Acknowledgments Majority of the work presented in this paper was performed at University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA. Mechanistic and in vivo experiments were performed at Texas Tech University Health Sciences Center, Amarillo, TX. Technical help of Srinivas Reddy Boreddy and Kartick C. Pramanik with the in vivo experiment is greatly appreciated. References 1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60: 277–300. 2. Bast RC, Xu FJ, Yu YH, Barnhill S, Zhang Z, et al. (1998) CA 125: the past and the future. Int J Biol Markers 13: 179–187. 3. Ozols RF, Bookman MA, du Bois A, Pfisterer J, Reuss A, et al. (2006) Intraperitoneal cisplatin therapy in ovarian cancer: comparison with standard intravenous carboplatin and paclitaxel. Gynecol Oncol 103: 1–6. 4. Zeineldin R, Muller CY, Stack MS, Hudson LG (2010) Targeting the EGF receptor for ovarian cancer therapy. J Oncol 2010: 414676. 5. Nicholson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37 Suppl 4: S9–15. 6. Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi H, et al. (1995) Epidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer 31A: 178–183. 7. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, et al. (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284: 31–53. 8. Turner T, Chen P, Goodly LJ, Wells A (1996) EGF receptor signaling enhances in vivo invasiveness of DU-145 human prostate carcinoma cells. Clin Exp Metastasis 14: 409–418. 9. Ahmed N, Maines-Bandiera S, Quinn MA, Unger WG, Dedhar S, et al. (2006) Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. Am J Physiol Cell Physiol 290: C1532– 1542. 10. Casanova ML, Larcher F, Casanova B, Murillas R, Fernandez-Acenero MJ, et al. (2002) A critical role for ras-mediated, epidermal growth factor receptor- dependent angiogenesis in mouse skin carcinogenesis. Cancer Res 62: 3402– 3407. 11. Lu Z, Jiang G, Blume-Jensen P, Hunter T (2001) Epidermal growth factor- induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol 21: 4016–4031. 12. Perrimon N (1994) Signalling pathways initiated by receptor protein tyrosine kinases in Drosophila. Curr Opin Cell Biol 6: 260–266. 13. Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A (2001) The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer 8: 11–31. 14. Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, et al. (2004) AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23: 5853–5857. 15. Gao N, Flynn DC, Zhang Z, Zhong XS, Walker V, et al. (2004) G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/ mTOR/p70S6K1 signaling in human ovarian cancer cells. Am J Physiol Cell Physiol 287: C281–291. 16. Boreddy SR, Pramanik KC, Srivastava SK (2011) Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway. Clin Cancer Res 17: 1784–1795. 17. Bosetti C, Negri E, Franceschi S, Pelucchi C, Talamini R, et al. (2001) Diet and ovarian cancer risk: a case-control study in Italy. Int J Cancer 93: 911–915. 18. Zhang M, Yang ZY, Binns CW, Lee AH (2002) Diet and ovarian cancer risk: a case-control study in China. Br J Cancer 86: 712–717. 19. Hecht SS (1996) Chemoprevention of lung cancer by isothiocyanates. Adv Exp Med Biol 401: 1–11. 20. Boreddy SR, Sahu RP, Srivastava SK (2011) Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-alpha/VEGF/ Rho-GTPases: pivotal role of STAT-3. PLoS One 6: e25799. 21. Kim SH, Sehrawat A, Sakao K, Hahm ER, Singh SV (2011) Notch activation by phenethyl isothiocyanate attenuates its inhibitory effect on prostate cancer cell migration. PLoS One 6: e26615. 22. Yan H, Zhu Y, Liu B, Wu H, Li Y, et al. (2011) Mitogen-activated protein kinase mediates the apoptosis of highly metastatic human non-small cell lung cancer cells induced by isothiocyanates. Br J Nutr 106: 1779–1791. 23. Huong le D, Shim JH, Choi KH, Shin JA, Choi ES, et al. (2011) Effect of beta- phenylethyl isothiocyanate from cruciferous vegetables on growth inhibition and apoptosis of cervical cancer cells through the induction of death receptors 4 and 5. J Agric Food Chem 59: 8124–8131. 24. Kandala PK, Srivastava SK (2012) Regulation of macroautophagy in ovarian cancer cells in vitro and in vivo by controlling Glucose regulatory protein 78 and AMPK. Oncotarget. PEITC Targets EGFR to Suppress Ovarian Cancer Author Contributions Conceived and designed the experiments: SKS. Performed the experi- ments: SL PKK PG. Analyzed the data: SL PKK PG SKS. Wrote the paper: PKK SKS. 25. Kandala PK, Srivastava SK (2010) Activation of checkpoint kinase 2 by 3,39- diindolylmethane is required for causing G2/M cell cycle arrest in human ovarian cancer cells. Mol Pharmacol 78: 297–309. 26. Kandala PK, Srivastava SK (2012) Diindolylmethane suppresses ovarian cancer growth and potentiates the effect of cisplatin in tumor mouse model by targeting signal transducer and activator of transcription 3 (STAT3). BMC Med 10: 9. 27. Pramanik KC, Srivastava SK (2012) Apoptosis Signal-Regulating Kinase 1- Thioredoxin Complex Dissociation by Capsaicin Causes Pancreatic Tumor Growth Suppression by Inducing Apoptosis. Antioxid Redox Signal. 28. Galbaugh T, Cerrito MG, Jose CC, Cutler ML (2006) EGF-induced activation of Akt results in mTOR-dependent p70S6 kinase phosphorylation and inhibition of HC11 cell lactogenic differentiation. BMC Cell Biol 7: 34. 29. Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, et al. (2007) PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 117: 730–738. 30. Beugnet A, Wang X, Proud CG (2003) Target of rapamycin (TOR)-signaling and RAIP motifs play distinct roles in the mammalian TOR-dependent phosphorylation of initiation factor 4E-binding protein 1. J Biol Chem 278: 40717–40722. 31. Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, et al. (2003) The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 278: 15461–15464. 32. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098–1101. 33. Bull Phelps SL, Schorge JO, Peyton MJ, Shigematsu H, Xiang LL, et al. (2008) Implications of EGFR inhibition in ovarian cancer cell proliferation. Gynecol Oncol 109: 411–417. 34. Flynn JF, Wong C, Wu JM (2009) Anti-EGFR Therapy: Mechanism and Advances in Clinical Efficacy in Breast Cancer. J Oncol 2009: 526963. 35. Sherwood ER, Van Dongen JL, Wood CG, Liao S, Kozlowski JM, et al. (1998) Epidermal growth factor receptor activation in androgen-independent but not androgen-stimulated growth of human prostatic carcinoma cells. Br J Cancer 77: 855–861. 36. Alper O, Bergmann-Leitner ES, Bennett TA, Hacker NF, Stromberg K, et al. (2001) Epidermal growth factor receptor signaling and the invasive phenotype of ovarian carcinoma cells. J Natl Cancer Inst 93: 1375–1384. 37. Chen A, Xu J, Johnson AC (2006) Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene 25: 278–287. 38. Milligan SA, Burke P, Coleman DT, Bigelow RL, Steffan JJ, et al. (2009) The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells. Clin Cancer Res 15: 4885–4894. 39. Watanabe H, Kanno H (1998) Experimental studies of the protective effect of deferoxamine mesilate on cisplatin induced toxicity. Nippon Jibiinkoka Gakkai Kaiho 101: 967–978. 40. Rho JK, Choi YJ, Jeon BS, Choi SJ, Cheon GJ, et al. (2010) Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation. Mol Cancer Ther 9: 3233–3243. 41. Stewart JR, O’Brian CA (2004) Resveratrol antagonizes EGFR-dependent Erk1/2 activation in human androgen-independent prostate cancer cells with associated isozyme-selective PKC alpha inhibition. Invest New Drugs 22: 107– 117. 42. Thoennissen NH, O’Kelly J, Lu D, Iwanski GB, La DT, et al. (2010) Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene 29: 285–296. 43. Kandala PK, Wright SE, Srivastava SK (2012) Blocking epidermal growth factor receptor activation by 3,39-diindolylmethane suppresses ovarian tumor growth in vitro and in vivo. J Pharmacol Exp Ther 341: 24–32. 44. Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, et al. (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10: 241–252. 45. Satyan KS, Swamy N, Dizon DS, Singh R, Granai CO, et al. (2006) Phenethyl isothiocyanate (PEITC) inhibits growth of ovarian cancer cells by inducing apoptosis: role of caspase and MAPK activation. Gynecol Oncol 103: 261–270. 46. Cowley S, Paterson H, Kemp P, Marshall CJ (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77: 841–852. PLOS ONE | www.plosone.org 10 August 2012 | Volume 7 | Issue 8 | e43577