Volume 16, Nº 2 (2016)

Acetogenins (ACG) are naturally occurring compounds that are chemically one of the least investigated families. In the review, we have provided a comprehensive listing of 133 of these compounds for which anti-tumor activity has been documented within the literature. We have compiled and studied their chemical structure, in-vitro as well as in-vivo anticancer biological activity. We observed that the relative potency of acetogenins can be categorized as adjacent bis-THF ACGs > nonadjacent bis-THF ACGs > mono-THF ACGs > linear-THF ACGs. Among adjacent bis-THF ACGs, asiminocin (A100), asiminecin (A101), asiminacin (A102) and asimin (A103) are the most active compounds with in-vitro activity (ED50) in the range of 10-9 to 10-12 µg/mL. For the nonadjacent bis-THF ACGs, gigantecin (A53) exhibited better cytotoxicity as compared to others in the series with an ED50 in the range of 10-6 to 10-8 µg/mL. Similarly, muricatetrocin-C (A36), a mono-THF and coriadienin (A116) a linear ACG has been reported to show promising cytotoxicity with an ED50 of 10-5 µg/mL. Moreover, in-vivo studies indicate that compounds like bullatacin (A83), desacetyluvaricin (A76), bullatalicin (A58) and annonacin (A8) have demonstrated significant activity in mouse models and thereby exhibiting potential for lead development as a potential anticancer agent/drug. Also, globally oncologists are looking towards compounds from natural origin that inhibits the growth of resistant tumor cells. We find that several acetogenins like bullatacin (A83), motrilin (A95), asimicin (A77), trilobacin (A96), annonacin (A8), gigantetronenin (A108) and squamocin (A73) are efficacious in suppressing the proliferation of the MDR MCF-7/Adr cells. The present analysis suggests that acetogenins can act as yet another important source for obtaining promising lead compounds in order to contribute to cancer prevention, however, in future extensive in-vivo studies in animal models will be needed to provide insight for lead development.

p53 protein is a prominent tumor suppressor to induce cell cycle arrest, apoptosis and senescence, which attracts significant interest to cancer treatment. Therefore, it would be particularly important to restore the wild–type p53 that retains latent functions in the approximately 50% of tumors. MDM2 (murine double minute 2), the principal cellular antagonist of p53, has long been believed to suppress p53 activity through two main mechanisms: promoting degradation via its E3 ligase activity and masking p53 transcriptional activation by direct binding. Targeting MDM2 E3 ligase activity is becoming a potential antitumor strategy resulting from MDM2's decisive role in controlling the fate of p53: p53 is going to degradation when entrapped into MDM2-mediated ubiquitination, where p53 can escape by abrogating MDM2 E3 ligase activity using regulators. The intensive focus on regulating MDM2 ubiquitin E3 ligase activity has led to the rapid progress of its inhibitors, which may be possible to help p53 escape from degradation and restore its function to control tumor growth. This review summarizes the current inhibitors of MDM2 E3 ligase in cancer therapy based on the understanding the regulation of MDM2 E3 ubiquitin ligase activity, including post-translational modification, interactions between MDM2 and its cofactors, and regulation of MDM2 stability.