Crotepoxide (a substituted cyclohexane diepoxide), isolated from Kaempferia pulchra (peacock ginger), although linked to antitumor and anti-inflammatory activities, the mechanism by which it exhibits these activities, is not yet understood. Because nuclear factor B (NF-B) plays a critical role in these signaling pathways, we investigated the effects of crotepoxide on NF-B-mediated cellular responses in human cancer cells. We found that crotepoxide potentiated tumor necrosis factor (TNF), and chemotherapeutic agents induced apoptosis and inhibited the expression of NF-B-regulated gene products involved in anti-apoptosis (Bcl-2, Bcl-xL, IAP1, 2 MCl-1, survivin, and TRAF1), apoptosis (Bax, Bid), inflammation (COX-2), proliferation (cyclin D1 and c-myc), invasion (ICAM-1 and MMP-9), and angiogenesis (VEGF). We also found that crotepoxide inhibited both inducible and constitutive NF-B activation. Crotepoxide inhibition of NF-B was not inducer-specific; it inhibited NF-B activation induced by TNF, phorbol 12-myristate 13-acetate, lipopolysaccharide, and cigarette smoke. Crotepoxide suppression of NF-B was not cell type-specific because NF-B activation was inhibited in myeloid, leukemia, and epithelial cells. Furthermore, we found that crotepoxide inhibited TAK1 activation, which led to suppression of IB␣ kinase, abrogation of IB␣ phosphorylation and degradation, nuclear translocation of p65, and suppression of NF-B-dependent reporter gene expression. Overall, our results indicate that crotepoxide sensitizes tumor cells to cytokines and chemotherapeutic agents through inhibition of NF-B and NF-B-regulated gene products, and this may provide the molecular basis for crotepoxide ability to suppress inflammation and carcinogenesis.Several chemotherapeutic, cytotoxic, and immunomodulating agents are commonly used to treat cancer. However, most modern medicines tend to target only one gene product or pathway at a given time. This is perhaps one of the major reasons that some of the recently discovered medicines are less effective. Besides being prohibitively expensive, many of these drugs are also associated with serious side effects and morbidity. Still, the search continues for an ideal treatment that has minimal side effects and is cost-effective. Therefore, traditional medicine, usually derived from plants is one of the alternatives to treat the chronic diseases including cancer. Although plantderived products have been used for centuries to treat various ailments, their active components and mechanisms are not fully understood. Identifying the active chemical entities and their molecular targets would facilitate the discovery of new clinical uses for such products.Crotepoxide (Fig. 1A), a highly substituted cyclohexane diepoxide linked with anticancer activity, was first isolated from the fruit of Croton macrostachys (1, 2). More recently, crotepoxide was identified as a main component in Kaempferia rotunda (3), a member of the Zingiberaceae, or ginger family whose tuber has traditionally been used to treat pneumonia, b...