Anti-neoplastic action of Cimetidine/Vitamin C on histamine and the PI3K/AKT/mTOR pathway in Ehrlich breast cancer

Abstract

The main focus of our study is to assess the anti-cancer activity of cimetidine and vitamin C via combating the tumor supportive role of mast cell mediators (histamine, VEGF, and TNF-α) within the tumor microenvironment and their effect on the protein kinase A(PKA)/insulin receptor substrate-1(IRS-1)/phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase-1 (AKT)/mammalian target of rapamycin (mTOR) cue in Ehrlich induced breast cancer in mice. In vitro study was carried out to evaluate the anti-proliferative activity and combination index (CI) of the combined drugs. Moreover, the Ehrlich model was induced in mice via subcutaneous injection of Ehrlich ascites carcinoma cells (EAC) in the mammary fat pad, and then they were left for 9 days to develop obvious solid breast tumor. The combination therapy possessed the best anti-proliferative effect, and a CI < 1 in the MCF7 cell line indicates a synergistic type of drug interaction. Regarding the in vivo study, the combination abated the elevation in the tumor volume, and serum tumor marker carcinoembryonic antigen (CEA) level. The serum vascular endothelial growth factor (VEGF) level and immunohistochemical staining for CD34 as markers of angiogenesis were mitigated. Additionally, it reverted the state of oxidative stress and inflammation. Meanwhile, it caused an increment in apoptosis, which prevents tumor survival. Furthermore, it tackled the elevated histamine and cyclic adenosine monophosphate (cAMP) levels, preventing the activation of the (PKA/IRS-1/PI3K/AKT/mTOR) cue. Finally, we concluded that the synergistic combination provided a promising anti-neoplastic effect via reducing the angiogenesis, oxidative stress, increasing apoptosis,as well as inhibiting the activation of PI3K/AKT/mTOR cue, and suggesting its use as a treatment option for breast cancer.