Synergistic Anticancer Potential of the Combination of the Novel Curcumin Analog EF24 and p38 MAPK Inhibitors

Abstract

Curcumin has been demonstrated to be an effective agent against human cancer cells. This anticancer activity has been in part attributed to the inhibition of the nuclear factor of kappa B (NFkB), a transcription factor that controls the expression of genes involved in cellular survival and the inflammatory response. This knowledge has been exploited to develop curcumin‐derived analogs, including the fluorinated EF24 compound, with higher potency in in vitro and in vivo models. In order to determine the mechanism of this analog, we examined the contribution of major mitogen‐activated protein kinases (MAPKs) in EF24 induced signaling pathways and revealed upregulated ERK, JNK, and p38 MAPK. We utilized pharmacological MAPK inhibitors to determine pathways that are important for EF24‐induced cell death. Interestingly, EF24 in combination with pyridinyl‐imidazole p38 MAPK inhibitors elicited cytotoxic synergy based on combination index (CI) analysis and colony formation assays. The synergy was associated with the induction of apoptosis. These studies suggest that p38 MAPK has a role in the survival response of lung cancer cells and is possibly one of the major survival pathways induced by EF24. Our finding suggests a potential therapeutic approach by combining a curcumin analog, such as EF24, with a p38 MAPK inhibitor for the effective treatment of lung cancer.