c-myc down-regulation induces apoptosis in human cancer cell lines exposed to RPR-115135 (C31H29NO4), a non-peptidomimetic farnesyltransferase inhibitor.
A therapeutic strategy that relies on the use of c-myc antisense in combination with a farnesyltransferase inhibitor, RPR-115135 (C31H29NO4), was studied in human cancer cell lines carrying different mutations (Ras, p53, myc amplification). Cell proliferation was strongly inhibited by the combination and was observed when c-myc oligo (at a concentration that down-regulates c-myc expression) was followed by RPR-115135. Cell cycle analysis demonstrated an accumulation in G0-G1 phase and a tendency to apoptosis (not detectable in cells treated with a single agent). Morphological examination and DNA fragmentation assays (filter binding and enzyme-linked immunosorbent assay DNA fragmentation) confirmed the induction of apoptosis. Apoptosis was not p53- and/or p21(waf-1)-dependent, and the key effector was caspase activation. The combination induced Bax expression and Bcl-2 inhibition. Down-regulation of c-myc amplification carried out a specific role exclusively when Ras was mutated. Exposure of human proliferating lymphocytes to combination did not result in cytotoxicity, suggesting that mechanisms regulating c-myc gene expression during normal T cell proliferation might not be involved. Because of the high percentage of human tumors overexpressing c-myc mRNA and/or protein and, simultaneously, harboring oncogenic Ras mutants (i.e., colon cancers), interrupting the myc- and Ras-signaling pathway would be one of the major focuses on therapy of these types of tumors.
Russo
Patrizia
P
Laboratory of Experimental Oncology, Molecular Pathology Section, National Institute for Research on Cancer, Genoa, Italy. patrizia.russo@istge.it
Arzani
Dario
D
Trombino
Sonya
S
Falugi
Carla
C
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D017353:Gene Deletion; D016259:Genes, myc / Q000187:drug effects / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D012333:RNA, Messenger; C426728:RPR115135; C007293:DAPI; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D020169:Caspases; D015689:Oncogene Protein p21(ras)