Inhibition of the AKT pathway with genistein combined polysaccharide (GCP) plus external beam radiation therapy (EBRT) in a prostate cancer (CaP) xenograft

Abstract

3135 Background: While EBRT is an effective treatment for primary CaP, many patients will fail biochemically within 5 years. Activation of the AKT pathway of survival has been identified in response to EBRT. Genistein, a primary component of GCP, is an isoflavone aglycone that acts as a protein kinase inhibitor. Single agent GCP inhibits CaP cell growth in vitro and in xenografts models. GCP-treated CaP cells have shown inhibition of the PI3-K/AKT pathway and our previous work showed near complete inhibition of colony formation after GCP + EBRT treatment. We hypothesized that combining a tyrosine kinase inhibitor, such as genistein, with EBRT would result in decreased activation of the AKT survival pathway and greater inhibition of tumor growth than EBRT alone. Methods: We examined the combination of GCP with EBRT in PC-3 xenografts. A clinically relevant dose of radiation (2 Gy) was used to determine either increased combined activity or antagonism by addition of GCP. PC-3 (5x106) cells were injected subcutaneously into Balb/c nu/nu mice. Tumors were treated with GCP alone, EBRT alone, GCP + EBRT, or were untreated. Animals receiving either GCP or GCP + EBRT therapy received daily oral doses of GCP (10% GCP in 0.1ml/10 kg body weight). Within 2 weeks after initial GCP treatment, animals in the EBRT and GCP + EBRT groups were irradiated locally at the tumor site (a single dose of 2Gy). Tumor volume was measured thrice weekly. Results: A reduction in tumor growth was seen in each of the single treatment groups GCP and EBRT (40%) versus untreated tumors up to 40 days. The combination of EBRT and GCP inhibited tumor growth (80%) versus untreated over the same time period. By day 70, 80% of GCP + EBRT-treated tumors showed a reduction in tumor volume with some tumors no longer measurable. Conclusion: 1) GCP + EBRT inhibited CaP tumor growth which was followed by tumor regressions in most animals. 2) These data support additional studies combining GCP with EBRT as a potential treatment for primary CaP. (Support: Amino Up Chemical Co., Ltd.) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amino Up Chemical Co., Ltd.