# COX2-Inhibitory and Cytotoxic Activities of Phytoconstituents of _Matricaria chamomilla_ L.
## 4 Discussion
There is a lot of published evidence that mutant p53 contributes to multidrug resistance [94]. It has been proposed to reduce drug resistance by increasing wild-type p53 in cancer. Myricetin increases the expression of the p53 protein and alters the function of Bcl-2 proteins, resulting in increased activity of apoptotic pathways such as Bax and Bak, which are also regulated by p53 [98]. This finding is particularly relevant because previous investigations showed that the PGE2 ligand-receptor complex induced by COX2 inhibited the activation of Bax [99]. Consequently, we hypothesize that the crosstalk between p53 and COX2 and the COX2 inhibition by myricetin may explain why p53 not cross-resistant to myricetin. Nevertheless, we also found HCT116p53\({}^{-/-}\) cells were resistant to our chamomile extract compared to HCT116p53\({}^{+/+}\) cells. An explanation could be that other compounds, but not myricetin, in the chamomile extract were responsible for the resistance. The epidermal growth factor receptor (EGFR) is a key factor in cell growth and is highly expressed in various carcinoma types, with lung and colon cancers being among the most affected. The activation of EGFR is essential for many cancer pathways, making it a prime target for cancer therapy. Despite the effectiveness of EGFR tyrosine kinase inhibitors in lung cancer treatment, resistance often develops through the activation of alternative pathways such as c-Met, HGF, and AXL, as well as divergent downstream pathways such as Ras/Raf/MAPK, Akt, and STAT. The Ras family, which includes H-Ras, N-Ras, and K-Ras, is one of the earliest discovered oncogenes and plays a crucial role in cell growth and proliferation by binding to the Raf and MAPK pathways controlled by EGFR. Mutations in Ras confer resistance to cancer drugs, making them a challenge in cancer therapy [100; 101; 102; 103]. It is now well known that Ras mutant tumors are inherently resistant to anticancer agents, necessitating the development of alternative treatment strategies, and several agents targeting signaling components in the MAPK and PI3K pathways downstream of mutant K-Ras are currently undergoing clinical trials [104]. Myricetin has been reported to interact with and alter pathways such as AKT [105; 106; 107; 108], which are linked to COX2. Myricetin-mediated COX2 inhibition might block EGFR- and Ras-related signaling cascades, potentially making tumor cells more sensitive to drugs and more susceptible to the blockade of cancer cell survival. In the NCI cell line panel, there was no cross-resistance of myricetin to epirubicin, myatnsing, vinblastine, pancratistatin (ABC transporters control drugs), erlotinib (EGFR inhibitor), melphalan (Ras control drug), 5-fluorouracil (p53 control drug), or ifosfamine (WT1 control drug). Nevertheless, there was a significant correlation with etoposide, which was used as the control drug for GSTP1. This is an enzyme mostly known for its detoxification, cytoprotective, and anti-apoptotic activities [109]. In aberrant crypt foci (ACF) in colonic adenoma, COX2 was inactive and GSTP1 was active, allowing ACF proliferation. ACF were also resistant to deoxycholic acid-induced apoptosis through this detoxification process rather than inflammation [110]. The activity of plant polyphenols and flavonoids against both GSTP1-1 and CS-X pumps on breast cancer cell lines has been investigated. Due to its multiple hydroxyl groups, myricetin had no inhibitory effect on GSTP1-1 and only a moderate effect on CS-X compared to two strongly active flavonoids, quercetin and luteolin [111]. GSTP1 plays an active role in cancer and contributes to drug resistance through its detoxification capability, and myricetin does not affect the function of GSTP1, which may explain the missing cross-resistance of GSTP1 to myricetin in the NCI cell line panel.