Anti-cancer Activity of Two Novel Heterocyclic Compounds through
Modulation of VEGFR and miRNA-122 in Mice Bearing Ehrlich Ascites
Carcinoma
Abstract
Background and Purpose: Metastasis in breast cancer is a leading cause
of mortality among women in many countries. This study investigated the
anti-cancer role of benzoimidazoquinazoline and benzimidazotriazin; two
novel compounds that were designed, synthesized, structurally
elucidated, and biologically evaluated as potent anti-angiogenic agents
that act through inhibition of vascular endothelial growth factor
receptor-2 (VEGFR2). A model of breast cancer was induced by inoculation
of Ehrlich Ascites Carcinoma (EAC) cells. Experimental Approach: Seventy
swiss albino mice were randomly divided into 7 groups, 10 animals each:
(1) normal, (2) control EAC group, (3) cisplatin treated group, (4&5)
benzoimidazoquinazoline treated (5mg/kg and 10mg/kg), (6&7)
benzimidazotriazin treated (5mg/kg and 10 mg/kg). The expression of
miRNA-122 was assessed in the tumor tissue by quantitative PCR, and the
VEGF level was determined in serum by ELISA. VEGFR2 and cluster of
differentiation (CD)34 were assessed by immunohistochemistry. Serum
levels of ALT, AST, creatinine, and urea were measured. Key Results:
Treatment with benzoimidazoquinazoline and benzimidazotriazin caused a
decrease in tumor weight and a significant decrease in the serum levels
of VEGF and the expression of VEGFR2 and CD34 in the tumor tissue.
MiRNA-122 was significantly upregulated especially in the group treated
by benzimidazotriazin (10mg/kg). Interestingly, the new compounds had
less renal toxicity compared to cisplatin. Conclusion and Implication:
The designed small molecules are promising anti-cancer candidates that
act through inhibition of angiogenesis and can provide a new strategy
for the advancement of chemotherapy through modulation of miRNA.