Selection of tumor cell variants for resistance to tumor necrosis factor also induces a form of pleiotropic drug resistance

Abstract

This study has addressed the question of whether there may be some common mechanism underlying the induction or expression of acquired cytokine and drug resistance in a tumor cell line. This study employed the tumor-necrosis-factor(TNF)-sensitive U937 tumor cell line as a model system to determine if selection of a tumor cell variant for cytokine resistance would also result in drug resistance and vice versa. Variants were selected by culturing in the presence of purified recombinant TNF or a mixed-lymphokine-containing supernatant derived from concanavalin-A-stimulated peripheral blood lymphocytes. The resulting variants were resistant not only to TNF, but also to certain chemotherapeutic drugs. The variants were most resistant to colchicine and the Vinca alkaloids, requiring drug concentrations 50- to 5000-fold higher to mediate levels of cytotoxicity comparable to that seen with the parental U937. The variants were moderately resistant to cycloheximide, actinomycin D, and mitomycin C. In contrast, these lines were relatively sensitive to doxorubicin or daunomycin. This phenomenon was not unique to U937 cells since we obtained a similar pattern of drug resistance by selecting TNF-resistant variants of the WEHI-164 tumor cell line. The cytokine-selected U937 variants were still lysed by NK cells, although they were somewhat less sensitive than the parental U937. Both variants were relatively resistant to lysis by activated macrophages, probably because of their TNF resistance. In an alternative selection procedure, U937 variants were derived by culturing in the presence of increasing concentrations of colchicine. The resulting variants were relatively resistant to TNF, providing further support for the existence of some common mechanism operating in induction or expression of acquired cytokine and drug resistance. The resistance mechanism apparently does not involve the P glycoprotein since the cytokine-selected U937 variants do not overexpress the mdr gene. This study has demonstrated that selection of TNF-resistant variants results in coexpression of a unique form of drug resistance that is characterized by resistance to microtubule-active drugs but not to the anthracycline antibiotics and is not associated with overexpression of the mdr gene.

The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model

“…Interestingly, the presence of apoptosis in the tumour treated with Mel, RA and NS was associated with increased levels of TNF‐α. In support, TNF‐α can induce apoptosis in tumour cell lines in vitro (Wright et al . 1992).…”

Tumor cell resistance to apoptosis due to a defect in the activation of sphingomyelinase and the 24 kDa apoptotic protease (AP24)

“…As a toolto furtheranalyze the mechanism of TNF-induced apoptosis,we developed a TNF-resistant variant by the prolonged culture of U937 cells in the presence of increasing sublethal concentrations of TNF as described previously (7). This variant (U9-TR) still expressed functional TNF receptors because it could activate the transcription factor NFKB in response to TNF (3).…”

Expression of tumour necrosis factor α and its receptors in carcinoma of the breast

“…This phenomenon may generate TNF-resistant clones of neoplastic cells in certain areas owing to exposure to low doses of TNF-a for sufficiently prolonged periods. Interestingly, TNF-c-resistant cells are resistant to certain chemotherapeutic drugs in vitro (Wright et al, 1992).…”