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

Céline Bressin·Véronique Bourgarel-Rey·Manon Carré·Bertrand Pourroy·Diego Arango·Diane Braguer·Yves Barra
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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.

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AdenocarcinomaAntineoplastic Agents, PhytogenicApoptosisColonic NeoplasmsCytochromes cDNA, AntisenseDown-RegulationDrug ToleranceG1 PhaseHumansMembrane PotentialsMitochondriaPoly(ADP-ribose) PolymerasesProto-Oncogene Proteins c-bcl-2Proto-Oncogene Proteins c-mycTumor Cells, CulturedTumor Suppressor Protein p53Vinblastinebcl-2-Associated X ProteinJournal Article

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Céline Bressin, Véronique Bourgarel-Rey, Manon Carré, Bertrand Pourroy, Diego Arango, Diane Braguer, Yves Barra. 2006. Decrease in c-Myc activity enhances cancer cell sensitivity to vinblastine.. https://doi.org/10.1097/00001813-200602000-00009

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