Retinoid targets for apoptosis induction

Abstract

Certain synthetic retinoid-related molecules induce apoptosis in cancer cells through a novel mechanism of retinoid action that is independent of the nuclear retinoid receptors. These compounds target protein kinases and protein phosphatases to trigger signal transduction pathways that lead to apoptosis. Whereas retinoid agonists such as CD437 activate stress kinases via inhibition of the phosphatase MKP-1, the retinoid antagonist MX781 inhibits the survival kinase IKK. These retinoid-mediated signaling pathways converge at the mitochondria, where they cause the release of cytochrome c and subsequent Apaf-1-dependent activation of caspases. Identification of the retinoid targets that mediate their apoptotic activity will enhance our understanding of the mechanism of this novel retinoid action, to allow appropriate optimization of currently available compounds to advance into the clinic as novel anticancer agents.

Astragali Radix elicits anti-inflammation via activation of MKP-1, concomitant with attenuation of p38 and Erk

“…In fact, attempts to develop drugs that target this signaling pathway represent an area of great interest. Currently, MKPs are emerging as new targets for drug discovery (Pfahl and Piedrafita, 2003;Furst et al, 2007). MKPs bind to and negatively regulate the activity and cellular localization of members of the MAP kinase family.…”

Adamantyl-Substituted Retinoid-Related Molecules Bind Small Heterodimer Partner and Modulate the Sin3A Repressor

“…Diverse mechanisms have been proposed to more clearly define the pathway(s) through which AHPN and its analogues exert their effects. These include the induction of specific proteins, inhibition of the mitogen-activated protein kinase-1 phosphatase resulting in c-Jun NH 2 -terminal kinase kinase activation, induction of DNA adducts, translocation of the nuclear transcription factor TR3 to mitochondria, and TR3 binding to Bcl-2 as well other proposed mechanisms (13,47,48). How AHPN/3-Cl-AHPC exerts these diverse effects in malignant cells is not clear.…”

Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-κB Activation

“…The introduction of a the 3-Cl ortho to the diaryl bonds resulted in the orientation of the 1-adamantyl group outside of the plane of the aromatic rings (64); this, in turn, resulted in the poor activation of RARg by 3-Cl-AHPC and its inability to disassociate RARg from its bound corepressors (64). The mechanism by which 3-Cl-AHPC and CD437 induces apoptosis in a number of cell types remains undefined.…”