Methotrexate and 5-aminoimidazole-4-carboxamide riboside exert synergistic anticancer action against human breast cancer and hepatocellular carcinoma.

Abstract

AIM:

To investigate the influences of methotrexate (MTX) on the anticancer actions and pharmacokinetics of 5-aminoimidazole-4-carboxamide riboside (AICA riboside) in human breast cancer and hepatocellular carcinoma.

METHODS:

Human breast cancer cell line MCF-7 and human hepatocellular carcinoma cell line HepG2 were examined. The cell proliferation was assessed using a sulforhodamine B assay. Western blotting and radioactivity assays were used to analyze the phosphorylation of AMPK. The DNA synthesis was analyzed with BrdU incorporation. Nude mice bearing MCF-7 cell xenografts were used to for in vivo study. MTX (50 mg/kg, ip, per week) and AICA riboside (200 mg/kg, ip, every other day) were administered the animals for 2 weeks. The concentrations of AICA riboside and its active metabolite AICA ribotide in the plasma and tumors were measured with HPLC.

RESULTS:

Synergistic cytotoxicity in vitro was observed with MTX (0.1, 0.5, and 1 μmol/L) combined with AICA riboside (0.25-1 mmol/L) in MCF-7 cells, and with MTX (0.5 and 1 μmol/L) combined with AICA riboside (0.5 and 1 mmol/L) in HepG2 cells. MTX (1 μmol/L) significantly enhanced the AICA riboside-induced AMPK activation and BrdU incorporation in both MCF-7 and HepG2 cells. Co-treatment with MTX and AICA riboside exerted more potent inhibition on the tumor growth in nude mice than either drug alone. After injection of AICA riboside (200 mg/kg, iv) in nude mice bearing MCF-7 xenografts, MTX (50 mg/kg, iv) significantly increased the concentrations of AICA riboside and its active metabolite AICA ribotide in tumors.

CONCLUSION:

MTX and AICA riboside exert synergistic anticancer action against MCF-7 and HepG2 cells in vitro and in vivo. MTX increases the concentration of AICA riboside and its active metabolite AICA ribotide in tumors in vivo.

• Authors: Xiao-liang Cheng, Tian-yan Zhou, Bo Li, Meng-yao Li, Liang Li, Zai-quan Li, Wei Lu
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 34 Issue 7 Pg. 951-9 (Jul 2013) ISSN: 1745-7254 [Electronic] United States
• PMID: 23603981 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoimidazole Carboxamide
• Methotrexate

Topics

• Aminoimidazole Carboxamide (administration & dosage)
• Animals
• Apoptosis (drug effects, physiology)
• Breast Neoplasms (drug therapy, pathology)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Proliferation (drug effects)
• Drug Synergism
• Female
• Hep G2 Cells
• Humans
• Liver Neoplasms, Experimental (drug therapy, pathology)
• MCF-7 Cells
• Methotrexate (administration & dosage)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Xenograft Model Antitumor Assays (methods)