title: Two-drug combinations that increase apoptosis and modulate bak and bcl-X(L) expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase.
abstract: Herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) gene therapy can induce apoptosis in tumor cells that are normally resistant to this type of cell death, although the cellular mechanisms by which this occurs remain to be elucidated. Human colon tumor cell lines expressing HSV-TK were treated with GCV or four other inducers of apoptosis: butyrate, camptothecin (CPT), Taxol (paclitaxel), or 7-hydroxystaurosporine (UCN-01). Over a 2-4 day treatment period with GCV or the other four drugs, protein levels of the apoptosis agonist Bak increased 1.5- to 3-fold, whereas a corresponding decrease in the levels of the apoptosis antagonist, Bcl-X(L), was observed in butyrate-, CPT-, and 7-hydroxystaurosporine (UCN-01)-treated cells. GCV and paclitaxel treatments resulted in increased levels of Bcl-X(L). In two-drug combinations with GCV plus one of the four other drugs, increased tumor cell killing was found with GCV plus UCN-01 or with some GCV/butyrate combinations; the other two tested combinations were largely antagonistic. The GCV/UCN-01 and GCV/butyrate combinations resulted in increased Bak and decreased Bcl-X(L) protein levels, while the GCV/CPT and GCV/paclitaxel combinations resulted in increased levels of both proteins. The results highlight the potential for new combination therapies of HSV-TK/GCV and chemotherapeutic drugs that result in increased tumor cell apoptosis for future treatments of colon cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: McMasters
authors.forename: T N
authors.initials: TN
authors.lastname: Wilbert
authors.forename: K E
authors.initials: KE
authors.lastname: Jones
authors.forename: K
authors.initials: K
authors.lastname: Pitlyk
authors.forename: R L
authors.initials: RL
authors.lastname: Saylors
authors.forename: M P
authors.initials: MP
authors.lastname: Moyer
authors.forename: T C
authors.initials: TC
authors.lastname: Chambers
authors.forename: R R
authors.initials: RR
authors.lastname: Drake
mesh_terms: D000470:Alkaloids / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000633:toxicity; D002166:Camptothecin / Q000633:toxicity; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D004347:Drug Interactions; D015774:Ganciclovir / Q000633:toxicity*; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000096:biosynthesis*; D017239:Paclitaxel / Q000633:toxicity; D010447:Peptide Hydrolases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000378:metabolism; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D019311:Staurosporine / Q000031:analogs & derivatives; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D002087:Butyrates; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C054852:7-hydroxystaurosporine; D013937:Thymidine Kinase; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C108711:DEVDase; D019311:Staurosporine; D017239:Paclitaxel; D015774:Ganciclovir; D002166:Camptothecin