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. 2021 Oct 29;21:574. doi: 10.1186/s12935-021-02282-3

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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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)

Inline graphic — 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)