S2 Fig). (1) In the mono-CQ treated group, the levels of LC3 and p62 were substantially increased compared with that of control, suggesting a blockade of the autophagy flux by CQ administration. (2) In the mono-DDP treated group, the levels of LC3 were increased whereas accumulation of p62 was decreased relative to control, which suggested that DDP, as a classical anti-tumor agent, caused autophagy induction in the tumors. (3) In the CQ+DDP treated group, a further increase of LC3 levels was observed compared with the mono-DDP treated group.

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