Smuggling Taxol into cancer cells

Some cancer cells evade chemotherapy by expressing cell membrane pumps to expel toxins. One such pump is the P-glycoprotein, which exports the widely used chemotherapy compound Taxol as it passes through the membrane. To counter P-glycoprotein efflux, Elena Dubikovskaya et al. modified Taxol’s structure, attaching a peptide that alters the mechanism by which the compound enters cells. The new conjugate, with different physical properties, is not a substrate for the pump. The authors attached the cellpenetrating peptide octaarginine to either the C2 or C7 position in Taxol by using a disulfide bridge, which made the compound water-soluble (eliminating the need to use a noxious vehicle) and enabled the drug to cross the cell membrane without conventional diffusion. Outside the cell, the compound is inactive, but the reducing environment inside the cell cleaves the disulfide bridge, setting Taxol free. The authors demonstrated increased lethality of the conjugate compound in Taxol-resistant cell lines. Delivered by injection, both versions of the conjugate were more effective than Taxol against resistant tumors in mice. The method also ensures sustained drug release, rather than the ‘‘bolus’’ effect seen with conventional treatment, the authors say. — K.M.