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Decrease in c-Myc activity enhances cancer cell sensitivity to vinblastine

Bressin, Célinea; Bourgarel-Rey, Véroniquea; Carré, Manona; Pourroy, Bertranda; Arango, Diegob; Braguer, Dianea; Barra, Yvesa

Preclinical Reports

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.

aCNRS FRE 2737, UFR Pharmacie, University of ‘La Mediterranée’, Marseille, France

bDepartment of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland

Correspondence to V. Bourgarel-Rey, CNRS FRE 2737, UFR Pharmacie, 27 boulevard Jean Moulin, 13385 Marseille Cedex 05, France

Tel: +33 4 91 83 56 03; fax: +33 4 91 83 55 94;

e-mail: veronique.rey@pharmacie.univ-mrs.fr

Received 29 August 2005 Accepted 11 October 2005

© 2006 Lippincott Williams & Wilkins, Inc.