Blockade of the Ras pathway by manumycin, a farnesyltransferase inhibitor, overcomes the resistance of myeloma plasma cells to Fas-induced apoptosis.
Ras activation (by point mutation or binding of IL-6) is frequently observed in multiple myeloma (MM). As farnesylation of Ras protein by farnesyltransferase is a critical step for Ras functional activity, farnesyltransferase inhibitors (FTI) have emerged as potential anti-cancer agents. Manumycin, a natural FTI, prevents proliferation and induces apoptosis of myeloma cells refractory to Fasand drug-induced cell death. Fas pathway analysis showed that Fas-resistant apoptosis of Fas-positive myeloma cells parallels FLIP (FLICE/caspase-8-inhibitory protein) expression. Treatment of fresh purified myeloma cells, myeloma cell clone-2 and U266 cell line with manumycin induced down-regulation of FLIP expression with concomitant expression of Apo 2.7 antigen, the marker of early apoptosis. Down-regulation of FLIP mRNA levels in drug-treated cells was associated to suppression of the transcription factor NF-kappaB that plays a central role in chemoresistance, survival and proliferation of myeloma cells. Further analysis showed that manumycin-induced apoptosis involved caspases activation and was prevented by the addition of caspases specific inhibitors. Finally, pretreatment of Fas-resistant/FLIP-positive cells with manumycin sensitised them to Fas-triggered apoptosis. Overall results indicate that manumycin-induced apoptosis involves Fas pathway. FTIs may thus be proposed as a promising class of anti-cancer agents which can boost the cytotoxic effect of conventional drugs by overcoming NF-kappaB activation and Fas-resistant apoptosis.
Frassanito
M A
MA
Department of Internal Medicine and Oncology (DIMO), University of Bari Medical School, Piazza G. Cesare 11, I-70124 Bari, Italy.
Mastromauro
L
L
Cusmai
A
A
Dammacco
F
F
D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000187:drug effects*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy; D010950:Plasma Cells; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D011090:Polyenes; D053284:Polyunsaturated Alkamides; C054474:manumycin