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Genistein potentiates the antitumor effect of 5-Fluorouracil by inducing apoptosis and autophagy in human pancreatic cancer cells.

ABSTRACT: Although 5-fluorouracil (5-FU)-based combination chemotherapy (i.e. FOLFIRINOX) has demonstrated effectiveness against pancreatic cancer, novel therapeutic strategies must be developed to increase the therapeutic window of these cytotoxic agents. Genistein is a soy-derived isoflavone with pleiotropic biological effects that can enhance the antitumor effect of chemotherapeutic agents.To understand how genistein potentiates the antitumor effects of 5-FU, we examined apoptosis and autophagy in MIA PaCa-2 human pancreatic cancer cells and their derived xenografts. Apoptosis was evaluated using DNA fragmentation assays, and western blots of poly(ADP ribose)polymerase and caspase-3. Meanwhile, autophagy was evaluated using western blots of microtubule-associated protein light chain 3 (LC3)-I/II, fluorescent microscopy observation of green fluorescent protein-LC3B puncta formation, and acidic vesicular organelle formation using acridine orange staining. Tumors from animal treatment studies were examined for apoptosis and autophagy using the TdT-mediated dUTP nick-end labeling assay and immunohistochemical staining of LC3B, respectively.We observed that genistein increased 5-FU-induced cell death through increased apoptosis, as well as autophagy. The increased autophagy was accompanied by decreased B-cell lymphoma 2 (Bcl2) and increased beclin-1 protein levels. Animal treatment studies supported these observations. The combination of 5-FU and genistein significantly reduced final xenograft tumor volume when compared to 5-FU-alone by inducing apoptosis as well as autophagy.Genistein can potentiate the antitumor effect of 5-FU by inducing apoptotic as well as autophagic cell death. These results demonstrate the potential of genistein as an adjuvant therapeutic agent against pancreatic cancer.

SUBMITTER: Suzuki R

PROVIDER: S-EPMC4240628 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Genistein potentiates the antitumor effect of 5-Fluorouracil by inducing apoptosis and autophagy in human pancreatic cancer cells.

Suzuki Rei R Kang Ya'an Y Li Xinqun X Roife David D Zhang Ran R Fleming Jason B JB

Anticancer research 20140901 9

<h4>Background</h4>Although 5-fluorouracil (5-FU)-based combination chemotherapy (i.e. FOLFIRINOX) has demonstrated effectiveness against pancreatic cancer, novel therapeutic strategies must be developed to increase the therapeutic window of these cytotoxic agents. Genistein is a soy-derived isoflavone with pleiotropic biological effects that can enhance the antitumor effect of chemotherapeutic agents.<h4>Materials and methods</h4>To understand how genistein potentiates the antitumor effects of ...[more]

PMID: 25202045

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Project description:BackgroundCancer stem cells (CSCs) are considered responsible for the recurrence and chemoresistance of cancer. Dysregulated autophagy is highly prevalent in many types of cancer including pancreatic cancer and has been implicated in cytoprotection and tumor promotion. This study aimed to investigate the role of autophagy in regulating cancer stemness and chemoresistance of pancreatic cancer.MethodsThe correlation between autophagy and CSCs and its clinical significance were analyzed using pancreatic cancer tissue microarrays. Genetic and pharmacological approaches were applied to explore the function of autophagy on CSC activity and gemcitabine resistance of pancreatic cancer cells in vitro and in vivo.ResultsLC3 expression positively correlated with the expression of CSC markers aldehyde dehydrogenase 1 (ALDH1), CD44, and CD133 in pancreatic cancer tissues. High coexpression of LC3/ALDH1 was associated with both poor overall survival and progression-free survival. In pancreatic cancer cell lines, higher LC3-II expression was observed in the sphere-forming cells than in the bulk cells. Blockade of autophagy by silencing ATG5, ATG7, and BECN1 or the administration of autophagy inhibitor chloroquine markedly reduced the CSC populations, ALDH1 activity, sphere formation, and resistance to gemcitabine in vitro and in vivo. Furthermore, osteopontin (OPN) was found to stimulate LC3-II, ALDH1, CD44, and CD133 expression in PANC-1 cells, whereas this effect could be prevented by OPN knockdown and autophagy blockade. After treatment with various inhibitors against the major signaling pathways downstream of OPN, only the inhibitor of NF-κB activation, BAY 1170-82, could effectively counteract OPN-induced autophagy and CSC activity. According to the histochemical results, pancreatic cancer patients manifesting high levels of OPN/LC3/ALDH1 and OPN/CD44/CD133 had poor survival.ConclusionsInduction of autophagy mediated by OPN/NF-κB signaling is required for maintenance of pancreatic CSC activity. Combination of gemcitabine with pharmacological autophagy inhibitors is a promising therapeutic strategy for pancreatic cancer.

Dataset Information

Genistein potentiates the antitumor effect of 5-Fluorouracil by inducing apoptosis and autophagy in human pancreatic cancer cells.

Publications

Genistein potentiates the antitumor effect of 5-Fluorouracil by inducing apoptosis and autophagy in human pancreatic cancer cells.

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