NATURAL COMPOUNDS AND THEIR ROLE IN APOPTOTIC CELL SIGNALING PATHWAYS Effect of Epidermal Growth Factor Receptor Inhibitor Alone and in Combination with Cisplatin on Growth of Vulvar Cancer Cells Su-Hyeon Kim, a Yoo-Cheol Song, a Su-Hyeong Kim, a Hoenil Jo, b and Yong-Sang Song a,b,c a Cancer Research Institute, b Department of Obstetrics and Gynecology, College of Medicine, and c Major in Biomodulation, World Class University, Seoul National University, Seoul, Korea A recent study reported on the efficacy of the EGFR inhibitor on locally advanced vulvar cancer. The aim of this study was to evaluate the effect of an EGFR tyrosine kinase inhibitor (AG1478) alone and in combination with cisplatin on vulvar cancer cells (A431 and SW962). We detected overexpression of EGFR in A431 cells and low expression in SW962 cells. We found that the growth inhibitory effect of AG1478 was dependent upon the expression level of EGFR. The combined treatment of AG1478 with cisplatin failed to exert any synergistic or additive effect in either cell line. In the EGFR signaling pathway, AG1478 decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) in parallel with decreased activity of EGFR in A431 cells, while no changes in ERK and Akt were observed in SW962 cells. The combination of AG1478 with cisplatin completely inhibited the phosphorylation of ERK and Akt in A431 cells but not in SW962 cells. Cisplatin alone and its combination with AG1478 increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) in both cell lines. In summary, AG1478 inhibited the growth activity of vulvar cancer cells, depending upon the expression level of EGFR, by inhibiting the activities of EGFR, Akt, and ERK. Given the absence of synergistic effects from the combination of AG1478 with cisplatin, combination therapy should be considered cautiously. Key words: EGFR; AG1478; cisplatin; vulvar cancer Introduction Vulvar cancer represents approximately 3– 5% of all gynecologic cancers. 1,2 Early de- tection followed by surgery has the best cur- ability potential in vulvar cancer. 3,4 However, around 30% of patients with vulvar cancer eventually experience relapse, 5–7 which often poses a challenge in therapeutic decisions. Al- though local recurrences could be managed properly with a surgical reexcision, there are a subset of patients who develop multiple local Address for correspondence: Yong-Sang Song, M.D., Ph.D., Depart- ment of Obstetrics and Gynecology, Seoul National University College of Medicine, 28 Yongun-dong, Chongno-gu, Seoul, 110-744, Korea. Voice: 82-2-2072-2822; fax: 82-2-3668-7401. yssong@snu.ac.kr recurrences that are difficult to manage and ultimately lead to deaths. 8 For relapsed pa- tients there is no standard therapy with lim- ited use of chemotherapeutic agents. Also, cur- rent chemotherapy for recurrent vulvar cancer produces a modest impact on survival. There- fore, new agents, or a combination of new or old agents, are obviously needed to improve survival. One of the strategies is identifying novel molecular targets, thus combining a new agent with conventional treatment for vulvar cancer. Over the last decade, epidermal growth fac- tor receptor (EGFR) has emerged as one of the most important signaling components for cell growth and survival. Also, EGFR is a molec- ular factor implicated in the development and Natural Compounds and Their Role in Apoptotic Cell Signaling Pathways: Ann. N.Y. Acad. Sci. 1171: 642–648 (2009). doi: 10.1111/j.1749-6632.2009.04893.x c  2009 New York Academy of Sciences. 642