Harmaline downregulates angiogenesis markers and suppresses the growth of 4T1 breast cancer cells in vivo and in vitro

The anti-angiogenic effects of harmaline, an alkaloid with emerging anti-tumor properties, are under investigation. In the present study, the effects of different doses of harmaline, either alone or in combination with doxorubicin (DOX), were assessed in mice models of breast tumor. Breast tumors were created by the subcutaneous injection of 4T1 cells into Balb/c mice. The mice received either normal saline, harmaline alone (10, 20, or 30 mg/kg), or harmaline (20 mg/kg) + DOX (10 mg/kg). Immunohistochemistry, ELISA, and real-time PCR were conducted to measure target parameters. Harmaline significantly increased tumor cells' sensitivity to DOX as confirmed by a significantly reduced tumor volume in the harmaline + DOX group after 24 days (P < 0.05). Also, the levels of Ki-67 (P < 0.001), MMP-2 (P < 0.001), and VEGF (P < 0.001) significantly decreased while the level of E-cadherin increased (P < 0.001) in the tumor tissues of the mice treated with 20 or 30 mg/kg harmaline or harmaline (20 mg/kg) + DOX (10 mg/kg) compared to the control group. There was a significant reduction in the serum level of IL-4 in tumor-bearing mice treated with harmaline (P < 0.05), and IFN-γ serum level was significantly augmented in all experimental groups compared to the control group (P < 0.05). The genes encoding VEGF, VEGF receptor 2, CD105, and COX2 were significantly down-regulated (P < 0.05 for all) in harmaline-treated (either alone or in combination with DOX) mice. In conclusion, harmaline seems to have the potential to be used as an anticancer agent for treating breast cancer.