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Inhibitory Effect on Proliferation of Cancer Cells and the Mitochondrial Mechanism of Both Asiatic Acid and Its Complexes with Rare Earth

Author: LinNa
Tutor: GaoJing；TangXinHui
School: Jiangsu University
Course: Pharmacognosy
Keywords: antitumor drugs asiatic acid mitochondria VDAC AA-rare earth complexes transgene yeast
CLC: R285.5
Type: Master's thesis
Year: 2009
Downloads: 97
Quote: 1
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Abstract


The purpose of this study is to investigate the antitumor activity and mitochondrial mechanism of asiatic acid（AA） and AA-Rare earth complexes, simultaneously establish a transgenic yeast model to screen antitumor drugs which can induce cell death mainly via mitochondria mediated apoptosis pathway.The anti-oxidantive activities of AA and its rare earth complexes in vitro were measured by hydroxy radical-scaveng test,the effect of AA and AA-rare earth complexes（AA-Ce,AA-Tb and AA-Eu） on proliferation of human hepatoma carcinoma cell line（HepG2）,human melanoma cell line（B16）,human cervical carcinoma cell line（Hela）,human esophageal carcinoma cell line（Eca109）,human lung adenocarcinoma cell line（A549） and human breast carcinoma cell line （MCF-7） were tested by MTT,meanwhile morphology of tumor cells was observed under inverted microscope;Intracellular reactive oxygen species（ROS） content was detected with DCFH-DA,intracellular ATP level was measured by ATP Assay Kit,mitochondrial membrane potential was detected with fluorescent probe JC-1,and the expression of voltage-dependent anion channel（VDAC） on mitochondrial out membrane was determined by RT-PCR and Western Blot;DNA fragmentation was determined by agarose gel electrophoresis;the oxygen consumption rate of mitochondrial was determined by Clark oxygen electrode;and Ca2+-induced mitochondrial swelling model was used to observe the direct effect of AA,AA-Tb and AA-Eu on mitochondria.In order to approach the interaction between AA and VDAC,we compare the effects of AA on proliferation of transgene yeasts（the wild type Saccharomyces cerevisiae M-3 and the VDAC1 deficient type M22-2） by monitoring OD600 and counting cell number, The results suggested that AA inhibited the proliferation of tumor cell lines dose-dependently in which HepG2 was more sensitive to AA,and cells rounded and shrank after treated with 100μmol/L AA for 24h.Mitochondrial membrane potential depolarized,intracellular ATP level dose-dependent decreased and ROS content dose-dependently increased afer treated with AA,and VDAC expression was up-regulated by 50μmol/L AA;Furthermore,isolated mitochondria were dose-dependently protected by AA against swelling induced by Ca2+,which suggested AA can react on mitochondria directly.The main active groups of AA-rare earth complexes are the same,but presented higher inhibitory effects on Eca109,Hela,A549 and MCF-7;Oxygen consumption rate decreased,and mitochondial swelling induced by Ca2+ was inhibited by treatment of AA-Tb or AA-Eu on Hela cells.The proliferation of M-3 and M22-2 yeast were inhibited by 5-Fu with no selectivity,suggesting VDAC was not invovled in cytotoxicity of 5-Fu.As2O3 and AA had conspicuous inhibitory effects on proliferation of M-3 but not of M22-2, illustrating that As2O3 and AA induced yeast apoptosis by interaction with VDAC.In conclusion,both AA and AA-rare earth complexes have good antitumor effects,which was related with mitochondria mediated apoptosis,and VDAC was involved in the pathway;Meanwhile a new platform to study the mechanism of antitumor drugs via mitochondrial-mediated apoptosis was established.

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