Chemotherapy is a most common and efficienttreatment for cancer.
Still, some cancers are inherently resistant to themajority of chemotherapeutic agents and many other cancer exhibitsbroad-spectrum or multidrug resistance (MDR) after several bouts ofchemotherapy. P-glycoprotein (P-gp), is a transmembrane protein encoded by the ATP-binding cassettesub-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 twotransmembrane domains, each one comprised of twelve highly hydrophobic?-helices and two intracellular nucleotide binding regions with ATPaseactivity.
The drug-binding site (DBS) is found in the intracellular part of theprotein, and when ATP activates P-gp, the substrate is extruded by a”flip-flop” mechanism to the luminal side. Its subsequent dephosphorylationleads to the transformation of the protein back to the initial state. Theoverexpression of P-gp is efflux of various hydrophobic chemotherapeutic agentsfrom cells, which consequences in low chemotherapy efficacy.
The P-gp shows broad substrate specificity towards Vinca alkaloids,anthracyclines, taxanes and epipodophylotoxins, and is responsible forintrinsic and acquired drug resistance in numerous human cancers. P-gp-mediateddrug resistance can be effectively overcome by either blocking its drug-pumpfunction or inhibiting its expression.To reverse cellular transport protein-mediateddrugresistance, recently many studies have been conducted to explore possiblemechanisms via signaling pathways. P-gp is highly regulated, especially at thetranscriptional level. This indicates a promising approach in blocking of MDR,by inactivation of P-gp expression than by blocking its function. Although themechanism for transcription regulation of MDR1 is still not fully understood, alarge number of transcription factors such as Ras , Sp1, p53, NF-kB and PKC. NF-kBis a protein complex that acts as a signal-induced transcription factor.
Intumour cells, NF-kB is activated by mutations in genes that encode NF-kB orthat control NF-kB activity, such as IkB genes. Phosphorylation of IkB by IkBkinase, which is essential for NF-kB activation, induces IkB ubiquitination anddegradation by the 26S proteasome, releasing the NF-kB subunits, which thentranslocate to the nucleus. Blocking NF-kB causes tumour cells to stopproliferating and die, or to become more sensitive to the action of antitumouragents. Previous studies have demonstrated that MDR1 activation occurs throughNF-kB activation. Inhibitor of kB (I-kB) binds to NF-kB and inactivates it bylocalizing NF-kB to the cytosol where it is unable to regulate transcription. Aktis reported to phosphorylate and activate IKK. Activation of IKK causesphosphorylation and degradation of I-kB, which leads to localization of NF-kBto the nucleus, where it can induce transcription of genes.
Recently,much attention has been focused on the involvement of the PI3K/Akt cell signaltransduction pathway in MDR. The promoterregion of mdr1 does not have a TATA box, but has a consensus CAAT box and two GCbox-like sequences. Transcription of the mdr1 is controlled by NF-?B transcriptionfactor. Previously, NF-kB /p65 protein complex and c-Fos transcription factors interacts withthe CAAT promoter region in MCF7 cells and negatively regulates the human mdr1 promoteractivity (Ogretmen and Safa, 1999). Recent papers reported that NF-kB wasinvolved in mdr1 expression in hepatocytes, in 2-acetylaminofluorene-inducedMDR expression in liver cells and in constitutive MDR expression indrug-resistant cells. Thus, agents are needed that can suppress the NF-?Bpathway and have potential against cancer multidrug resistance.
Naturecompounds are in advance increasing interest in cancer therapy. Some agentsextracted from fruits, vegetables, oilseeds, and plant herbs were able tomodulate the activity of P-gp. Ferulic acid (FA), a natural phenolicphytochemical present in seeds, leaves, such as wheat, rice and barley bothinits free form and covalently conjugated to the plant cell wall polysaccharides,glycoproteins,polyamines, lignin and hydroxy fatty acids. FA exhibits widevariety of biological activities such as antioxidant, antiinflammatory, hepatoprotective,anticarcinogenic, antithrombotic, metal chelation, modulation of enzymeactivity, activation and inhibition of transcriptional factors and geneexpression.
Recently we have reported that ferulic acid could reverse the P-gpassociated multidrug resistance in cancer. Furthermore, in this study we describednew experimental evidence that ferulic acid downregulates P-gp expression at thetranscriptional level via Phosphatidyinositol3-kinase (PI3K)/Akt/nuclear factor-?B (NF-?B) signal cascade in themultidrug-resistant KBChR 8-5 cells.