Enhancing perifosine's anticancer efficacy by preventing autophagy.
1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. ssun@emory.edu
Autophagy
|December 22, 2009
Summary
Perifosine, an anticancer drug, inhibits cancer growth by degrading mTOR signaling components, leading to autophagy and apoptosis. Combining perifosine with lysosomal inhibitors enhances its efficacy by blocking protective autophagy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Perifosine is an alkylphospholipid with demonstrated antitumor activity.
- Its mechanism involves Akt inhibition, but further understanding is needed.
- Current research explores its effects on mTOR signaling and cell death pathways.
Purpose of the Study:
- To elucidate the anticancer mechanism of perifosine.
- To investigate perifosine's interaction with mTOR signaling pathway.
- To explore the role of autophagy in perifosine's efficacy.
Main Methods:
- Investigated perifosine's effect on mTOR components (mTOR, raptor, rictor) degradation.
- Assessed induction of autophagy and apoptosis by perifosine.
- Evaluated combination therapy of perifosine with a lysosomal inhibitor in xenograft models.
Main Results:
- Perifosine inhibits mTOR signaling by facilitating the degradation of key mTOR axis components, distinct from rapamycin.
- Perifosine significantly induces both autophagy and apoptosis.
- Combination of perifosine with a lysosomal inhibitor enhanced apoptosis and suppressed tumor growth in vivo.
- Perifosine-induced autophagy appears to protect cancer cells from apoptosis.
Conclusions:
- Perifosine exhibits anticancer activity through a novel mechanism of degradation-mediated mTOR inhibition.
- Autophagy induced by perifosine may confer resistance to apoptosis.
- Inhibiting autophagy could be a viable strategy to potentiate perifosine's therapeutic efficacy in cancer treatment.
Related Concept Videos
01:27Autophagy
Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
01:36Delivery Pathways to the Lysosome
Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
01:18Autophagic Cell Death
Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and pro-apoptotic...
01:15Drugs that Stabilize Microtubules
Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
03:03mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
01:10Drugs that Destabilize Microtubules
Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...