Departments: Original ArticleApoptosis-Inducing Effect of Chemotherapeutic Agents Is Potentiated by Soy Isoflavone Genistein, a Natural Inhibitor of NF-κB in BxPC-3 Pancreatic Cancer Cell LineLi, Yiwei MD*; Ellis, Kerrie-Lynn BS*; Ali, Shadan MS†; El-Rayes, Basil F. MD†; Nedeljkovic-Kurepa, Ana MS*; Kucuk, Omer MD†; Philip, Philip A. MD†; Sarkar, Fazlul H. PhD* Author Information From the *Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan; †Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan. Received for publication October 14, 2003; accepted January 23, 2004. This work was partly funded by grants from the National Cancer Institute, NIH (1R01CA101870-01 and 5R01CA083695-03) to F.H.S. and also partly supported by a subcontract award (F.H.S.) from the University of Texas MD Anderson Cancer Center through a SPORE grant (1P20-CA010193-01, PP-SC1) on pancreatic cancer awarded to James Abbruzzese. We also sincerely thank Aventis Pharmaceuticals for their generous contribution to support this work. Reprints: Fazlul H. Sarkar, PhD, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 715 Hudson Webber Cancer Research Center, 110 E Warren, Detroit, MI 48201 (e-mail: [email protected]). Pancreas 28(4):p e90-e95, May 2004. Buy Abstract Cancer chemotherapeutic strategies should be devised to provide higher tumor response and lower toxicity for combination chemotherapy. Genistein has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. The antitumor effects of genistein could be in part due to inactivation of NF-κB activity. In contrast, chemotherapeutic agents inadvertently induce NF-κB activity, which may lead to chemoresistance. In this study, we investigated whether the inactivation of NF-κB by genistein would enhance the efficacy of chemotherapeutic agents. BxPC-3 pancreatic cancer cells were pretreated with 30 μmol/L genistein for 24 hours and then exposed to lower concentrations of chemotherapeutic agents for an additional 24 hours. Cell growth inhibition assay, apoptosis assay, and NF-κB EMSA were performed. The combination of 30 μmol/L genistein with 1 nmol/L docetaxel or 100 nmol/L cisplatin elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced more apoptosis in BxPC-3 cells compared with single agents. Moreover, the NF-κB activity was significantly increased within 2 hours of docetaxel or cisplatin treatment, and the NF-κB–inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results clearly suggest that genistein pretreatment, which inactivates NF-κB activity, together with other cellular effects of genistein, may contribute to increased cell growth inhibition and apoptosis inducing effects of nontoxic doses of docetaxel and cisplatin, which could be a novel strategy for the treatment of pancreatic cancer. © 2004 Lippincott Williams & Wilkins, Inc.