Perifosine sensitizes curcumin-induced anti-colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro.

Abstract

Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor-κB as well as activation of c-Jun N-terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl-2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors.

• Authors: Min-Bin Chen, Xiao-Yang Wu, Guo-Qing Tao, Chao-Ying Liu, Jian Chen, Li-Qiang Wang, Pei-Hua Lu
• Journal: International journal of cancer (Int J Cancer) Vol. 131 Issue 11 Pg. 2487-98 (Dec 01 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 22438101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 UICC.

Chemical References

• Ceramides
• I-kappa B Proteins
• Multiprotein Complexes
• NF-kappa B
• NFKBIA protein, human
• Nfkbia protein, mouse
• Proteins
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Phosphorylcholine
• Cyclin D1
• NF-KappaB Inhibitor alpha
• perifosine
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• JNK Mitogen-Activated Protein Kinases
• Curcumin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Caco-2 Cells
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Ceramides (metabolism)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Curcumin (administration & dosage, pharmacology)
• Cyclin D1 (antagonists & inhibitors)
• Down-Regulation (drug effects)
• Drug Synergism
• Endoplasmic Reticulum (drug effects)
• Female
• HCT116 Cells
• HT29 Cells
• Humans
• I-kappa B Proteins (antagonists & inhibitors)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, SCID
• Multiprotein Complexes
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Phosphorylcholine (administration & dosage, analogs & derivatives, pharmacology)
• Proteins (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases
• Xenograft Model Antitumor Assays