Title:Natural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action
Volume: 19
Issue: 33
Author(s): J.-J. Qin, S. Nag, S. Voruganti, W. Wang and R. Zhang
Affiliation:
Keywords:
MDM2, MDM2 inhibitors, MDM2-p53 interaction, mechanisms of action, natural product anticancer agents, p53-dependent, p53-independent, p53 wild-type, p53 mutant, small molecule inhibitors of MDM2
Abstract: The mdm2 oncogene has recently been suggested to be a valuable target for cancer therapy and prevention. Overexpression of
mdm2 is often seen in various human cancers and correlates with high-grade, late-stage, and more treatment-resistant tumors. The
MDM2-p53 auto-regulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main
focus of anti-MDM2 drug discovery. Much effort has been expended in the development of small molecule MDM2 antagonists targeting
the MDM2-p53 interaction, and a few of these have advanced into clinical trials. However, MDM2 exerts its oncogenic activity through
both p53-dependent and -independent mechanisms. Recently, there is an increasing interest in identifying natural MDM2 inhibitors; some
of them have been shown to decrease MDM2 expression and activity in vitro and in vivo. These identified natural MDM2 inhibitors
include a plethora of diverse chemical frameworks, ranging from flavonoids, steroids, and sesquiterpenes to alkaloids. In addition to a
brief review of synthetic MDM2 inhibitors, this review focuses on natural product MDM2 inhibitors, summarizing their biological
activities in vitro and in vivo and the underlying molecular mechanisms of action, targeting MDM2 itself, regulators of MDM2, and/or
the MDM2-p53 interaction. These MDM2 inhibitors can be used alone or in combination with conventional treatments, improving the
prospects for cancer therapy and prevention. Their complex and unique molecular architectures may provide a stimulus for developing
synthetic analogs in the future.
