1. Decrease in c-Myc activity enhances cancer cell sensitivity to vinblastine.
- Author
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Bressin C, Bourgarel-Rey V, Carré M, Pourroy B, Arango D, Braguer D, and Barra Y
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma metabolism, Apoptosis drug effects, Colonic Neoplasms metabolism, Cytochromes c metabolism, DNA, Antisense pharmacology, Down-Regulation, Drug Tolerance, G1 Phase drug effects, Humans, Membrane Potentials drug effects, Mitochondria drug effects, Poly(ADP-ribose) Polymerases metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Tumor Cells, Cultured, Tumor Suppressor Protein p53 metabolism, bcl-2-Associated X Protein metabolism, Antineoplastic Agents, Phytogenic therapeutic use, Colonic Neoplasms drug therapy, Proto-Oncogene Proteins c-myc metabolism, Vinblastine therapeutic use
- Abstract
The c-myc oncogene encodes for a transcriptional factor involved in many cellular processes such as proliferation, differentiation and apoptosis. According to these different functions, the role of c-Myc protein in cellular sensitivity to anti-cancer drugs is controversial. We defined the role of c-Myc in cancer cell sensitivity to vinblastine (VLB) using human colon cancer cells: LoVo wild-type or transfected with a plasmid containing the human c-myc gene in antisense orientation (LoVo-mycANS). Analysis of VLB cytotoxicity demonstrated a 3-fold increase in VLB sensitivity in LoVo-mycANS cells. Comparison between cells revealed different apoptosis kinetics: accumulation of cells in sub-G1 phase and poly(ADP-ribose) polymerase cleavage occurred earlier in LoVo-mycANS. Then, we demonstrated a mitochondrial membrane potential disruption followed by cytochrome c release that indicates the involvement of mitochondria in this apoptotic signaling pathway. This earlier apoptosis was accompanied by a Bcl-2 decrease and a p53 increase. In conclusion, the decrease in c-Myc expression enhanced the VLB sensitivity, triggering earlier apoptosis through induction of the intrinsic pathway. Thus, c-myc induction is a resistance factor and our findings suggest that tumors carrying low levels of c-Myc protein could be more responsive to vinca alkaloids treatment. Moreover, the downregulation of c-myc oncogene by an antisense strategy might represent a useful goal for improving the efficacy of this anti-neoplastic drug family.
- Published
- 2006
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