Gemcitabine intercellular diffusion mediated by gap junctions: new implications for cancer therapy

Molecular Cancer

Research

Sylvine Cottin¹  Pedro Otavio de Campos-Lima¹  Manuel Caruso¹  Karim Ghani¹ 

[1] Centre de Recherche en Cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, G1R 2J6, Qc, Canada;

关键词: Gemcitabine;    Calcein;    Bystander Effect;    Osteosarcoma Cell Line;    Herpes Simplex Virus Thymidine Kinase;   

DOI  :  10.1186/1476-4598-9-141

 received in 2009-12-15, accepted in 2010-06-10,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundSolid tumors are often poorly vascularized, with cells that can be 100 μm away from blood vessels. These distant cells get less oxygen and nutrients and are exposed to lower doses of chemotherapeutic agents. As gap junctions allow the passage of small molecules between cells, we tested the possibility that the chemotherapeutic agent gemcitabine can diffuse through gap junctions in solid tumors.ResultsWe first showed with a dye transfer assay that the glioblastoma and the osteosarcoma cells used in this study have functional gap junctions. These cells were genetically engineered to express the herpes simplex virus thymidine kinase (TK), and induced a "bystander effect" as demonstrated by the killing of TK-negative cells in presence of the nucleoside analogue ganciclovir (GCV). The ability of gemcitabine to induce a similar bystander effect was then tested by mixing cells treated with 3 μM gemcitabine for 24 hours with untreated cells at different ratios. In all cell lines tested, bystander cells were killed with ratios containing as low as 5% treated cells, and this toxic effect was reduced in presence of α-glycyrrhetinic acid (AGA), a specific gap junction inhibitor. We also showed that a 2- or a 24-hour gemcitabine treatment was more efficient to inhibit the growth of spheroids with functional gap junctions as compared to the same treatment made in presence of AGA. Finally, after a 24-hour gemcitabine treatment, the cell viability in spheroids was reduced by 92% as opposed to 51% in presence of AGA.ConclusionThese results indicate that gemcitabine-mediated toxicity can diffuse through gap junctions, and they suggest that gemcitabine treatment could be more efficient for treating solid tumors that display gap junctions. The presence of these cellular channels could be used to predict the responsiveness to this nucleoside analogue therapy.

【 授权许可】

Unknown   
© Cottin et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.