Effects of Tumor Necrosis Factor-Alpha on Growth and Doxorubicin Sensitivity of Multidrug Resistant Tumor Cell Lines

Abstract

Biological agents might offer various therapeutic opportunities in the treatment of cancer, including a direct and/or host- mediated antiproliferative effect as well as the possibility to favourably modulate tumor sensitivity to antineoplastic drugs (Alexander et al., 1987; Kikuchi et al., 1992; Wadler and Schwartz, 1990). However, information on their activity on chemoresistant tumors is still scanty (Billi et al., 1991; Bonavida et al., 1989; D’Alessandro, 1993; Fruehauf et al., 1991; Liddill et al., 1988; Mihich and Ehrke, 1991). Here we have focused on tumor necrosis-alpha (TNF-α) and studied its in vitro effects on the growth of two tumor cell lines, the mouse B16 melanoma and Friend erythroleukemia, both as doxorubicin (DXR)-sensitive (B16, FLC) and -resistant (B16/DXR, FLC/DXR) variants; the resistant lines were endowed with “typical” multidrug resistance (MDR), including cross-resistance to vincristine and the overexpression of P-glycoprotein, detected by immunocytochemistry or immunoblotting (Crescimanno et al., 1991; Schisselbauer et al., 1989). In addition, since in some tumors TNF-α may act through oxidative stress (Zimmerman et al., 1989; Wong and Goeddel, 1988) with greater efficacy in cells depleted of their glutathione content (Zimmerman et al., 1989), we studied the antiproliferative effects of the cytokine in combination with glutathione-depleting concentrations of buthionine sulfoximine (BSO). Finally, experiments were performed to ascertain whether co-treatment with TNF-α could modify the sensitivity to DXR of the drug-sensitive and — resistant cell lines.