4-oxo-N-(4-hydroxyphenyl)retinamide: two independent ways to kill cancer cells.

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.
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 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.
These 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.
AuthorsPaola Tiberio, Elena Cavadini, Gabriella Abolafio, Franca Formelli, Valentina Appierto
JournalPloS one (PLoS One) Vol. 5 Issue 10 Pg. e13362 ( 2010) ISSN: 1932-6203 [Electronic] United States
PMID20976277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-oxofenretinide
  • Antineoplastic Agents
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Fenretinide
  • MAP Kinase Kinase 4
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Down-Regulation (drug effects)
  • Fenretinide (analogs & derivatives, pharmacology)
  • Humans
  • MAP Kinase Kinase 4 (metabolism)
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasms (enzymology, metabolism, pathology)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Reactive Oxygen Species (metabolism)
  • Signal Transduction
  • Up-Regulation (drug effects)

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