The potential role of anibamine, a natural product CCR5 antagonist, and its analogues as leads toward development of anti-ovarian cancer agents

Chemokines and their receptors play important roles in the development of primary tumors and their metastases. Particularly CC chemokine receptor 5 (CCR5) and its ligand CC chemokine ligand 5 (CCL5/RANTES) seem to be critical in proliferation and invasion of ovarian cancer, the leading cause of death from gynecological malignancies in the United States. Anibamine, the first natural product CCR5 antagonist, and its analogues were examined for their effects on proliferation of the OVCAR-3 ovarian cancer cells in order to validate their candidacy as leads to develop novel anti-ovarian cancer agents. Acting as CCR5 antagonists, anibamine and its analogues significantly suppressed CCL5-induced intracellular Ca(2+) flux. The compounds also inhibited the proliferation of OVCAR-3 at micromolar to submicromolar range. Moreover, anibamine and several analogues did not show significant cytotoxicity in NIH 3T3 cells at concentrations up to 20μM. Based on these results, anibamine and one of its synthetic analogues were defined as potential leads to develop novel agents against ovarian cancer.