Down-regulation of Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 Expression by Soy Isoflavones Enhances Prostate Cancer Radiotherapy In vitro and In vivo

Abstract

We previously showed that genistein, the major bioactive component of soy isoflavones, acts as a radiosensitizer and potentiates prostate tumor cell killing by radiation in vitro and in animal tumor models in vivo. However, when given alone in vivo, pure genistein promoted increased lymph node metastasis, which was not observed with a soy isoflavone mixture consisting of genistein, daidzein, and glycitein. In this study, we show that soy inhibits tumor cell growth and potentiates radiation-induced cell killing in vitro like pure genistein. In an orthotopic model, combining soy isoflavones with tumor irradiation inhibited prostate tumor growth. To determine the molecular mechanisms by which soy isoflavones potentiate radiotherapy, we investigated apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) and nuclear factor KB (NF-KB), two signaling molecules involved in survival pathways. Soy isoflavones decreased APE1/Ref-1 expression in vitro, whereas radiation up-regulated it. Pretreatment with soy isoflavones followed by radiation inhibited APE1/Ref-1 expression. APE1/Ref-1 decrease correlated with decreased DNA-binding activity of NF-KB mediated by soy isoflavones and radiation, thus promoting cell killing. In vivo treatment of prostate tumors with soy isoflavones and radiation downregulated APE1/Ref-1 protein expression and NF-KB activity, confirming the molecular alterations observed in vitro. The down-regulation of APE1/Ref-1 and NF-KB by isoflavones, in vitro and in vivo, supports our hypothesis that these markers represent biological targets of isoflavones. Indeed, a 2-fold increase in APE1/Ref-1 expression, obtained by cDNA transfection, resulted in a 2-fold increase in NF-KB DNA-binding activity, and both of which were downregulated by soy isoflavones, confirming the cross-talk between these molecules and, in turn, causing radiosensitization. [Cancer Res 2007;67(5):2141-9]

Chimeric adenoviral vector Ad5/F35-mediated APE1 siRNA enhances sensitivity of human colorectal cancer cells to radiotherapy in vitro and in vivo

“…Several studies have reported that APE1 inhibitor could enhance conventional cancer treatment such as radiotherapy. 38,39 Our previous study has demonstrated that vector-based APE1 siRNA decreased specifically APE1 levels and enhanced the chemosensitivity of multiple myeloma to melphalan. 40 The present study is the first to confirm that adenovirus-mediated transfer of APE1 siRNA enhances sensitivity of human CRC cells to radiotherapy in vitro and in vivo.…”

Multi-targeted therapy of cancer by genistein

“…Moreover, Raffoul et al reported that genistein also enhanced prostate cancer radiotherapy through the downregulation of apurinic-apyrimidine endonuclease 1/redox factor-1 expression [85]. Among the STAT family of transcription proteins, constitutive activation of STAT-3 and STAT-5 has been identified as responsible for cell survival and growth by preventing apoptosis through increased expression of antiapoptotic proteins such as Bcl-2 and Bcl-x L .…”

Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor

“…These findings suggest that antiresistance chemotherapeutic targeting AP endo activity is pharmacologically tractable and potentially efficacious. Additionally, it has been confirmed that soy isoflavones, resveratrol and E3330 have effects on perturbing APE1/Ref-1 levels/function (21,28,35,39).…”

“…It was shown that potent downregulation of APE1/Ref-1 with siRNA arrests cell proliferation and causes apoptosis with accumulation of abasic DNA damage in several human cell lines (33). APE1/Ref-1 has been implied to have a key role in regulation of p53 transcriptional activity by both redox-dependent andindependent means (34), and the ability of p53 to induce apoptosis is affected by APE1/Ref-1 levels (34,35). A potential link has been found between APE1/Ref-1 expression and p53 status in different tumors with their resistance to chemotherapeutic drugs (36).…”