HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

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

AbstractBACKGROUND:
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 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/SIGNIFICANCE:
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
Topics
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: