Tramadol and Flurbiprofen Depress the Cytotoxicity of Cisplatin via Their Effects on Gap Junctions

Purpose: Cancer patients are often concurrently treated with analgesics and antineoplastic drugs, yet the influence of analgesic agents on therapeutic activity of antineoplastic drugs is largely unexplored. This study investigates the effects of three commonly used analgesics, which produce analgesia by different mechanisms, on cytotoxicity induced by cisplatin, a widely used antitumor agent, and the relation between those effects and modulation of gap junction function by the analgesics. Experimental Design: The role of gap junctions in the modulation of cisplatin toxicity is explored by manipulation of connexin expression, and gap junction presence and function, using clinically relevant concentrations of the analgesics and cisplatin. Results: Short-term exposure of transformed cells to cisplatin reduced the clonogenic survival in low-density cultures (without gap junction formation) and in high density (with gap junction formation), but the toxic effect was greater at high density. In the absence of connexin expression or with block of connexin channels, cell density had no effect on cisplatin toxicity. Tramadol and flurbiprofen, but not morphine, significantly reduced cisplatin cytotoxicity, but this effect required functional gap junctions between the cells. Tramadol and flurbiprofen inhibited dye-coupling through gap junctions, but morphine did not. Conclusions: The results suggest that the density dependence of cisplatin toxicity is mediated by gap junctions. They further indicate that tramadol and flurbiprofen depress cisplatin cytotoxicity through inhibition of gap junction activity, and more generally, that agents that depress junctional communication can counteract the effects of antitumor agents. (Clin Cancer Res 2009;15(18):5803–10)