Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling.

Abstract

BACKGROUND:

Pancreatic cancer is a leading cause of cancer-related deaths in the world with a 5-year survival rate of less than 6%. Currently, there is no successful therapeutic strategy for advanced pancreatic cancer, and new effective strategies are urgently needed. Recently, an arginine deprivation agent, arginine deiminase, was found to inhibit the growth of some tumor cells (i.e., hepatocellular carcinoma, melanoma, and lung cancer) deficient in argininosuccinate synthetase (ASS), an enzyme used to synthesize arginine. The purpose of this study was to evaluate the therapeutic efficacy of arginine deiminase in combination with gemcitabine, the first line chemotherapeutic drug for patients with pancreatic cancer, and to identify the mechanisms associated with its anticancer effects.

METHODS:

In this study, we first analyzed the expression levels of ASS in pancreatic cancer cell lines and tumor tissues using immunohistochemistry and RT-PCR. We further tested the effects of the combination regimen of arginine deiminase with gemcitabine on pancreatic cancer cell lines in vitro and in vivo.

RESULTS:

Clinical investigation showed that pancreatic cancers with reduced ASS expression were associated with higher survivin expression and more lymph node metastasis and local invasion. Treatment of ASS-deficient PANC-1 cells with arginine deiminase decreased their proliferation in a dose- and time-dependent manner. Furthermore, arginine deiminase potentiated the antitumor effects of gemcitabine on PANC-1 cells via multiple mechanisms including induction of cell cycle arrest in the S phase, upregulation of the expression of caspase-3 and 9, and inhibition of activation of the NF-κB survival pathway by blocking NF-κB p65 signaling via suppressing the nuclear translocation and phosphorylation (serine 536) of NF-κB p65 in vitro. Moreover, arginine deiminase can enhance antitumor activity of gemcitabine-based chemotherapy in the mouse xenograft model.

CONCLUSIONS:

Our results suggest that arginine deprivation by arginine deiminase, in combination with gemcitabine, may offer a novel effective treatment strategy for patients with pancreatic cancer and potentially improve the outcome of patients with pancreatic cancer.

• Authors: Jiangbo Liu, Jiguang Ma, Zheng Wu, Wei Li, Dong Zhang, Liang Han, Fengfei Wang, Katie M Reindl, Erxi Wu, Qingyong Ma
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 686 (Sep 20 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 25240403 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• STAT3 Transcription Factor
• Deoxycytidine
• Proto-Oncogene Proteins c-akt
• Hydrolases
• arginine deiminase
• Argininosuccinate Synthase
• Gemcitabine

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Apoptosis (drug effects, genetics)
• Argininosuccinate Synthase (deficiency, genetics)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Transformation, Neoplastic (genetics, metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression
• Humans
• Hydrolases (genetics, metabolism)
• Male
• Mice
• Middle Aged
• NF-kappa B (metabolism)
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplasm Staging
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Phosphorylation
• Protein Transport
• Proto-Oncogene Proteins c-akt (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Tumor Burden
• Xenograft Model Antitumor Assays
• Gemcitabine