PMID- 35798765
OWN - NLM
STAT- MEDLINE
DCOM- 20220711
LR  - 20220914
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Jul 7
TI  - Anti-neoplastic action of Cimetidine/Vitamin C on histamine and the PI3K/AKT/mTOR 
      pathway in Ehrlich breast cancer.
PG  - 11514
LID - 10.1038/s41598-022-15551-6 [doi]
LID - 11514
AB  - 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-alpha) 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.
CI  - (c) 2022. The Author(s).
FAU - Ibrahim, Sherihan Salaheldin Abdelhamid
AU  - Ibrahim SSA
AUID- ORCID: 0000-0003-3467-5172
AD  - Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos 
      University in Alexandria, Alexandria, Egypt. sherihan.abdelhamid@pua.edu.eg.
FAU - El-Aal, Sarah A Abd
AU  - El-Aal SAA
AD  - Department of Pharmacy, Kut University College, Al Kut, Wasit, 52001, Iraq.
FAU - Reda, Ahmed M
AU  - Reda AM
AD  - Department of Pharmacy, Kut University College, Al Kut, Wasit, 52001, Iraq.
AD  - Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, 
      Badr City, Cairo, Egypt.
FAU - Achy, Samar El
AU  - Achy SE
AD  - Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, 
      Egypt.
FAU - Shahine, Yasmine
AU  - Shahine Y
AD  - Department of Microbiology & Immunology, Faculty of Pharmacy, Pharos University 
      in Alexandria, Alexandria, Egypt.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220707
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 80061L1WGD (Cimetidine)
RN  - 820484N8I3 (Histamine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - PQ6CK8PD0R (Ascorbic Acid)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - *Ascorbic Acid/pharmacology
MH  - *Breast Neoplasms/drug therapy
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - *Cimetidine/pharmacology
MH  - Female
MH  - Histamine/pharmacology
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tumor Microenvironment
MH  - Vascular Endothelial Growth Factor A/pharmacology
PMC - PMC9262990
COIS- The authors declare no competing interests.
EDAT- 2022/07/08 06:00
MHDA- 2022/07/12 06:00
PMCR- 2022/07/07
CRDT- 2022/07/07 23:20
PHST- 2022/01/26 00:00 [received]
PHST- 2022/06/24 00:00 [accepted]
PHST- 2022/07/07 23:20 [entrez]
PHST- 2022/07/08 06:00 [pubmed]
PHST- 2022/07/12 06:00 [medline]
PHST- 2022/07/07 00:00 [pmc-release]
AID - 10.1038/s41598-022-15551-6 [pii]
AID - 15551 [pii]
AID - 10.1038/s41598-022-15551-6 [doi]
PST - epublish
SO  - Sci Rep. 2022 Jul 7;12(1):11514. doi: 10.1038/s41598-022-15551-6.