The flip side of doxorubicin: Inflammatory and tumor promoting cytokines.

Cardiac toxicity is a major dose-limiting factor for the anthracycline drug doxorubicin. The reasons why doxorubicin causes heart damage are not fully understood, and the manuscript by Wong et al. postulates that inflammatory cytokines released from macrophages or other cell types may play a significant role in the damage process in response to doxorubicin and possibly other chemotherapeutic agents.(1) Expression of many cytokines requires activation of both the p38 MAPK and JNK pathways and, additionally, doxorubicin toxicity can be blocked by combined inhibition of both pathways.(2,3) The MAP3K responsible for doxorubicin-induced p38 MAPK and JNK activation in keratinocytes was previously shown by these authors to be ZAK.(4) ZAK is of note because it can be targeted by FDA approved agents such as nilotinib and sorafenib.(4-7)