4-oxo-fenretinide: Anticancer activity via two independent mechanisms

Retinoids are structurally related to vitamin A and has been reported to modulate fundamental cellular processes including cell proliferation, differentiation and apoptosis. In this post anticancer activity of the 4-oxo-fenretidine or 4-oxo-N-(4-hydroxyphenyl) retinamide (4-oxo-4-HPR), which is a polar metabolite of fenretinide or 4-hydroxyphenyl retinamide (4-HPR), will be discussed as reported in PLOS one by Tiberio et. al.

Authors have identified 4-oxo-4-HPR from the analysis of plasma samples of 4-HPR treated patients (participating in Phase III breast cancer prevention trial). This metabolite has been associated with antiproliferative and apoptotic effects in various cancer cell lines and is two to four times more effective than 4-HPR in inhibiting cell growth. Interestingly, 4-oxo-4-HPR is also effective in 4-HPR-resistant cells and, in combination with 4-HPR, has a synergistic effects. 4-HPR and 4-oxo-4-HPR has several similar signaling intermediates like ROS generation, increase of intracellular ceramide levels, and activation of caspase-3 and -9. But its (4-oxo-4-HPR) effectiveness towards 4-HPR resistance cells indicates that it has additional mechanism of action compared to 4-HPR. From the study, it is found that it targets microtubules and inhibits tubulin polymerization causing mitotic arrest and formation of multipolar spindles without loss of centrosome integrity.

In this study, they have found that the mitotic arrest and the coupled formation of multipolar spindles induced by 4-oxo-4-HPR were independent from ROS-related signaling cascade. 4-oxo-4-HPR induced ROS generation occurred earlier than the mitotic arrest. The result was further supported by the finding that inhibition of ROS-related pathway by vitamin C or PLAB silencing did not prevent the ability of 4-oxo-4-HPR to exert its antimicrotubule activity. The ability of 4-oxo-4-HPR to act through at least two independent mechanisms has probably been the explanation behind its higher potency than the 4-HPR and effectiveness to 4-HPR resistant cell lines.

Authors believed that modification in position 4 of the cyclohexene ring is responsible for 4-oxo-HPR antimicrotubule activity, but does not affect the ability of the retinoid to induce ROS generation and to activate the ROS-related signaling cascade.