Enhancing perifosine's anticancer efficacy by preventing autophagy.
Our long-term research goal is to develop efficacious regimens for cancer therapy through our understanding of cancer biology and drug mechanisms. Perifosine is an alkylphospholipid exhibiting antitumor activity and is currently being tested in clinical trials. Its activity is partly associated with its ability to inhibit Akt activity. In an effort to understand the mechanism by which perifosine exerts its anticancer activity, our recent work shows that perifosine, in addition to inhibition of Akt, inhibits mTOR signaling through a different mechanism than classical mTOR inhibitors such as rapamycin via facilitating the degradation of major components in the mTOR axis including mTOR, raptor and rictor. Accordingly, perifosine substantially induces autophagy in addition to apoptosis. The combination of perifosine with a lysosomal inhibitor enhances apoptosis and inhibition of the growth of xenografts in nude mice, suggesting that perifosine-induced autophagy protects cells from undergoing apoptosis. Thus, our findings highlight a novel mechanism accounting for perifosine's anticancer activity involving degradation-mediated mTOR inhibition and also suggest a potential strategy to enhance perifosine's anticancer efficacy by preventing autophagy.
Sun
Shi-Yong
SY
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. ssun@emory.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000008:administration & dosage; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; D002738:Chloroquine