4-oxo-n-(4-hydroxyphenyl)retinamide two independent ways to kill cancer cells(4-oxo-n)- 4-hydroxyphenyl retinamide两个独立的方法来杀死癌细胞.pdfVIP

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4-oxo-n-(4-hydroxyphenyl)retinamide two independent ways to kill cancer cells(4-oxo-n)- 4-hydroxyphenyl retinamide两个独立的方法来杀死癌细胞.pdf

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4-oxo-n-(4-hydroxyphenyl)retinamide two independent ways to kill cancer cells(4-oxo-n)- 4-hydroxyphenyl retinamide两个独立的方法来杀死癌细胞

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells Paola Tiberio*, Elena Cavadini, Gabriella Abolafio, Franca Formelli, Valentina Appierto Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS ‘‘Istituto Nazionale dei Tumori’’, Milan, Italy Abstract Background: The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines. Methodology/Principal Findings: We provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than m