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Synergistic anti‐tumor effect by a combination treatment with the dietary flavonoid luteolin and the chemotherapy drugs Tasigna or Adrucil in human pancreatic cancer cells
Author(s) -
Aksamitiene Edita,
Achanta Sirisha,
Kiyatkin Anatoly,
Hoek Jan B
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.999.4
Subject(s) - apoptosis , cancer research , pancreatic cancer , chemistry , protein kinase b , cyclin d1 , cell growth , cancer cell , pharmacology , cancer , biology , medicine , cell cycle , biochemistry
Effects of luteolin (LU) alone or in combination with chemotherapy drugs Tasigna (nilotinib) or Adrucil (5‐fluorouracil) were explored in Bcl‐2(+) (PL5, MiaPaCa‐2) and Bcl‐2(−) (Panc1, Capan‐2) pancreatic cancer cells. Parameters of cell growth, viability, responses to growth factors and resistance to anti‐cancer agents were deteremined. Growth inhibition dose‐response curves following 72 h exposure to LU, Tasigna, Adrucil or DMSO control in 1% FBS‐containing medium were generated by fluorometric AlamarBlue assay. LU downregulated basal levels of c‐Src, FAK, STAT3 and Akt activities, reduced Bcl‐2, cyclin D1 and vimentin expression, activated Rb protein and promoted caspase‐3 and PARP cleavage in a dose‐dependent manner as shown by immunoblotting analysis. Restoration of Akt phosphorylation by PP2A inhibition did not rescue cells from LU‐induced apoptosis, which occurred in a c‐Myc‐dependent manner and was further augmented by MAPK inhibition in Bcl‐2(−) cells. By contrast, c‐Myc inhibiton increased LU‐induced apoptotic signals in Bcl‐2(+) cells. The ability of LU to synergize with drugs to accelerate PARP cleavage was cell type‐dependent and more pronounced in IGF‐1‐treated cells, suggesting that EGF engaged compensatory survival mechanism(s) mediated by ERK1/2. LU may yield additional benefit in combined chemotherapy applications in preclinical in vivo studies of pancreatic cancer.