Antitumor activity of PBI-1737 in xenograft human prostate PC-3 cancer by inhibition of cell adhesion and migration

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Cell adhesion, proteolytic degradation of extracellular matrix and cell migration are interrelated processes responsible for the invasion and metastasis of cancer. In prostate cancer, androgen-independence and bone metastasis are lethal complications in patients. PBI-1737 is a low molecular weight, orally active molecule that inhibits invasion and adhesion of androgen-independent human PC-3 cells. PBI-1737 demonstrated an inhibition of the EGF-induced PC-3 invasion in a two-dimension cell mobility assay. Furthermore, the addition of different concentrations of PBI-1737 induces in a dose dependent manner an inhibition of PC-3 cells adhesion to laminin, matrigel and collagen. The antitumor efficacy of oral administration of PBI-1737 with or without combination of cyclophosphamide on xenograft human prostate PC-3 tumor was also studied. Oral administration of PBI-1737 (50 mg/kg) induces a significant (p < 0.05) inhibition of tumor volume with a T/C between 14% to 40%. Cyclophosphamide (i.p., 100 mg/kg, once a week for 4 weeks) induces a significant inhibition (p < 0.05) of tumor volume with a T/C between 1% to 39%. Mice treated with the combination of cyclophosphamide and oral administration of PBI-1737 demonstrated a significant (p < 0.01) inhibition of tumor volume with a T/C between 1% to 40% accompanied with tumor regression. These in-vivo and in vitro data indicate that oral administration of PBI-1737 demonstrated significant antitumor activity via an inhibition of cell adhesion and migration of human prostate PC-3 cancer cells. A synergistic effect (regression of the tumor) is also observed with the combination of PBI-1737 and cyclophosphamide.