1,25-Dihydroxyvitamin D₃ increases the sensitivity of human renal carcinoma cells to tumor necrosis factor α but not to interferon α or lymphokine-activated killer cells

Renal cell carcinoma is a chemotherapy-resistant tumor which is relatively responsive to immunotherapy. Immunotherapeutic regimes employ interferons or interleukin 2 with or without lymphokine-activated killer cells. Secondary cytokines, induced by interleukin 2 or interferon, may have an important impact on their anti-neoplastic activity. Notable among them is tumor necrosis factor (TNFα). We assessed the effect of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) on the susceptibility of the human renal cell carcinoma cell line SK-RC-29 to the cytotoxic and cytostatic actions of TNFα, interferon α and lymphokine-activated killer cells. Using uptake of the vital dye neutral red as an indicator of viable cell number, we found that addition of 1,25(OH)₂D₃ (100 nM) to TNFα (30 ng/ml)-treated cultures resulted in a 2.6 ± 0.2-fold (mean ± S.E.) increase in the cytotoxic effect of the cytokine. The potentiating effect of 1,25(OH)₂D₃ was dose-dependent, and significant at concentrations equal to or higher than 10 nM. Another dihydroxylated vitamin D metabolite, 24,25(OH)₂D₃, had no effect on TNFα action. The cytotoxic effect of TNFα increased whereas the potentiation by 1,25(OH)₂D₃ decreased with cell density in culture. 1,25(OH)₂D₃, in contrast to its potentiating effect on TNFα action, did not modulate the cytostatic effect of interferon α or the susceptibility of SK-RC-29 to killing by lymphokine-activated killer cells. The findings reported here may explain some of the in vivo anti-tumor activity of 1,25(OH)₂D₃ and provide a rationale for the employment of active vitamin D analogs during immune anti-cancer therapy.