# COX2-Inhibitory and Cytotoxic Activities of Phytoconstituents of _Matricaria chamomilla_ L.
## 4 Discussion
Considering this, we investigated the potential of chamomile tea to inhibit COX2 and its cytotoxic effects against different cancer types. For that purpose, we conducted resazurin assays to measure the growth-inhibitory effects of chamomile extract against hematopoietic tumor cell lines (leukemia, multiple myeloma) and colon cancer cells. Hematopoietic cancer cells are frequently more sensitive to cytotoxic agents than solid cancer cells. This was also observed with our chamomile extract. We used two colon cancer cell lines: a p53 wildtype and a knockout line. The tumor suppressor p53 is not only a major driver of carcinogenesis if it is mutated but also causes resistance to anticancer drugs [75]. In previous investigations, we found that HCT116 p53\({}^{-/-}\) cells were resistant to the standard anticancer drug doxorubicin [76]. The p53 knockout cells were also moderately but significantly resistant to the chamomile extract compared to p53 wildtype cells (2.65-fold). We have also performed virtual screening and molecular docking. By calculating the lowest binding energies of more than 200 compounds, we were able to focus on a few promising molecules to conduct a COX2 inhibitor screening assay for testing their activity against COX2. Subsequently, we narrowed our focus on myricetin to study its effect against cancer in addition to inflammation by conducting multiple advanced analyses such as oncobiogram, proteome, and Kaplan-Meier survival analyses. Our results from molecular docking and the COX2 inhibition screening assay were significantly correlative. Seven of our compounds (\(\beta\)-sitosterol, \(\beta\)-amyrin, dausosterol, \(\beta\)-eudesmol, apigenin, farnesol, and myricetin) demonstrated high affinity binding to COX2. Moreover, the 60 NCI analyses have shown that \(\beta\)-sitosterol, \(\beta\)-eudesmol, and daucosterol were less effective on cancer cells compared to apigenin, myricetin, and farnesol. As we previously worked on apigenin and farnesol [55; 56], we turned our focus to myricetin in the present investigation. The latter compound was more active against colon and lung cancer than other tumor types. This correlated with previous studies revealing that colon and lung cancers, among other tumor types, exhibited excessive COX2 expression [77; 78]. More importantly, cell proliferation and anti-apoptosis effects were activated in colon cancer by the binding of prostaglandin E2 to its corresponding prostaglandin E2 receptor and to its respective G-protein, which stimulated the release of epidermal growth receptor (EGR) responsible for the activation of extracellular kinase ERK and the AKT/PI3 kinase pathway, and in lung cancer, the PGE2-EP1R-Gq complex triggered cell growth through the activation of phospholipase C and ERK [79]. An important aspect is that the expression of target proteins such as COX2 may not be of equal prognostic value in all cancer types. We mined the KM Plotter database to associate COX2 expression with survival times in various tumor types. This approach was recently also applied to antioxidant response genes and tumor suppressor genes [48; 80]. High COX2 expression was significantly associated with a shorter survival probability in renal clear cell carcinoma patients, indicating that COX2 inhibition by myricetin might positively affect the survival times for patients suffering from this tumor type. Here, we found that high COX2 expression in renal clear cell carcinoma was associated with shorter overall survival times for patients, and female patients with high COX2 expression died significantly earlier than those with low COX2 expression. Moreover, patients with a low neoantigen load and high COX2 expression had a worse survival prognosis than those with high COX2 expression. It can be speculated that patients with low neoantigen loads might be less susceptible to immunotherapy approaches than those with high neoantigen loads and, thus, might be more immunotherapy-resistant [47].