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Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine.

Duong HQ, Yi YW, Kang HJ, Hong YB, Tang W, Wang A, Seong YS, Bae I - Int. J. Oncol. (2013)

Bottom Line: The effect of PIK-75 on the level and activity of NRF2 was characterized using various assays including reporter gene, quantitative PCR, DNA-binding and western blot analyses.PIK-75 also reduced the gemcitabine-induced NRF2 levels and the expression of its downstream target MRP5.Co-treatment of PIK-75 augmented the antitumor effect of gemcitabine both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

ABSTRACT
We describe the potential benefit of PIK-75 in combination of gemcitabine to treat pancreatic cancer in a preclinical mouse model. The effect of PIK-75 on the level and activity of NRF2 was characterized using various assays including reporter gene, quantitative PCR, DNA-binding and western blot analyses. Additionally, the combinatorial effect of PIK-75 and gemcitabine was evaluated in human pancreatic cancer cell lines and a xenograft model. PIK-75 reduced NRF2 protein levels and activity to regulate its target gene expression through proteasome-mediated degradation of NRF2 in human pancreatic cancer cell lines. PIK-75 also reduced the gemcitabine-induced NRF2 levels and the expression of its downstream target MRP5. Co-treatment of PIK-75 augmented the antitumor effect of gemcitabine both in vitro and in vivo. Our present study provides a strong mechanistic rationale to evaluate NRF2 targeting agents in combination with gemcitabine to treat pancreatic cancers.

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PIK-75 enhances the antitumor effect of gemcitabine in vivo. Mice (five mice per group) bearing tumors of MIA PaCa-2 were administered as indicated. (A) The tumor sizes were measured three times per week as described in Materials and methods. *P≤0.05. (B) The body weights of mice in (A) were measured three times per week.
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f7-ijo-44-03-0959: PIK-75 enhances the antitumor effect of gemcitabine in vivo. Mice (five mice per group) bearing tumors of MIA PaCa-2 were administered as indicated. (A) The tumor sizes were measured three times per week as described in Materials and methods. *P≤0.05. (B) The body weights of mice in (A) were measured three times per week.

Mentions: The effect of PIK-75/gemcitabine combination was further demonstrated by in vivo mouse xenograft model. Mice bearing tumors of MIA PaCa-2 were administered with gemcitabine (20 mg/kg), PIK-75 (2 mg/kg), or combination of both drugs. Since PIK-75 is a reversible inhibitor, PIK-75 was administered 5 times per week to ensure maintaining sufficient inhibitory effects. Gemcitabine was administered twice per week. As shown in Fig. 7A, gemcitabine or PIK-75 reduced the tumor growth to similar degree. Beneficial effect of PIK-75/gemcitabine was evident as this combination markedly reduced the tumor growth in vivo without affecting the body weights of mice (Fig. 7B).


Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine.

Duong HQ, Yi YW, Kang HJ, Hong YB, Tang W, Wang A, Seong YS, Bae I - Int. J. Oncol. (2013)

PIK-75 enhances the antitumor effect of gemcitabine in vivo. Mice (five mice per group) bearing tumors of MIA PaCa-2 were administered as indicated. (A) The tumor sizes were measured three times per week as described in Materials and methods. *P≤0.05. (B) The body weights of mice in (A) were measured three times per week.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928470&req=5

f7-ijo-44-03-0959: PIK-75 enhances the antitumor effect of gemcitabine in vivo. Mice (five mice per group) bearing tumors of MIA PaCa-2 were administered as indicated. (A) The tumor sizes were measured three times per week as described in Materials and methods. *P≤0.05. (B) The body weights of mice in (A) were measured three times per week.
Mentions: The effect of PIK-75/gemcitabine combination was further demonstrated by in vivo mouse xenograft model. Mice bearing tumors of MIA PaCa-2 were administered with gemcitabine (20 mg/kg), PIK-75 (2 mg/kg), or combination of both drugs. Since PIK-75 is a reversible inhibitor, PIK-75 was administered 5 times per week to ensure maintaining sufficient inhibitory effects. Gemcitabine was administered twice per week. As shown in Fig. 7A, gemcitabine or PIK-75 reduced the tumor growth to similar degree. Beneficial effect of PIK-75/gemcitabine was evident as this combination markedly reduced the tumor growth in vivo without affecting the body weights of mice (Fig. 7B).

Bottom Line: The effect of PIK-75 on the level and activity of NRF2 was characterized using various assays including reporter gene, quantitative PCR, DNA-binding and western blot analyses.PIK-75 also reduced the gemcitabine-induced NRF2 levels and the expression of its downstream target MRP5.Co-treatment of PIK-75 augmented the antitumor effect of gemcitabine both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

ABSTRACT
We describe the potential benefit of PIK-75 in combination of gemcitabine to treat pancreatic cancer in a preclinical mouse model. The effect of PIK-75 on the level and activity of NRF2 was characterized using various assays including reporter gene, quantitative PCR, DNA-binding and western blot analyses. Additionally, the combinatorial effect of PIK-75 and gemcitabine was evaluated in human pancreatic cancer cell lines and a xenograft model. PIK-75 reduced NRF2 protein levels and activity to regulate its target gene expression through proteasome-mediated degradation of NRF2 in human pancreatic cancer cell lines. PIK-75 also reduced the gemcitabine-induced NRF2 levels and the expression of its downstream target MRP5. Co-treatment of PIK-75 augmented the antitumor effect of gemcitabine both in vitro and in vivo. Our present study provides a strong mechanistic rationale to evaluate NRF2 targeting agents in combination with gemcitabine to treat pancreatic cancers.

Show MeSH
Related in: MedlinePlus