title: Antiproliferative and proapoptotic effects of a pyrrole containing arylthioindole in human Jurkat leukemia cell line and multidrug-resistant Jurkat/A4 cells.
abstract: Recently, a series of novel arylthioindole compounds, potent inhibitors of tubulin polymerization and cancer cell growth, were synthesized. In the present study the effects of 2-(1H-pyrrol-3-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole (ATI5 compound) on cell proliferation, cell cycle progression, and induction of apoptosis in human T-cell acute leukemia Jurkat cells and their multidrug resistant Jurkat/A4 subline were investigated. Treatment of the Jurkat cells with the ATI5 compound for 48 hrs resulted in a strong G2/M cell cycle arrest and p53-independent apoptotic cell death accompanied by the induction of the active form of caspase-3 and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage. ATI5 treatment also caused non-cell death related mitotic arrest in multidrug resistant Jurkat/A4 cells after 48 hrs of treatment suggesting promising opportunities for the further design of pyrrole-containing ATI compounds as anticancer agents. Cell death resistance of Jurkat/A4 cells to ATI5 compound was associated with alterations in the expression of pro-survival and anti-apoptotic protein-coding and microRNA genes. More importantly, findings showing that ATI5 treatment induced p53-independent apoptosis are of great importance from a therapeutic point of view since p53 mutations are common genetic alterations in human neoplasms.
authors.affiliation: a R. E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology; National Academy of Sciences of Ukraine ; Kyiv , Ukraine.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Philchenkov
authors.affiliation: a R. E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology; National Academy of Sciences of Ukraine ; Kyiv , Ukraine.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Zavelevich
authors.affiliation: b Division of Biochemical Toxicology; National Center for Toxicological Research ; Jefferson , AR USA.
authors.forename: Volodymyr P
authors.initials: VP
authors.lastname: Tryndyak
authors.affiliation: a R. E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology; National Academy of Sciences of Ukraine ; Kyiv , Ukraine.
authors.forename: Ludmila M
authors.initials: LM
authors.lastname: Kuiava
authors.affiliation: c N. N. Blokhin Cancer Research Center ; Moscow , Russian Federation.
authors.forename: Dmitry Yu
authors.initials: DY
authors.lastname: Blokhin
authors.affiliation: d Miyagi Cancer Center ; Natori , Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Miura
authors.affiliation: e Istituto Pasteur-Fondazione Cenci Bolognetti; Sapienza Università di Roma ; Roma , Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.affiliation: b Division of Biochemical Toxicology; National Center for Toxicological Research ; Jefferson , AR USA.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3
keywords: G2/M arrest; Jurkat leukemia cells; apoptosis; arylthioindoles; drug resistance; gene expression; microRNA