title: Novel β-Carboline/Hydroxamic Acid Hybrids Targeting Both Histone Deacetylase and DNA Display High Anticancer Activity via Regulation of the p53 Signaling Pathway.
abstract: A novel series of hybrids from β-carboline and hydroxamic acid were designed and synthesized. Several compounds (5m, 11b-d, and 11h) not only exerted significant antiproliferation activity against four human colorectal cancer (CRC) cell lines but also showed histone deacetylase inhibitory effects in vitro. The most potent compound, 11c, exhibited anticancer potency sevenfold higher than that of SAHA. 11c triggered more significant cancer cell apoptosis than did SAHA by cleavage of both PARP and caspase 3 in a dose-dependent manner. Furthermore, 11c simultaneously increased the acetylation of histone H3 and α-tubulin, enhanced expression of DNA damage markers histone H2AX phosphorylation and p-p53 (Ser15), and activated p53 signaling pathway in HCT116 cells. Finally, 11c showed low acute toxicity in mice and inhibited the growth of implanted human CRC in mice more potently than did SAHA. Together, 11c possessed potent antitumor activity and may be a promising candidate for the potential treatment of human CRC.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ling
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P.R. China.
authors.forename: Chenjun
authors.initials: C
authors.lastname: Xu
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.forename: Jingyi
authors.initials: J
authors.lastname: Cao
authors.forename: Jiao
authors.initials: J
authors.lastname: Feng
authors.forename: Yu
authors.initials: Y
authors.lastname: Xue
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Caoyun
authors.initials: C
authors.lastname: Ju
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute , Buffalo, New York, USA.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P.R. China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute , Buffalo, New York, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ling
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D004247:DNA; D006655:Histone Deacetylases