Retinoids, Interferon α, 1,25-dihydroxyvitamin D3 and their combination inhibit angiogenesis induced by non-HPV-harboring tumor cell lines. RARα mediates the antiangiogenic effect of retinoids

Retinoids combined with interferon α-2a (IFNα) or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] have shown marked synergistic inhibitory effects on angiogenesis induced by tumor cell lines harboring DNA of oncogenic human papillomaviruses (HPV) type 16 or 18. This report demonstrates comparable effects of these compounds on angiogenesis induced by non-HPV-bearing transformed cell lines, including breast carcinoma (T47D) and vulval carcinoma (A431) cell lines. Systemic treatment of mice with all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid, IFNα or 1,25(OH)2D3 significantly decreased tumor cell-induced angiogenesis (TIA). In vitro pretreatment of T47D and A431 cells with these compounds also led to inhibition of their angiogenic capability when tested in the TIA assay. The inhibitory effects of retinoids could be counteracted by a selective antagonist of the nuclear retinoic acid receptor RARα, suggesting a RARα mediated mechanism of angiogenesis inhibition. The antiangiogenic effect of retinoids could be significantly enhanced by combination with IFNα or 1,25(OH)2D3. The results provide a further basis for the use of combinations of retinoids with IFNα or 1,25(OH)2D3 in the treatment of angiogenesis-dependent malignancies.