title: NF-kappaB does not influence the induction of apoptosis by Ukrain.
abstract: Ukrain is a reaction product of different alkaloids from Chelidonium majus L. (celandine) conjugated with thiophosphoric acid. It has immunoregulatory effects on T lymphocyte subsets and cytotoxic and cytostatic effects on various malignant cells. Although Ukrain has been reported to induce alterations in the cell cycle and tubulin polymerization, the specific cellular target has not been described. Since antineoplasic agents induce NF-kappaB and their effects are regulated by this transcription factor, we investigated its possible participation in the apoptotic effects of Ukrain. Ukrain induced apoptosis in a panel of cancer cell lines by activating the intrinsic cell death pathway, as demonstrated by the cleavage of caspase 9 and the upregulation and cleavage of caspase 3. The effect was reversible, since long exposures (24 hours or more) were needed, as verified by clonogenic assays. Gene reporter assays showed that Ukrain activated NF-kappa B. Nevertheless, this activation was not required for, and did not modulate, the Ukrain effect: neither blockage of activation by a dominant negative version of Ikappa-B alpha or a Bcl-3 siRNA, nor activation of the pathway by overexpression of IKK2, changed the response to the drug. In conclusion, Ukrain induced apoptosis in HeLa cervical cancer cells by activating the intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B.
authors.affiliation: Molecular Biology Laboratory, Subdireccion de Investigacion Basica, Instituto Nacional de Cancerologia, Mexico City, Mexico.
authors.forename: Julia
authors.initials: J
authors.lastname: Mendoza
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.forename: Juan C
authors.initials: JC
authors.lastname: Gallardo
authors.forename: Gisela
authors.initials: G
authors.lastname: Ceballos
authors.forename: Aida
authors.initials: A
authors.lastname: Aldana
authors.forename: Magali
authors.initials: M
authors.lastname: Espinosa
authors.forename: Vilma
authors.initials: V
authors.lastname: Maldonado
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000081242:B-Cell Lymphoma 3 Protein; D001600:Berberine Alkaloids / Q000494:pharmacology*; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D053453:Caspase 9 / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010617:Phenanthridines / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D001600:Berberine Alkaloids; D016328:NF-kappa B; D010617:Phenanthridines; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C060921:ukrain; D051550:I-kappa B Kinase; D053148:Caspase 3; D053453:Caspase 9