Studies On The Mechanism Of Annonaceous Acetogenins Mimic AA005's Selective Anticancerous Cell Activity

The physiological and biochemical functions in cells are not independent. Furthermore,they connect with each other and construct complicated network in cells. To explore the mechanisms of controlling cell cycle,cell death and tumorgenesis, a compound, Annonaceous acetogenins mimic AA005, was used as a tool to treat cancerous cells. Annonaceous acetogenins are a family of natural products with anticancer activities. Its polyether mimicking compound, termed AA005,was synthesized by Yao's lab. Then the cytotoxicity mechanism of AA005 was investigated. It was found that AA005 could induce cell death of gastric tumor cells AGS. Most of AA005-induced cell death was due to necrosis, whereas partial and p53-independent apoptosis was detected. An expanded study with the gastric tumor cells and the cell free system indicated that AA005 could inhibit NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport system. Further studies indicated that AA005 has selective anticancer activity both in vitro and in vivo. The mechanism of this character was studied. Fluorescence imaging and mass spectrometric analysis demonstrated that more AA005 molecules accumulated in cancerous cells than that in non-cancerous cells. Further analysis showed that the activity of AA005 was tightly correlated with the concentration of glucose and its transport systems GLUTs, and glucose could reduce the accumulation of AA005 in cells in a dose-dependent manner. It was also found that the transportation of AA005 could also be regulated by PI(3)K/Akt pathway. Furthermore, inhibition of the activity of GLUT4, one member of GLUTs regulated by PI(3)K/Akt, resulted in the decrease of AA005-transportation and increase of AA005-resistance in cancerous cells. These data demonstrated that GLUT4 was involved in the selective accumulation of AA005 in cancerous cells. Additionally, our experiments showed that GLUT4 molecules localized in caveolae of plasma membrane of non-cancerous cells but not in cancerous cells. Moreover, knock-down of Caveolin-1 to damage the caveolae could result in the increase of AA005-transportation and decrease of AA005-resistance in non-cancerous cells. It indicated that this kind of differential localization of GLUT4 and caveolae involved in the selective accumulation of AA005 in cancerous cells. In a word, our study identified a previously undescribed compound with potential selective tumoricidal activity and presented a new strategy for cancer therapy.