Enhanced anticancer activity of combined treatment of imatinib and dipyridamole in solid Ehrlich carcinoma-bearing mice
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.
KeywordsEhrlich 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.
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.
- Chiu C-F, Lai G-Y, Chen C-H, Chiu CC, Hung SW, Chang CF (2019) 6,7-Dihydroxy-2-(4′-hydroxyphenyl) naphthalene induces HCT116 cell apoptosis through activation of endoplasmic reticulum stress and the extrinsic apoptotic pathway. Drug Des Devel Ther Volume 13:1609–1621. https://doi.org/10.2147/DDDT.S193914 CrossRefGoogle Scholar
- Cristofanilli M, Morandi P, Krishnamurthy S, Reuben JM, Lee BN, Francis D, Booser DJ, Green MC, Arun BK, Pusztai L, Lopez A, Islam R, Valero V, Hortobagyi GN (2008) Imatinib mesylate (Gleevec) in advanced breast cancer-expressing C-kit or PDGFR-beta: clinical activity and biological correlations. Ann Oncol Off J Eur Soc Med Oncol 19:1713–1719. https://doi.org/10.1093/annonc/mdn352 CrossRefGoogle Scholar
- Haines DM, Chelack BJ (1991) Technical considerations for developing enzyme immunohistochemical staining procedures on formalin-fixed paraffin-embedded tissues for diagnostic pathologyGoogle Scholar
- Huang H-Y, Huang W-W, Lin C-N, Eng HL, Li SH, Li CF, Lu D, Yu SC, Hsiung CY (2006a) Immunohistochemical expression of p16INK4A, Ki-67, and Mcm2 proteins in gastrointestinal stromal tumors: prognostic implications and correlations with risk stratification of NIH consensus criteria. Ann Surg Oncol 13:1633–1644. https://doi.org/10.1245/s10434-006-9188-4 CrossRefPubMedGoogle Scholar
- Isacoff WH, Bendetti JK, Barstis JJ, Jazieh AR, Macdonald JS, Philip PA (2007) Phase II trial of infusional fluorouracil, leucovorin, mitomycin, and dipyridamole in locally advanced unresectable pancreatic adenocarcinoma: SWOG S9700. J Clin Oncol 25:1665–1669. https://doi.org/10.1200/JCO.2006.06.7637 CrossRefPubMedGoogle Scholar
- Legros L, Bourcier C, Jacquel A, Mahon FX, Cassuto JP, Auberger P, Pagès G (2004) Imatinib mesylate (STI571) decreases the vascular endothelial growth factor plasma concentration in patients with chronic myeloid leukemia. Blood 104:495–501. https://doi.org/10.1182/blood-2003-08-2695 CrossRefPubMedGoogle Scholar
- Magiorakos A-P, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL (2012) Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18:268–281. https://doi.org/10.1111/j.1469-0691.2011.03570.x CrossRefGoogle Scholar
- Mediavilla-Varela M, Luddy K, Noyes D, Khalil FK, Neuger AM, Soliman H, Antonia SJ (2013) Antagonism of adenosine A2A receptor expressed by lung adenocarcinoma tumor cells and cancer associated fibroblasts inhibits their growth. Cancer Biol Ther 14:860–868. https://doi.org/10.4161/cbt.25643 CrossRefPubMedPubMedCentralGoogle Scholar
- Mikami J, Kurokawa Y, Takahashi T, Miyazaki Y, Yamasaki M, Miyata H, Nakajima K, Takiguchi S, Mori M, Doki Y (2016) Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study. Gastric Cancer 19:817–826. https://doi.org/10.1007/s10120-015-0556-2 CrossRefPubMedGoogle Scholar
- Mirza A, Basso A, Black S, Malkowski M, Kwee L, Pachter JA, Lachowicz JE, Wang Y, Liu S (2005) RNA interference targeting of A1 receptor-overexpressing breast carcinoma cells leads to diminished rates of cell proliferation and induction of apoptosis. Cancer Biol Ther 4:1355–1360. https://doi.org/10.4161/cbt.4.12.2196 CrossRefPubMedGoogle Scholar
- Negi LM, Talegaonkar S, Jaggi M, Verma AK (2019) Hyaluronated imatinib liposomes with hybrid approach to target CD44 and P-gp overexpressing MDR cancer: an in-vitro , in-vivo and mechanistic investigation. J Drug Target 27:183–192. https://doi.org/10.1080/1061186X.2018.1497039 CrossRefPubMedGoogle Scholar
- Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, Huang X, Caldwell S, Liu K, Smith P, Chen JF, Jackson EK, Apasov S, Abrams S, Sitkovsky M (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 103:13132–13137. https://doi.org/10.1073/pnas.0605251103 CrossRefPubMedPubMedCentralGoogle Scholar
- Ozaslan M, Karagoz I, Kilic I, Guldur M (2002) African journal of biotechnology. Academic JournalsGoogle Scholar
- Rahman A, Makpol S, Jamal R, Harun R, Mokhtar N, Ngah WZ (2014) Tocotrienol-rich fraction, -Gingerol and epigallocatechin gallate inhibit proliferation and induce apoptosis of glioma cancer cells. Molecules 19:14528–14541. https://doi.org/10.3390/molecules190914528 CrossRefPubMedPubMedCentralGoogle Scholar
- Rosenzweig SA (2018) Acquired resistance to drugs targeting tyrosine kinases. Adv Cancer Res:71–98Google Scholar
- Shimada H, Chatten J, Newton WA et al (1984) Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. JNCI J Natl Cancer Inst 73:405–416. https://doi.org/10.1093/jnci/73.2.405 CrossRefPubMedGoogle Scholar
- Spano D, Marshall J-C, Marino N, de Martino D, Romano A, Scoppettuolo MN, Bello AM, di Dato V, Navas L, de Vita G, Medaglia C, Steeg PS, Zollo M (2013) Dipyridamole prevents triple-negative breast-cancer progression. Clin Exp Metastasis 30:47–68. https://doi.org/10.1007/s10585-012-9506-0 CrossRefPubMedGoogle Scholar
- Sumida T, Kitadai Y, Shinagawa K, Tanaka M, Kodama M, Ohnishi M, Ohara E, Tanaka S, Yasui W, Chayama K (2011) Anti-stromal therapy with imatinib inhibits growth and metastasis of gastric carcinoma in an orthotopic nude mouse model. Int J Cancer 128:2050–2062. https://doi.org/10.1002/ijc.25812 CrossRefPubMedGoogle Scholar
- van Meerloo J, Kaspers GJL, Cloos J (2011) Cell sensitivity assays: the MTT assay. Methods Mol Biol:237–245Google Scholar
- Weigel MT, Dahmke L, Schem C, Bauerschlag DO, Weber K, Niehoff P, Bauer M, Strauss A, Jonat W, Maass N, Mundhenke C (2010) In vitro effects of imatinib mesylate on radiosensitivity and chemosensitivity of breast cancer cells. BMC Cancer 10:412. https://doi.org/10.1186/1471-2407-10-412 CrossRefPubMedPubMedCentralGoogle Scholar
- Wu G, Lu J, Guo J, et al (2013) Synergistic anti-cancer activity of the combination of dihydroartemisinin and doxorubicin in breast cancer cells. 453–459Google Scholar
- Zhang WW, Cortes JE, Yao H, Zhang L, Reddy NG, Jabbour E, Kantarjian HM, Jones D (2009) Predictors of primary imatinib resistance in chronic myelogenous leukemia are distinct from those in secondary imatinib resistance. J Clin Oncol 27:3642–3649. https://doi.org/10.1200/JCO.2008.19.4076 CrossRefPubMedPubMedCentralGoogle Scholar