Fig. 3

The schematic apoptosis and autophagy induction by apigenin when it is simultaneously used with a chemo drug. Two dimers of the RTK phosphorylate together in multiple tyrosine sites within the RTK intracellular domain which mediate different downstream signaling cascades such as PI3K/AKT pathway. PI3K/AKT signaling is initiated through interaction between activated RTK and adaptor proteins. PI3K phosphorylates AKT protein and p-AKT triggers the activation of several proteins playing critical role in apoptosis. The over-activation of PI3K/AKT results in the over-expression of the anti-apoptic proteins such as Bcl-2, Bcl-xL, Bax, Bad and Mcl-1. These proteins inhibit the down-stream cascade of apoptosis and cause indefinite cell proliferation. Co-administration of apigenin and chemo drugs induces apoptosis by the inhibition of the anti-apoptic proteins. Autophagy is the other activated mechanism by apigenin-chemo drugs suggested in different studies. In autophagy, apigenin-chemo drugs increases JNK. It has been reported that activation of JNK can induce Bcl-2 phosphorylation, resulting in the release of Beclin-1and autophagy activation. Generally, these results revealed a fundamental role of JNK in apigenin-induced autophagy and apoptosis. Nrf2, a redox-sensitive transcription factor, regulates the expression of cytoprotective genes and protective cells against oxidative/electrophilic agents-induced damages. Nrf2 binds to the AREs in the promoters of various cytoprotective genes and regulates their expression. Nrf2 overexpression increases chemoresistance, therefore, its inhibition by apigenin plus chemo drugs sensitizes different cancer cells against chemo drugs. NF-κB, is inhibited by the inhibitory IκB protein in the cell cytoplasm. External stimuli causes to the ubiquitination of IκB and NF-κB release. Then, NF-κB enters to the nucleus and starts the transcription of target genes, such as TNF-α, IL-1β and TGFβ to promote inflammatory responses. These proteins play critical roles in the nephrotoxicity which is induced by some of the chemo drugs such as cisplatin. Apigenin dramatically reduced chemo drugs-induced kidney dysfunction by anti-oxidant and anti-inflammatory effects by inhibition of the NF-κB- IκB complex separation by p38 protein. (Inhibition  Activation)