## 4 Discussion
### Selectivity Index of S. triloba for U2 OS and SKOV3 Cells
RUNX2 is also often upregulated in epithelial ovarian cancer tissue and this overexpression is generally associated with poor prognosis [81]. RUNX2 is further involved in regulating the transcription of multiple luteal related genes in murine ovaries, indicating that it likely plays vital roles in ovarian homeostasis [82]. Overall, RUNX2 is known to modulate diverse pathways such as those involved in cell proliferation, migration, and invasion [80]. p53, another key transcription factor implicated in cancer, serves to halt the proliferation of cells that either possess genetic alterations or are stressed [83]. One pathway by which p53 exerts its anti-proliferation effect is via induction of the intrinsic apoptotic pathway through the pro-apoptotic protein, BAX [84; 85]. p53 mediates BAX expression either directly or indirectly through the Bcl-2 family protein Puma [86]. BAX mediates the principal event of the intrinsic apoptotic pathway, which is the release of cytochrome c from the mitochondria into the cytosol, ultimately leading to cell death [87; 88]. Additionally, p53 activity is regulated by multiple posttranslational modifications that influence its stability. The principle antagonist of p53 is the E3 ubiquitin ligase, MDM2 that marks p53 for proteasomal degradation. MDM2 thus maintains low p53 levels through an autoregulatory negative feedback loop with p53. Conversely the methyl transferase, SETD7, is reported to regulate various genes including p53. SETD7 promotes p53 stabilization along with inhibiting its nuclear export via p53 methylation [89]. Several studies have suggested that SETD7 methylation is essential for p53 activity, however there is growing evidence that by itself, SETD7 could be insufficient for p53 activation, and that its absence is likely compensated for by other pathways that are yet to be discovered [90]. Similarly, the PI3K/AKT pathway is often over activated in several cancers, including both osteosarcoma and ovarian cancer. The PI3K/AKT pathway is reported to promote cell proliferation, migration, invasion, tumorigenesis, metastasis and chemo-resistance [91; 92]. Aberrations in the PI3K/AKT pathway are most likely essential for the development and progression of both osteosarcoma and ovarian cancer, since alterations in the pathway were reported in 100% of advanced-stage osteosarcoma and 70% of ovarian cancer cases [91; 92]. Finally, the \(\beta\)-catenin pathway plays a critical role in regulating various cellular processes such as cell fate, polarity, and migration, in addition to neural development, and organogenesis during embryonic development [93]. This pathway is regulated by Wnt glycoproteins which initiate a signaling cascade that eventually leads to phosphorylation of the \(\beta\)-catenin destruction complex and accumulation of unphosphorylated \(\beta\)-catenin. Unphosphorylated \(\beta\)-catenin functions as a coactivator of several downstream target genes when translocated to the nucleus [94; 95]. Aberrant Wnt signaling is reported to either initiate or drive the progression of a variety of cancers including colorectal cancer [96], breast cancer [97], hepatocellular carcinoma (HCC) [98], as well as bone [99] and ovarian cancer [100]. \(\beta\)-catenin deregulation is further reported in SKOV3 cells, and mechanisms for deregulation include either mutations in the CTNNB1 gene that encode \(\beta\)-catenin, or mutational inactivation of the \(\beta\)-catenin destruction complex proteins (APC, AXIN1, and AXIN2) [101]. Several plant-based bioactive compounds have been reported to affect gene expression by modulating various interrelated oncogenic transcription factors including RUNX2, p53, and Wnt/B-catenin [102; 103; 104; 105; 106]. RUNX2 was implicated in p53 regulation after DNA damage by possibly interacting with HDAC6 to impede p53 mediated pro-apoptotic activity [107; 108]. It was further suggested that RUNX2 neutralizes p53 activity through its ability to prevent p53 induced apoptosis [109].