Cellular resistance to vincristine suppresses NF-kappa B activation and apoptosis but enhances c-Jun-NH2-terminal protein kinase activation by tumor necrosis factor

Tumor necrosis factor (TNF) is a pleiotropic cytokine that potentiates the cytotoxic effects of chemotherapeutic drugs. Although emergence of resistan ce to chemotherapeutic drugs is a major problem in cancer therapy, its mech anism is incompletely understood. Recently, activation of a nuclear transcr iption factor NF-kappa B has been reported to be a signal for anti-apoptosi s. In this report, we investigated the effect of TNF on activation of NF-ka ppa B, c-Jun N-terminal kinase (JNK), and apoptosis in vincristine-resistan t human histiocytic lymphoma U937-VR cells. Unlike the parent clone (U937-V S), no activation of caspase-3, known to be required for apoptosis, was fou nd in vincristine-resistant cells on exposure to vincristine. These cells w ere 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 a lso suppressed. However, vincristine resistance enhanced TNF-induced JNK ac tivation. When examined for apoptosis, vincristine resistance suppressed th e cytotoxic effects and caspase-3 activation by TNF. The resistant phenotyp e in U937-VR cells was independent of the expression of the apoptosis-suppr essor, Bcl-2. Thus, overall these results indicate that vincristine resista nce correlates with suppression of NF-kappa B activation, cytotoxicity, and caspase-3 activation but enhancement of JNK activation by TNF.