Targeting MDR-1 gene expression, BAX/BCL2, caspase-3, and Ki-67 by nanoencapsulated imatinib and hesperidin to enhance anticancer activity and ameliorate cardiotoxicity.

Abstract

There is a great demand to introduce new approaches into cancer treatment field due to incidence of increased breast cancer all over the world. The current study was designed to evaluate the role of imatinib mesylate (IM) and/or hesperidin (HES) nanoparticles alone or in combination in enhancing the anticancer activity and to investigate the ability of nanoencapsulation to reduce cardiotoxicity of IM in solid Ehrlich carcinoma (SEC)-bearing mice. IM and HES were loaded into PLGA (poly(lactic-co-glycolic acid) polymer. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n=10). On day 28 from tumor inoculation, mice were sacrificed and blood samples were collected in heparinized tubes for hematological studies, biochemical determination of lactate dehydrogenase (LDH), and glutamic oxaloacetic transaminase (SGOT) levels. In addition, tumor and cardiac tissues were utilized for histopathological examination as well as determination of MDR-1 gene expression. Immunohistochemical staining of BAX and BCL-2 was done. Nano IM- and/or Nano HES-treated groups showed a significant reduction in tumor volume, weight, hematological, cardiac markers, and tumor MDR-1 gene downregulation compared to free conventional treated groups. In conclusion, the use of HES as an adjuvant therapy with IM could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, nanoencapsulation of IM and/or HES with PLGA polymer showed a remarkable anticancer activity.