Antagonistic anticancer effect of paclitaxel and digoxin combination

Despite the growing interest in the antitumor effect of cardiotonic steroids, combination treatments with well‐established chemotherapy drugs like paclitaxel have been rarely investigated. Moreover, paclitaxel has been suggested as a Na+/K+‐ATPase inhibitor. Here we investigated the effect of paclitaxel and digoxin alone or in combination on the viability of human lung (A549) and cervical cancer (HeLa) cell lines and the inhibitory effect of paclitaxel on several mammalian Na+/K+‐ATPases. Although the viability of both tumor cell lines was concentration‐dependently affected by digoxin treatment after 48 hours (A549 IC50 = 31 nM and HeLa IC50 = 151 nM), a partial effect was observed for paclitaxel, with a maximal inhibitory effect of 45% at 1000 nM with A549 and around 70% with HeLa cells (IC50 = 1 nM). Although the two drugs were cytotoxic, their combined effect in HeLa cells was revealed to be antagonistic, as estimated by the combination index. No direct inhibitory effect of paclitaxel was detected in human, pig, rat, and mouse Na+/K+‐ATPase enzymes, but high concentrations of paclitaxel decreased the Na+/K+‐ATPase activity in HeLa cells after 48 hours without affecting protein expression. Our findings demonstrate that, under our conditions, paclitaxel and digoxin cotreatment produce antagonistic cytotoxic effects in HeLa cells, and the mechanism of action of paclitaxel does not involve a direct inhibition of Na+/K+‐ATPase. More studies shall be designed to evaluate the consequences of the interaction of cardiotonic steroids and chemotherapy drugs. The effect of paclitaxel and digoxin alone or in combination on the viability of human lung (A549) and cervical cancer (HeLa) cell lines and the inhibitory effect of paclitaxel on several mammalian Na+/K+‐ATPases were investigated. Our findings demonstrate that, under our conditions, although they have a partial or complete antitumor effect when used alone, the combination of paclitaxel and digoxin produces antagonistic cytotoxic effects, and paclitaxel does not directly inhibit the Na+/K+‐ATPase activity. The effect of such drug combinations should not be intuitively deduced, and further research is needed to evaluate the consequences of the interaction of cardiotonic steroids and chemotherapy drugs.