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Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma.

Zhao T, Ren H, Jia L, Chen J, Xin W, Yan F, Li J, Wang X, Gao S, Qian D, Huang C, Hao J - Oncotarget (2015)

Bottom Line: However, Gem is usually ineffective to the PDAC because of high degree of drug resistance.Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization.We propose that inhibition HIF-1α elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is the worst prognoses among all the malignancies. Now, gemcitabine (Gem) is the first line chemotherapeutic drug for advanced pancreatic cancer. However, Gem is usually ineffective to the PDAC because of high degree of drug resistance. Hypoxia and immune suppressive milieu are the best-described hallmarks of PDAC; therefore, we investigated the impact of hypoxia inducible factor-1 (HIF-1) inhibitor, PX-478, in combination with Gem on the induction of immunogenic cell death (ICD). We verified that combined treatment with Gem/PX-478 significantly enhanced the anti-tumor effect and increased proportion of tumor infiltrating T-lymphocytes in Panc02-bearing immune-competent but not in immune-deficient mice. Vaccination using Panc02 cell line treated with single agent or in combination showed significant anti-tumor effects. Pancreatic cell lines treated with Gem and PX-478 can induce an increase in eIF2α phosphorylation was correlated with down-regulation of HIF-1α and elicited exposure of CRT and release of HMGB1 and ATP. Only co-treated cells induced DC maturation/phagocytosis and IFN-γ secretion by cytotoxic T lymphocytes. Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization. We propose that inhibition HIF-1α elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD.

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Therapeutic effects of Gem and/or PX-478 in immune-competent and immune-deficient miceMurine PDAC cell line Panc02 was inoculated into the right flank of C57BL/6 mice (7 mice/group) and nude mice (5 mice/group) and subsequently treated with saline (control), Gem (i.p at 15 mg/kg on days 1, 3, 5 every week) and PX-478 (p.o. gavage at 30 mg/kg ×2 consecutive days) and Gem plus PX-478. (A and B) Representative images of tumors formed in C57BL/6 mice. (D and E) Representative images of tumors formed in nude mice. (C and F) Statistical comparisons of tumor volumes in C57BL/6 (C) and nude mice (F). Time-dependent tumor growth of treated groups was analysed by Two-way ANOVA with Bonferroni post-hoc test by comparison with untreated group or Gem/PX-478 treated group compared with single treatment. ***P<0.001. NS indicates no significance.
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Figure 1: Therapeutic effects of Gem and/or PX-478 in immune-competent and immune-deficient miceMurine PDAC cell line Panc02 was inoculated into the right flank of C57BL/6 mice (7 mice/group) and nude mice (5 mice/group) and subsequently treated with saline (control), Gem (i.p at 15 mg/kg on days 1, 3, 5 every week) and PX-478 (p.o. gavage at 30 mg/kg ×2 consecutive days) and Gem plus PX-478. (A and B) Representative images of tumors formed in C57BL/6 mice. (D and E) Representative images of tumors formed in nude mice. (C and F) Statistical comparisons of tumor volumes in C57BL/6 (C) and nude mice (F). Time-dependent tumor growth of treated groups was analysed by Two-way ANOVA with Bonferroni post-hoc test by comparison with untreated group or Gem/PX-478 treated group compared with single treatment. ***P<0.001. NS indicates no significance.

Mentions: In vitro experiments showed that inhibition of HIF1α by PX-478 sensitized PDAC cells lines to GEM induced apoptosis (data not shown). To evaluate the antineoplastic effects of this combination in vivo, we implanted Panc02 cells in immune-competent C57BL/6 and immune-deficient nude mice and treated them with Gem and/or PX-478. Gem or PX-478 alone significantly reduced tumor growth in both immune-competent and incompetent mice (Figure 1) and there was no significant difference when either single treatment efficacy was compared between two mice models. When Gem combined with PX-478, the tumor suppression effect of Gem or PX-478 was significantly increased in immune-competent in C57BL/6 mice (Figure 1A, B and C) but not in nude mice (Figure 1 D, E and F) compared with treated with Gem alone. This suggests that the therapeutic efficacy of this combined treatment with Gem and PX-478 may depend on the presence of thymus-dependent T lymphocytes because it was deficient in nude mice. These results indicate that Gem and PX-478 combination may induce a tumor antigen-specific immune response which in turn elicits elimination of tumor cells.


Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma.

Zhao T, Ren H, Jia L, Chen J, Xin W, Yan F, Li J, Wang X, Gao S, Qian D, Huang C, Hao J - Oncotarget (2015)

Therapeutic effects of Gem and/or PX-478 in immune-competent and immune-deficient miceMurine PDAC cell line Panc02 was inoculated into the right flank of C57BL/6 mice (7 mice/group) and nude mice (5 mice/group) and subsequently treated with saline (control), Gem (i.p at 15 mg/kg on days 1, 3, 5 every week) and PX-478 (p.o. gavage at 30 mg/kg ×2 consecutive days) and Gem plus PX-478. (A and B) Representative images of tumors formed in C57BL/6 mice. (D and E) Representative images of tumors formed in nude mice. (C and F) Statistical comparisons of tumor volumes in C57BL/6 (C) and nude mice (F). Time-dependent tumor growth of treated groups was analysed by Two-way ANOVA with Bonferroni post-hoc test by comparison with untreated group or Gem/PX-478 treated group compared with single treatment. ***P<0.001. NS indicates no significance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385849&req=5

Figure 1: Therapeutic effects of Gem and/or PX-478 in immune-competent and immune-deficient miceMurine PDAC cell line Panc02 was inoculated into the right flank of C57BL/6 mice (7 mice/group) and nude mice (5 mice/group) and subsequently treated with saline (control), Gem (i.p at 15 mg/kg on days 1, 3, 5 every week) and PX-478 (p.o. gavage at 30 mg/kg ×2 consecutive days) and Gem plus PX-478. (A and B) Representative images of tumors formed in C57BL/6 mice. (D and E) Representative images of tumors formed in nude mice. (C and F) Statistical comparisons of tumor volumes in C57BL/6 (C) and nude mice (F). Time-dependent tumor growth of treated groups was analysed by Two-way ANOVA with Bonferroni post-hoc test by comparison with untreated group or Gem/PX-478 treated group compared with single treatment. ***P<0.001. NS indicates no significance.
Mentions: In vitro experiments showed that inhibition of HIF1α by PX-478 sensitized PDAC cells lines to GEM induced apoptosis (data not shown). To evaluate the antineoplastic effects of this combination in vivo, we implanted Panc02 cells in immune-competent C57BL/6 and immune-deficient nude mice and treated them with Gem and/or PX-478. Gem or PX-478 alone significantly reduced tumor growth in both immune-competent and incompetent mice (Figure 1) and there was no significant difference when either single treatment efficacy was compared between two mice models. When Gem combined with PX-478, the tumor suppression effect of Gem or PX-478 was significantly increased in immune-competent in C57BL/6 mice (Figure 1A, B and C) but not in nude mice (Figure 1 D, E and F) compared with treated with Gem alone. This suggests that the therapeutic efficacy of this combined treatment with Gem and PX-478 may depend on the presence of thymus-dependent T lymphocytes because it was deficient in nude mice. These results indicate that Gem and PX-478 combination may induce a tumor antigen-specific immune response which in turn elicits elimination of tumor cells.

Bottom Line: However, Gem is usually ineffective to the PDAC because of high degree of drug resistance.Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization.We propose that inhibition HIF-1α elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is the worst prognoses among all the malignancies. Now, gemcitabine (Gem) is the first line chemotherapeutic drug for advanced pancreatic cancer. However, Gem is usually ineffective to the PDAC because of high degree of drug resistance. Hypoxia and immune suppressive milieu are the best-described hallmarks of PDAC; therefore, we investigated the impact of hypoxia inducible factor-1 (HIF-1) inhibitor, PX-478, in combination with Gem on the induction of immunogenic cell death (ICD). We verified that combined treatment with Gem/PX-478 significantly enhanced the anti-tumor effect and increased proportion of tumor infiltrating T-lymphocytes in Panc02-bearing immune-competent but not in immune-deficient mice. Vaccination using Panc02 cell line treated with single agent or in combination showed significant anti-tumor effects. Pancreatic cell lines treated with Gem and PX-478 can induce an increase in eIF2α phosphorylation was correlated with down-regulation of HIF-1α and elicited exposure of CRT and release of HMGB1 and ATP. Only co-treated cells induced DC maturation/phagocytosis and IFN-γ secretion by cytotoxic T lymphocytes. Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization. We propose that inhibition HIF-1α elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD.

Show MeSH
Related in: MedlinePlus