title: Cellular resistance to vincristine suppresses NF-kappa B activation and apoptosis but enhances c-Jun-NH2-terminal protein kinase activation by tumor necrosis.
abstract: Tumor necrosis factor (TNF) is a pleiotropic cytokine that potentiates the cytotoxic effects of chemotherapeutic drugs. Although emergence of resistance to chemotherapeutic drugs is a major problem in cancer therapy, its mechanism is incompletely understood. Recently, activation of a nuclear transcription factor NF-kappa B has been reported to be a signal for anti-apoptosis. In this report, we investigated the effect of TNF on activation of NF-kappa B, c-Jun N-terminal kinase (JNK), and apoptosis in vincristine-resistant human histiocytic lymphoma U937-VR cells. Unlike the parent clone (U937-VS), no activation of caspase-3, known to be required for apoptosism was found in vincristine-resistant cells on exposure to vincristine. These cells were also more resistant than U-937-VS cells to doxorubicin, daunomycin, and taxol. TNF-induced NF-kappa B activation, I kappa B alpha degradation, and nuclear translocation of p65 were all found to be highly suppressed in the U-937-VR cells. NF-kappa B activation by LPS, H2O2, and okadaic acid was also suppressed. However, vincristine resistance enhanced TNF-induced JNK activation. When examined for apoptosis, vincristine resistance suppressed the cytotoxic effects and caspase-3 activation by TNF. The resistant phenotype in U937-VR cells was independent of the expression of the apoptosis-suppressor, Bcl-2. Thus, overall these results indicate that vincristine resistance correlates with suppression of NF-kappa B activation, cytotoxicity, and caspase-3 activation but enhancement of JNK activation by TNF.
authors.affiliation: Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Giri
authors.forename: P
authors.initials: P
authors.lastname: Pantazis
authors.forename: B B
authors.initials: BB
authors.lastname: Aggarwal