Abstract
BackgroundThe 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 FindingsWe 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 mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest.Conclusions/SignificanceThese data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance.
Highlights
Retinoids are a class of chemical compounds structurally related to vitamin A that modulate fundamental cellular processes, including cell proliferation, differentiation and apoptosis [1]
We have recently reported that in ovarian cancer cells, 4-HPR-induced apoptosis is mediated by the proapoptotic PLAcental Bone morphogenetic protein (PLAB) and that its upregulation by 4-HPR occurs through the activation of a signaling cascade starting from increase of reactive oxygen species (ROS) generation, leading to induction of endoplasmic reticulum (ER) stress response and Jun N-terminal Kinase (JNK) activation [9,10]
We have recently reported that 4-HPR triggers apoptosis through activation of a signaling cascade that starts from ROS generation and that involves ER stress responses, JNK activation and PLAB upregulation [9]
Summary
Retinoids are a class of chemical compounds structurally related to vitamin A that modulate fundamental cellular processes, including cell proliferation, differentiation and apoptosis [1]. 4-HPR and 4-oxo-4-HPR share several signaling intermediates, such as ROS generation, increase of intracellular ceramide levels, and activation of caspase-3 and caspase-9 [12] Despites these similarities, 4-oxo-4-HPR seems to have additional mechanisms of action compared to the parent drug, suggested by its ability to be effective in 4-HPR resistant cells [12]. We have demonstrated that, like 4-HPR, 4-oxo-4-HPR causes increase of ROS generation, followed by induction of ER stress response, activation of JNK and PLAB upregulation and that this signaling cascade is partially involved in the antiproliferative effect of the retinoid. The 4-oxo-4-HPR antimitotic effect is functionally independent from the abovementioned apoptotic cascade, indicating that 4-oxo-4-HPR antitumor effect is due to at least two independent mechanisms of action
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
