# COX2-Inhibitory and Cytotoxic Activities of Phytoconstituents of _Matricaria chamomilla_ L.
## 4 Discussion
Our findings suggest that targeting COX2 expression with compounds such as myricetin could be a promising strategy for improving the survival prognosis of patients with renal clear cell carcinoma, especially tumors with low neoantigen loads. It may be hypothesized that myricetin might be effective in this subgroup of patients. Furthermore, we also found from the oncobiogram analysis that myricetin may also inhibit tubulin and tyrosine kinases. Substantially, this finding has been reinforced with our obtained data from immunofluorescence microscopy of the effect of myricetin on \(\alpha\)-tubulin. Myricetin at concentrations of 0.1 and 1 \(\upmu\)M has blocked microtubule polymerization in a comparable manner as vincristine at 1 \(\upmu\)M. Microtubules are composed of tubulin. They are responsible for the maintenance and stabilization of endothelial cells. The discovery of novel tubulin inhibitors plays an important role in tumor vasculature-based therapies [81]. Hence, the inhibition of tubulin by myricetin may not only be linked to the inhibition of COX2 but also to the inhibition of endothelial cell responses. Interestingly, many authors suggested that COX2 and PGE2 may work together to activate receptor tyrosine kinases, which are involved in regulating cell growth and division, e.g., in colon cancer [82; 83]. In addition, COX2 overexpression in cancer cells elevated PGE2 production, which in turn activated vascular endothelial growth factor (VEGF) and/or other endothelial cell responses, promoting angiogenesis [73; 79; 84]. Additionally, in our analysis, we found that myricetin is not related to classical anticancer drug resistance mechanisms such as ATP-binding cassette (ABC) transporters (P-glycoprotein/ABCB1, ABCB5, ABCC1, ABCG2), tumor suppressors (TP53, WT1), or oncogenes (EGFR, RAS), except for glutathione S-transferase P (GSTP) and cellular proliferation rates. COX2 overexpression contributed to P-glycoprotein-mediated multidrug resistance via regulation of c-Jun N-terminal protein kinase (JNK), which phosphorylates the transcription factor c-Jun on its N-terminus at Ser63/73 (pc-Jun) in colorectal cancer [85]. This could be an explanation for the absence of cross-resistance of P-glycoprotein-expressing cells towards myricetin. WT1 is a tumor suppressor that produces different transcription factors that promote cell growth and survival. While its mutation has been initially linked to childhood kidney cancer (Wilms tumor), studies have suggested that WT1 can play either a promoting or inhibitory role in tumor formation and apoptosis in many tumor types [86; 87; 88]. A combined therapy targeting COX2 and WT1 has been proposed, as the two pathways have been shown to synergistically promote tumor cell proliferation in lung cancer. The authors found that suppressing the COX2 pathway with celecoxib increased WT1 expression, which may explain why myricetin did not appear to affect cross-resistance in WT1-expressing tumors [89]. Knocking down the WT1 gene led to an upregulation of COX2, particularly in [PERSON] tumors, suggesting that inhibiting COX2 in combination with other targeted treatments could be beneficial in treating cancer [90; 91]. P53 is also a tumor suppressor that regulates cell growth and promotes apoptosis (controlling cell cycle arrest) but, in parallel, also plays a crucial role in the progression of many cancer types when it is mutated. The _TP53_ gene is mutated in several cancer types, including lung and colon cancer, and regaining its functions is an important therapeutic approach in cancer [92; 93; 94]. Genotoxic stress-induced p53 activated the Ras/Raf/MAPK pathway that led to COX2 expression downstream [95]. Moreover, COX2 promoted tumorigenesis by inhibiting the transcriptional activity of normal functional p53 and DNA damage-induced apoptosis. Further, The COX2-inhibitor NS-398 blocked the interaction between COX2 and p53, which activated apoptosis [96]. It has been discussed that the crosstalk between COX2 and p53 happens through different pathways [97].