The impact of a novel vicenin-2 and oral docetaxel combinatorial regimen in androgen-independent prostate cancer.

Abstract

e13534 Background: A major challenge in the management of androgen-independent prostate cancer (AIPC) is the emergence of dose-limiting toxicities like febrile neutropenia while on i.v. docetaxel (DTL) treatment which has lead to investigation of alternate routes of DTL administration and drug combinations. Hence, we tested the potency of a novel flavonoid vicenin-2 (VCN-2) alone and in combination with oral DTL in AIPC. Methods: Cell survival was tested at various drug concentrations to determine in vivo doses by MTT and colony forming assays in PC-3 cells which have been established from the bone metastases of a 62 yr old male Caucasian with grade IV metastatic AIPC. Protein levels were analyzed by Western blot. For in vivo model studies, nu/nu nude mice (n=20) were implanted with 2 x 106 PC-3 cells subcutaneously into one flank and divided in to 4 groups. From tenth day after implantation, each group (n=5) were treated with corn oil (control), VCN-2 (3 mg/m2), DTL (0.03 mg/m2) and VCN-2 plus DTL in corn oil orally on alternate day. Tumor growth and body weight were monitored everyday. On day 60, tumors were excised for histopathological examination. Results: VCN-2 alone inhibited the survival of AIPC (p<0.01). The combination of VCN-2 and DTL induced synergistic effect in AIPC both in vitro and in vivo (~90% inhibition, CI <1 [Chou-Talalay test], p<0.0001). Tumor lysate analysis revealed that VCN-2 and DTL inhibited critical signaling proteins like pIGF1R, pRb, pAkt, PCNA and cyclin D1 to a greater extent in combination than either drugs alone. Histology of tumor sections revealed decreased levels of PSMA, ki67, CD31 and increase in the pro-differentiation marker E-cadherin. No overt toxicity was observed due to co-administration of VCN-2 and DTL. Conclusions: Oral administration of VCN-2 and DTL is effective and tolerable in vivo model of advanced AIPC. The salient feature of this study was the potent synergistic effect of VCN-2 and a low dose of DTL (0.03 mg/m2 of DTL and 3 mg/m2 of VCN-2 orally on alternate days compared to clinical dose in AIPC: 75 mg/m2 of DTL i.v. once in 3 wks. plus 5 mg prednisone twice daily) which strongly supports further development of VCN-2 and DTL combinatorial regimens for clinical use in AIPC.