Chemotherapy PKC. NF-kB is a protein complex that acts

Chemotherapy is a most common and efficient
treatment for cancer. Still, some cancers are inherently resistant to the
majority of chemotherapeutic agents and many other cancer exhibits
broad-spectrum or multidrug resistance (MDR) after several bouts of
chemotherapy.  
P-glycoprotein (P-gp), is a transmembrane protein encoded by the ATP-binding cassette
sub-family B member 1 (ABCB1) gene, belongs to the ATP-binding cassette (ABC)
family. P-gp is composed of 1280 amino acids (170 kDa) organized in two
transmembrane domains, each one comprised of twelve highly hydrophobic
?-helices and two intracellular nucleotide binding regions with ATPase
activity. The drug-binding site (DBS) is found in the intracellular part of the
protein, and when ATP activates P-gp, the substrate is extruded by a
“flip-flop” mechanism to the luminal side. Its subsequent dephosphorylation
leads to the transformation of the protein back to the initial state. The
overexpression of P-gp is efflux of various hydrophobic chemotherapeutic agents
from cells, which consequences in low chemotherapy efficacy. The
P-gp shows broad substrate specificity towards Vinca alkaloids,
anthracyclines, taxanes and epipodophylotoxins, and is responsible for
intrinsic and acquired drug resistance in numerous human cancers. P-gp-mediated
drug resistance can be effectively overcome by either blocking its drug-pump
function or inhibiting its expression.

To reverse cellular transport protein-mediated
drugresistance, recently many studies have been conducted to explore possible
mechanisms via signaling pathways. P-gp is highly regulated, especially at the
transcriptional level. This indicates a promising approach in blocking of MDR,
by inactivation of P-gp expression than by blocking its function. Although the
mechanism for transcription regulation of MDR1 is still not fully understood, a
large number of transcription factors such as Ras , Sp1, p53, NF-kB and PKC. NF-kB
is a protein complex that acts as a signal-induced transcription factor. In
tumour cells, NF-kB is activated by mutations in genes that encode NF-kB or
that control NF-kB activity, such as IkB genes. Phosphorylation of IkB by IkB
kinase, which is essential for NF-kB activation, induces IkB ubiquitination and
degradation by the 26S proteasome, releasing the NF-kB subunits, which then
translocate to the nucleus.

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Blocking NF-kB causes tumour cells to stop
proliferating and die, or to become more sensitive to the action of antitumour
agents. Previous studies have demonstrated that MDR1 activation occurs through
NF-kB activation. Inhibitor of kB (I-kB) binds to NF-kB and inactivates it by
localizing NF-kB to the cytosol where it is unable to regulate transcription. Akt
is reported to phosphorylate and activate IKK. Activation of IKK causes
phosphorylation and degradation of I-kB, which leads to localization of NF-kB
to the nucleus, where it can induce transcription of genes. Recently,
much attention has been focused on the involvement of the PI3K/Akt cell signal
transduction pathway in MDR.  The promoter
region of mdr1 does not have a TATA box, but has a consensus CAAT box and two GC
box-like sequences. Transcription of the mdr1 is controlled by NF-?B transcription
factor. Previously, NF-kB /p65 protein complex  and c-Fos transcription factors interacts with
the CAAT promoter region in MCF7 cells and negatively regulates the human mdr1 promoter
activity (Ogretmen and Safa, 1999). Recent papers reported that NF-kB was
involved in mdr1 expression in hepatocytes, in 2-acetylaminofluorene-induced
MDR expression in liver cells and in constitutive MDR expression in
drug-resistant cells. Thus, agents are needed that can suppress the NF-?B
pathway and have potential against cancer multidrug resistance.

Nature
compounds are in advance increasing interest in cancer therapy. Some agents
extracted from fruits, vegetables, oilseeds, and plant herbs were able to
modulate the activity of P-gp. Ferulic acid (FA), a natural phenolic
phytochemical present in seeds, leaves, such as wheat, rice and barley bothin
its free form and covalently conjugated to the plant cell wall polysaccharides,
glycoproteins,polyamines, lignin and hydroxy fatty acids. FA exhibits wide
variety of biological activities such as antioxidant, antiinflammatory, hepatoprotective,
anticarcinogenic, antithrombotic, metal chelation, modulation of enzyme
activity, activation and inhibition of transcriptional factors and gene
expression. Recently we have reported that ferulic acid could reverse the P-gp
associated multidrug resistance in cancer. Furthermore, in this study we described
new experimental evidence that ferulic acid downregulates P-gp expression at the
transcriptional level via  Phosphatidyinositol
3-kinase (PI3K)/Akt/nuclear factor-?B (NF-?B) signal cascade in the
multidrug-resistant KBChR 8-5 cells.