Study on anti-cancer activity of butyrolactones isolated from Aspergillus terreus with prostate and breast cancer cell lines文献综述

Proposed title for dissertation: Study on anti-cancer activity of butyrolactones isolated from Aspergillus terreus with prostate and breast cancer cell linesI. BackgroundFungi from marine environments are widely recognized as emerging sources of biologically active and structurally unique secondary metabolites [1]. Due to the demand for production of mass bioactive compounds and the technical progress in related field, more and more researchers pay attention on these organisms and marine-derived fungi are considered to be a new frontier for natural products research.[2]Meanwhile, prostate cancer is one of the most common cancers affecting men with gt;1,100,000 new cases and 300,000 deaths worldwide each year[3] while Breast cancer has become one of the most common malignant tumors in the world, and it is also an important cause of death in women. According to current trends, the number of cases and deaths of breast cancer is expected to reach 2.64 million and 1.7 million by 2030.[4]II. Research Questions, Methodology and Its significanceSo far, the prolonged latency, high prevalence, and morbidity, associated with significant mortality make prostate cancer and breast cancer immediate medical problems to resolve and The global health care system is under enormous strain. Therefore, if butyrolactones affiliation compounds (Butyrolactone II, 2-furancarboxylic acid) are proven to have anti-cancer property for these cancer, this will be a big discovery.This dissertation aims at finding the anti-cancer effect of butyrolactone affiliation compound for unexamined cancer cell type prostate cancer- and breast cancer- cell lines (PC-3, DU-145, MDA-MB-231, BT-549). The research is mainly divided into two part: 1. Literature research, collect relevant research materials to prepare for future research. 2. Experimental verification: test cell viability by CCK-8 and estimate anti-cancer effect with paclitaxel, doxorubicin and 5-FU.III. Literature ReviewCell division (mitosis) is one of the basic requirements for multicellular organisms. A successful division cycle implies there is a precise adherence of sequence and termination of each phase. Cyclin-dependent kinases (CDKs) plays a central role in the crossing of these checkpoints. Abnormal regulation of the control mechanism in the cell cycle leads to an excessive cell proliferation and is the cause of cancer. These years search of low molecular weight specific inhibitor of CDKs becomes popular and these inhibitors can block cell cycle progression and display anti-cancer effect[5]1.Anti-cancer effect of Butyrolactone I and mechanismButyrolactone I, a natural product isolated from Aspergillus terreus, has been found to exhibit antiproliferative activity against colon and pancreatic carcinoma, human lung cancer and prostatic cancer. It is a selective inhibitor of CDK enzyme, specifically inhibiting Cdk2 and Cdc2 kinase[6] which play an important role in cell suppression from G1 to S phase. It also inhibited the H1 histone phosphorylation in nuclear extracts [7-8]. Documents record that Bcl-2 and Bax are important genes in the progress of cell apoptosis, Bcl-2 is responsible for inhibiting apoptosis while Bax promotes the cell apoptosis. The ratio of Bax/ Bcl-2 protein was the key factor in determining the inhibition of Apoptosis. In butyrolactone-treated-PANC-1 and AsPC-1 cells, butyrolactone I demonstrates significant suppression of pRb phosphorylation and cyclin A expression, upregulation of Bax expression and downregulation of Bcl-2 expression, which causes apoptosis induction in tumor cells.[7] Its inhibitory effect is due to competition with ATP binding at CDK and block the activation of transcription factor E2F-1 phosphorylation.2. Functional structure of Butyrolactone I Due to its excellent anticancer properties, researchers become interested in studying this compound and a series of analogues of butyrolactone I. two of analogues are the focus of my research. (Butyrolactone I) R=-OH(Butyrolactone II )R=H,R1=3-methybut-2-enyl (2-Furancarboxylic acid)According to the previous experiment, analogues where the 3-methylbut-2enyl present in butyrolactone I has been eliminated are used to do biological evaluation. The results show that one of analogues, Butyrolactone II, was completely inactive against four cell lines (human colon carcinoma, human cervical carcinoma, and human prostate carcinoma). It suggested that the presence of the alkenyl chain is essential for antitumor activity [8]. Besides there was a molecular modeling study on the mode of interaction of both enantiomers of butyrolactone I with CDK2 by making use of automated docking method. The statistic indicated that (R)-enantiomer is more stable[9] and in the proposed binding mode of the natural product, the ester group lies below the Ar2 ring, whereas in all other derivatives, the butyrolactone moiety is the one which lies below this system. It was related to the steric hindrance of the 3-methyl-2-butenyl group and that is why the synthesized compounds did not have the same antitumor effect as butyrolactone I.[8]3. Current research progress of three compounds and OutlookSince butyrolactone I was found in 1977[10], researchers have a complete understand about its anti-cancer effect. Buytrolactone I was previously studied in three different human prostate cell lines (PC-3, DU145, LNCaP), cancer cell growth in all three cell lines were suppressed.[11]However due to the structural complexity of butyrolactone I, little is known about its binding mode to its target [12]. For other two compounds (butyrolactone II and 2-furancarboxylic acid), there is few researches about their antiproliferative activity. Researchers used to evaluate the antiviral activities of 2-furancarboxylic acid and other compounds while it exhibited weak ability.[13]but they are very similar with butyrolactone I in chemical structure. These compounds are most likely to be potential anti-cancer drugs in the futureIV. References[1]Bhatnagar, I; Kim,S.K. Immense essence of excellence: Marine microbial bioactive compounds. Mar.Drugs 2010,8,2673-2701[2]Hu,G.-P.;Yuan,J;Sun,L.;She Z.-G.;Wu,J.-H.;Lan,X.-J;Zhu,X.;Lin,Y.-C;Chen,S.-P. Statistical research on marine natural product based on data obtained between 1985 and 2008. Mar.Drugs 2011,9,514-525[3]Tao ZQ, Shi AM, Wang KX, Zhang WD. Epidemiology of prostate cancer: current status. Eur Rev Med Pharmacol Sci. 2015;19(5):805-12.[4]Sally NA, Temidayo O, Clement A. Emerging breast cancer epidemic: evidence from Africa [J], Breast Cancer Res.2010,12(S4):8.[5]A.Huwe, R.Mazitschek and A.Giannis, Angew.Chem.,Int.Ed., 2003.42, 2122-2138[6] M. Kitagawa, T. Okabe, H. Ogino, H. Matsumoto, I. Suzuki-Takahashi, T. Kokubo, H. Higashi, S. Saitoh and Y. Taya, Oncogene,1993, 8, 24252432.[7] K.P. Lu, T. Hunter, Evidence for a NIMAlike mitotic pathway in vertebrate cells, Cell 81 (1995) 413424.[8] E. Okumura, T. Sekiai, S. Hisanaga, K. Tachibana, T. Kishimoto, Initial triggering of M-phase in starsh oocytes, a possible novel component of maturation-promoting factor besides cdc2 kinase, J. Cell Biol. 132 (1996) 125135[9]Wada,M. et al. 1998 Anticancer Res. 18 2559-2566. PMID: 9703910[10] Miguel F. Braa,*a M. Luisa Garca,a Berta Lpez,a Beatriz de Pascual-Teresa,a Ana Ramos,aJose M. Pozuelo b and M. Teresa Domnguez b Synthesis and biological evaluation of analogues of butyrolactone I and molecular model of its interaction with CDK2 2004[11] K. V. Rao, A. K. Sadhukhan, M. Veerender, V. Ravikumar, E. V. S. Mohan, S. D. Dhanvantri, M. Sitaramkumar, J. M. Babu, K. Vyas and G. O. Reddy, Chem. Pharm. Bull., 2000, 48, 559562.[12]N. Kiriyama, K. Nitta, Y. Sakaguchi, Y. Taguchi and Y. Yamamoto, Chem. Pharm. Bull., 1977, 25, 25932601.[13] Makoto Suzuki*, Yoshio Hosaka, Hisashi Matsushima, Toshitaka Goto, Tadaichi Kitamura, Kazuki KawabeCancer Letters 138 (1999) 121130[14] H. Morishima, K. Fujita, M. Nakano, S. Atsumi, M. Ookubo,M. Kitagawa, H. Matsumoto, A. Okuyama and T. Okabe, (BanyuPharma Co. Ltd.), Jpn. Kokai Tokkyo Koho 06 100, 445, 1994[15] MA Xinhua1), ZHU Tianjiao1), GU Qianqun1), XI Rui2), WANG Wei1), *, and LI Dehai1), *Structures and Antiviral Activities of Butyrolactone Derivatives Isolated from Aspergillus terreus MXH-23 2014

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