الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Breast cancer is the second most common cause of cancer mortality among women. Breast cancer development is a multi-step process involving numerous cell types, and prevention remains a global challenge. Early detection of breast cancer is one of the most effective ways to avoid the illness. Because of early detection, the 5-year relative survival rate of breast cancer patients in certain industrialized nations exceeds 80%. In the last decade, significant progress has been achieved in both the knowledge of breast cancer and the development of prevention measures.
PI3K/AKT/mTOR pathway is recognized to be peculiarly triggered in abundant human cancers including breast cancer (Kamal, Nayak et al. 2016). This pathway has a dominant role in numerous biological processes encompassing: proliferation, growth, survival and metabolism and there is now substantial evidence that different elements of this pathway are validated as possible cancer therapy molecular targets as indicated by preceding studies. (Vara, Casado et al. 2004, Garcia-Echeverria and Sellers 2008, Yap, Garrett et al. 2008). Moreover, biological studies have revealed that deregulated signaling through the PI3K/AKT/mTOR pathway has been linked to endocrine-resistance and hence sensitivity towards endocrine treatment can be restored by targeting this pathway (Yu, Toral-Barza et al. 2001, Clark, West et al. 2002, Shoman, Klassen et al. 2005).
In her-2 enriched breast cancer, growth and survival signals triggered by activated HER-2 are largely mediated via PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling (Ortega, Fraile-Martínez et al. 2020). Evidences recommend that Ras/Raf/MEK/ERK pathway is aberrantly stimulated in breast cancer with great frequency, especially through upstream activation of epidermal growth factor receptor (EGFR), hence enormous concern has been assigned on manipulating this pathway (Friday and Adjei 2008, Ahmad and Sarkar 2013).
TNBC is distinguished by the lack of expression of ER and progesterone receptor (PR) as well as the absence of HER-2 (Schmadeka, Harmon et al. 2014, Massihnia, Galvano et al. 2016). Hence, successful targeted therapy against TNBC is not approved due to lack of specific oncogene driver (Massihnia, Galvano et al. 2016). Therefore, looking for new alternative activities for natural or synthetic candidates modulating pathways involved in carcinogenesis is required.
Combretastatin A4 is a cis-stilbene that was discovered in 1989 in the South African bushwillow tree (Pettit, Singh et al. 1989). CA4 and its related chemical, colchicine, are members of the colchicinoids family of substances. CA4 has been discovered to be a powerful microtubule targeting drug capable of significantly suppressing cancer cell growth in vitro during the last several decades. CA4P’s inability to cause tumour regression in human patients has been attributed to its short half-life in the human body, which is generally two to three hours, as well as its intrinsic conformational instability (Lu, Chen et al. 2012).
CA-4 exhibits potent cytotoxicity against several human cancer cells. CA-4 exerts its activity through inhibiting tubulin polymerization as it binds to the colchicine binding site of β-tubulin. In vivo, CA- 4 shows a drastic decrease in its activity because the cisoid configuration is isomerized into trans form. In this respect, several research groups introduced various heterocyclic rings (oxadiazoles, triazoles, imidazoles, and thiadiazoles) to restrict the emerged rotation of the olefinic double bond (Tron, Pirali et al. 2006).
In this study, we analyzed the anti-cancer effect of novel CA-4 (OMA1520) analogue in human breast cancer cells and the molecular mechanism underlying it’s effect was also elucidated.
The cytotoxic effect of OMA1520 on MCF-7, MDA-MB231 and MDA-MB453 was evaluated the results showed that OMA1520 was more potent that CA-4 in terms of toxicity. Components of PI3K/AKT/mTOR and RAS /RAF/MEK/ERK pathways was evaluated using western blotting. Results showed that treatment with OMA1520 down-regulated p-PI3K, p-AKT, p-MEK and p-ERK. Furthermore, gene expression studies showed a drastic down regulation of PIA3K, AKT, MEK1 MEK2, ERK1 and ERK2 expression following OMA1520 treatment.
In conclusion, this investigation showed that OMA1520 inhibited the growth of the breast cancer cell line (MCF-7, MDA-MB231 and MDA-MB453) and showed that this rational designed new synthetic CA4 analogue is more potent than the parent CA-4. The antiproliferative activity of OMA1520 is mediated via dually inhibiting the two most predominant signaling pathways: PI3K/Akt/mTOR and RAS/RAF/MEK/ERK. Hence, OMA1520 can be considered as potential anticancer drug for the effective treatment of breast cancer.