Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells

• Published in: Cancer letters 2009-04, Vol.276 (2), p.180-188
• Main Authors: Yang, Lu, Wu, Dingfang, Luo, Kewang, Wu, Shihua, Wu, Ping
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Andrographolide; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - chemistry; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Caspase 8 - physiology; Caspase 9 - physiology; Caspase-8-dependent; Cell cycle; Cell Line, Tumor; Chemotherapy; Cytochromes c - physiology; Diterpenes - pharmacology; Drug resistance; Drug Synergism; Fluorouracil - pharmacology; Hematology, Oncology and Palliative Medicine; Hepatocellular carcinoma; Humans; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Medical prognosis; Medical research; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mortality; Proteins; Response rates; Studies; Tumor Suppressor Protein p53 - physiology; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2008.11.015

Abstract Despite recent significant advances in the treatment of human carcinoma (HCC), the results of chemotherapy to date remain unsatisfactory. 5-Fluorouracil (5-FU) still represents the cornerstone of treatment of carcinoma, and resistance to the actions of 5-FU is a major obstacle to successful chemotherapy. More effective treatment strategies may involve combinations of agents with activity against HCC. Andrographolide (ANDRO), a natural bicyclic diterpenoid lactone isolated from Andrographis paniculata , has been shown to suppress the growth of HCC cells and trigger apoptosis in vitro. To assess the suitability of ANDRO as a chemotherapeutic agent in HCC, its cytotoxic effects have been evaluated both as a single agent and in combination with 5-FU. ANDRO potentiates the cytotoxic effect of 5-FU in HCC cell line SMMC-7721 through apoptosis. ANDRO alone induces SMMC-7721 apoptosis with p53 expression, Bax conformation and caspase-3,8,9 activation. Surprisingly, the addition of ANDRO to 5-FU induces synergistic apoptosis, which could be corroborated to the increased caspase-8, p53 activity and the significant changes of Bax conformation in these cells, resulting in increased losses of mitochondrial membrane potential, increased release of cytochrome c , and activation of caspase-9 and caspase-3. Suppression of caspase-8 with the specific inhibitor z-IETD-fmk abrogates largely ANDRO/5-FU biological activity by preventing mitochondrial membrane potential disappearance, caspase-3,9 activation and subsequent apoptosis. The results suggest that ANDRO may be effective in combination with 5-FU for the treatment of HCC cells SMMC-7721.