Enhanced anticancer activity of combined treatment of imatinib and dipyridamole in solid Ehrlich carcinoma-bearing mice

  • Alaa E. El-Sisi
  • Samia S. Sokar
  • Hanaa A. IbrahimEmail author
  • Sally E. Abu-Risha
Original Article


The current study was designed to evaluate potential enhancement of the anticancer activity of imatinib mesylate (IM) with dipyridamole (DIP) and to investigate the underlying mechanisms of the combined therapy (IM/DIP) to reduce hepatotoxicity of IM in solid Ehrlich carcinoma (SEC)-bearing mice. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into seven groups (n = 10): SEC vehicle, IM50 (50 mg/kg), IM100 (100 mg/kg), DIP (35 mg/kg), a combination of IM50/DIP and IM100/DIP. On day 28th, mice were sacrificed and blood samples were collected for hematological studies. Biochemical determination of liver markers was evaluated. Glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT) and alkaline phosphatase (ALP) levels were assessed. In addition, MDR-1 gene expression and immunohistochemical staining of BAX and BCL-2 was done. Also, in vitro experiment for determination of IC50 of different treatments and combination index (CI) were assessed in both MCF-7 and HCT-116 cell lines. IM- and/or DIP-treated groups showed a significant reduction in tumor volume, weight, and serum levels of SGOT, SGPT, and AIP compared to vehicle group. In addition, reduction of VEGF, Ki67, and adenosine contents was also reported by treated groups. Also, IM/DIP combination showed lower IC50 than monotherapy. Combination index is less than 1 for IM/DIP combination in both cell lines. DIP as an adjuvant therapy potentiated the cytotoxic effect of IM, ameliorated its hepatic toxicity, and showed synergistic effect with IM in vitro cell lines. Furthermore, the resistance against IM therapy may be overcome by the use of DIP independent on mdr-1 gene expression.


Ehrlich carcinoma Imatinib Mesylate Dipyridamole Hepatotoxicity MDR-1, p-GP 



The authors acknowledge Dr. Mohammed Fawzy, professor of pathology, faculty of medicine, Mansoura University. Also, the authors acknowledge Dr. Eman G. Khedr, professor of Biochemistry, Faculty of Pharmacy, Tanta University; Dr. El-Zeiny M. Ebeid professor of Physical Chemistry, Faculty of Science, Tanta University; and prof. Abdel-Aziz A. Zidan, Zoology Department, Faculty of Science, Damanhour University, Egypt and also worked at Center of Excellence in cancer Research (CECR), Tanta University, Tanta, Egypt for their valuable assistance and evaluation of histopathological studies, biochemical and genetic work, respectively.

Authors’ contributions

El-Sisi and Sokar conceived and designed the experiments, conducted the experiments, analyzed the data, and composed the manuscript. Abu-Risha and Ibrahim contributed reagents, materials, and analysis tools. All the authors read and approved the final manuscript.

Compliance with ethical standards

The experimental work described in this study complies with guidelines for the care and the use of laboratory animals and the ethical principles adopted by the “Research Ethics Committee”, Faculty of pharmacy, Tanta University.

Conflict of interest

The authors declare that there are no conflicts of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Alaa E. El-Sisi
    • 1
  • Samia S. Sokar
    • 1
  • Hanaa A. Ibrahim
    • 1
    Email author
  • Sally E. Abu-Risha
    • 1
  1. 1.Department of Pharmacology and Toxicology, college of pharmacyUniversity of TantaTantaEgypt

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