title: LG308, a Novel Synthetic Compound with Antimicrotubule Activity in Prostate Cancer Cells, Exerts Effective Antitumor Activity.
abstract: Microtubule plays many different essential roles in the process of tumorigenesis in many eukaryotes, and targeting mitotic progression by disturbing microtubule dynamics is used as a common strategy for cancer treatment. Microtubule-targeted drugs, including paclitaxel and Vinca alkaloids, were previously considered to work primarily by increasing or decreasing the cellular microtubule mass. The tubulin/microtubule system, which is an integral component of the cytoskeleton, is a therapeutic target for prostate cancer. In this study, we found a novel synthetic compound, 8-fluoro-N-phenylacetyl-1, 3, 4, 9-tetrahydro-β-carboline (LG308), which disrupted the microtubule organization via inhibiting the polymerization of microtubule in PC-3M and LNCaP prostate cancer cell lines. Further study proved that LG308 induced mitotic phase arrest and inhibited G2/M progression significantly in LNCaP and PC-3M cell lines in a dose-dependent manner, and these were associated with the upregulation of cyclin B1 and mitotic marker MPM-2 and the dephosphorylation of cdc2. Besides, the cell proliferation and colony formation of PC-3M and LNCaP cells were effectively inhibited by LG308. Furthermore, LG308 induced apoptosis and cell death in PC-3M and LNCaP cell lines in vitro. In vivo, LG308 dramatically suppressed the growth and metastasis of prostate cancer in both xenograft and orthotopic models. All these data indicate that LG308 is a promising anticancer candidate with antimitotic activity for the treatment of prostate cancer.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Min
authors.initials: M
authors.lastname: Qin
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Shihong
authors.initials: S
authors.lastname: Peng
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Meichun
authors.initials: M
authors.lastname: Hu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Yundong
authors.initials: Y
authors.lastname: He
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Huang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Ang
authors.initials: A
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.).
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.) yhchen@bio.ecnu.edu.cn zfyi@bio.ecnu.edu.cn.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China (M.Q., S.P., N.L., M.H., Y.H., G.L., H.C., Y.H., A.C., X.W., M.L., Y.C., Z.Y.); and Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A & M University Health Science Center, Houston, Texas (M.L.) yhchen@bio.ecnu.edu.cn zfyi@bio.ecnu.edu.cn.
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D008940:Mitotic Index; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050257:Tubulin Modulators / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056744:Cyclin B1; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D050257:Tubulin Modulators; D016203:CDC2 Protein Kinase