Abstract 5180: Effects of soy isoflavones and SRC inhibitors on metastatic activity in prostate cancer

Abstract

Abstract Background: In advanced prostate cancer (PCa), cells escape from the primary tumor and enter the bloodstream, preferentially targeting the bone. This results in weakened bones, spinal compressions, fractures and intense pain. Efforts to interfere with early steps in the metastatic cascade by affecting the tumor microenvironment have led to the development of promising small molecule targeting agents. The tyrosine kinase inhibitors, saracatinib and dasatinib, have been shown to inhibit activation of Src and downstream effectors thought to be involved in cancer cell dissemination. Soy-derived isoflavones (ISFs) have been shown to have cytostatic effects on PCa cells without toxicity. Aim: The aim of these studies was to determine if ISFs enhance the effects of Src inhibitors on PCa cells, resulting in lower doses of these agents needed to produce optimum results. Methods: PC-3 ML and LNCaP cells were treated with either a Src inhibitor (dasatinib or saracatinib), a soy isoflavone extract (ISFs), or a combination. Modified Boyden transwell chambers were used to evaluate migration and invasion. Cell cycle and proliferation were measured using FACS analyses and trypan blue staining, respectively. Results: ISFs and Src inhibitors did not cause cytotoxicity or reduce proliferation. However, Src inhibitors produced an increase in cells in G1 phase, while ISFs increased cells in G2/M phase. When ISFs were combined with Src inhibitors, both phases were increased with a concomitant decrease in S phase cells. In transwell migration studies, all agents significantly decreased the number of cells found on the bottom of the membrane: dasatinib>saracatinib>ISFs. Lower doses of Src inhibitors were needed to produce inhibition of migration when ISFs were added to the treatment. Invasion studies with PC-3 ML and LNCaP cells suggest that ISFs can reduce metastatic activity by 39% and 35%, respectively. Therefore, by adding ISFs, lower doses of inhibitors might be used to achieve optimal response and decrease toxicity. Conclusions: In vitro studies suggested that a combination of a Src inhibitors and ISFs, at non-cytotoxic doses, results in greater inhibition of metastatic or invasion activity than either alone. Further studies are needed to determine if this strategy could be used clinically to treat patients with lower doses of small molecule inhibitors by including soy isoflavone concentrates in the treatment regimen. Citation Format: Lori P. Rice, Dietmar W. Siemann. Effects of soy isoflavones and SRC inhibitors on metastatic activity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5180. doi:10.1158/1538-7445.AM2017-5180