Curtailing side effects in chemotherapy: a tale of PKCδ in cisplatin treatment

Abstract

The efficacy of chemotherapy is often limited by side effects in normal tissues. This is exemplified by cisplatin, a widely used anti-cancer drug that may induce serious toxicity in normal tissues and organs including the kidneys. Decades of research have delineated multiple signaling pathways that lead to kidney cell injury and death during cisplatin treatment. However, the same signaling pathways may also be activated in cancer cells and be responsible for the chemotherapeutic effects of cisplatin in tumors and, as a result, blockade of these pathways is expected to reduce the side effects as well as the anti-cancer efficacy. Thus, to effectively curtail the side effects, it is imperative to elucidate and target the cell killing mechanisms that are specific to normal (and not cancer) tissues. Our recent work identified protein kinase C δ (PKCδ) as a new and critical mediator of cisplatin-induced kidney cell injury and death. Importantly, inhibition of PKCδ enhanced the chemotherapeutic effects of cisplatin in several tumor models while alleviating the side effect in kidneys, opening a new avenue for normal tissue protection during chemotherapy.

Keywords: chemotherapy; cisplatin; protein kinase C δ; side effect.

Figure 1. PKCδ inhibition enhances anti-cancer therapy while protecting kidneys during cisplatin treatment

Cisplatin induces cell death in both cancer and kidney cells, resulting in chemotherapy in tumors and acute kidney injury and kidney failure. Genetic or pharmacologic inhibition of PKCδ enhances the chemotherapy effect of cisplatin in tumors and diminishes cisplatin-induced side effect in kidneys.

Figure 2. PKCδ in survival of normal versus cancer cells

PKCδ is not required for the survival normal cells. However, it is required for the survival and proliferation of cancer cells with an oncogenic stress phenotype and, as a result, suppression of PKCδ leads to cell injury and death in tumors.