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Retinoid Related Molecules an Emerging Class of Apoptotic Agents with Promising Therapeutic Potential in Oncology: Pharmacological Activity and Mechanisms of Action

[ Vol. 10 , Issue. 4 ]

Author(s):

Enrico Garattini, Maurizio Gianni and Mineko Terao   Pages 433 - 448 ( 16 )

Abstract:


Retinoic acid and derivatives (retinoids) exert their anti-neoplastic action through three different, though partially overlapping mechanisms: growth-inhibition, cyto-differentiation and apoptosis. Retinoid related molecules (RRMs) are a promising class of synthetic retinoic acid derivatives endowed with selective apoptotic activity on a large variety of leukemic and solid tumor cells. The in vitro apoptotic activity of RRMs translates into in vivo efficacy in a number of experimental models of neoplasia. The prototype of this novel family of cytotoxic agents is CD437, a conformation restricted retinoid originally developed as a selective RARγ agonist. A number of new RRM congeners, including ST1926, MM002, MM11453 and MX-3350-1, have been recently reported in the literature. Some of these compounds have a stronger apoptotic potential, a lower level of toxicity and a better pharmacokinetic profile than CD437. RRMs have a molecular mechanism of action that is entirely different from that of many other known chemotherapeutics. These compounds induce apoptosis in retinoic acid- and multi-drug-resistant neoplastic cells. The apoptotic process triggered by RRMs is independent of p53 activation and proceeds through a novel pathway in which the mitochondrion seems to play a pivotal role. RRMs show only very limited cross-resistance with other classes of chemotherapeutic agents and show synergistic interactions with a number of classical cyto-toxic agents. The article presents a critical overview of the current knowledge on the pharmacology of RRMs focussing on such issues as the spectrum of cytotoxic activity, the molecular mechanisms of action and the pre-clinical basis of clinical development.

Keywords:

Retinoid,Apoptotic Agents,mitochondrion,chemotherapeutic,CD437,Oncology

Affiliation:

, , Laboratory of MolecularBiology, Centro Catullo e Daniela Borgomainerio, Istituto di RicercheFarmacologiche “Mario Negri”, via Eritrea 62 20157 Milano, Italy



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