Synthetic analogue of rocaglaol displays a potent and selective cytotoxicity in cancer cells: involvement of apoptosis inducing factor and caspase-12.
Flavaglines constitute a family of natural anticancer compounds. We present here 3 (FL3), the first synthetic flavagline that inhibits cell proliferation and viability (IC(50) approximately 1 nM) at lower doses than did the parent compound, racemic rocaglaol. Compound 3 enhanced doxorubicin cytotoxicity in HepG2 cells and retained its potency against adriamycin-resistant cell lines without inducing cardiomyocyte toxicity. Compound 3 induced apoptosis of HL60 and Hela cells by triggering the translocation of Apoptosis Inducing Factor (AIF) and caspase-12 to the nucleus. A fluorescent conjugate of 3 accumulated in endoplasmic reticulum (ER), suggesting that flavaglines bind to their target in the ER, where it triggers a cascade of events that leads to the translocation of AIF and caspase-12 to the nucleus and probably inhibition of eIF4A. Our studies highlight structural features critical to their antineoplastic potential and suggest that these compounds would retain their activity in cells refractory to caspase activation.
Thuaud
Frédéric
F
Therapeutic Innovation Laboratory, UMR7200, CNRS/Universite de Strasbourg, Illkirch, France.
Bernard
Yohann
Y
Türkeri
Gülen
G
Dirr
Ronan
R
Aubert
Geneviève
G
Cresteil
Thierry
T
Baguet
Aurélie
A
Tomasetto
Catherine
C
Svitkin
Yuri
Y
Sonenberg
Nahum
N
Nebigil
Canan G
CG
Désaubry
Laurent
L
D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053454:Caspase 12 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C550442:3a-(4-bromophenyl)-6,8-dimethoxy-3-phenyl-1,2,3,3a-tetrahydro-cyclopenta(b)benzofuran-1,8b(1H)-diol; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D001572:Benzofurans; C510144:rocaglaol; D004317:Doxorubicin; D053454:Caspase 12