curcumin and perifosine

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caco-2 Cells; Cell Death; Cell Line, Tumor; Cell Proliferation; Ceramides; Colorectal Neoplasms; Curcumin; Cyclin D1; Down-Regulation; Drug Synergism; Endoplasmic Reticulum; Female; HCT116 Cells; HT29 Cells; Humans; I-kappa B Proteins; JNK Mitogen-Activated Protein Kinases; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, SCID; Multiprotein Complexes; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Phosphorylcholine; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays