Crotepoxide Chemosensitizes Tumor Cells through Inhibition of Expression of Proliferation, Invasion, and Angiogenic Proteins Linked to Proinflammatory Pathway

Abstract

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...

[6]-Gingerol Prevents Disassembly of Cell Junctions and Activities of MMPs in Invasive Human Pancreas Cancer Cells through ERK/NF-κB/Snail Signal Transduction Pathway

“…Also, the transcription factor Snail translocates into the nucleus in metastatic human cancer [35]. In the current study, we found that [6]-gingerol inhibited the nuclear translocation of Snail, which is regulated by NF- κ B. Inhibition of Snail and MMP-9 could be the mechanism of [6]-gingerol-induced inhibition of cancer cell metastasis.…”

3-Formylchromone Interacts with Cysteine 38 in p65 Protein and with Cysteine 179 in IκBα Kinase, Leading to Down-regulation of Nuclear Factor-κB (NF-κB)-regulated Gene Products and Sensitization of Tumor Cells

“…In this study, 3-FC inhibited constitutive NF-B activation, a critical element in the survival and proliferation of various tumor cell types (35). The inhibition of NF-B activation by 3-FC was specific, as it failed to inhibit Oct-1 activation.…”

“…The protein was prepared using the default parameters of the protein preparation workflow in the Schrödinger suite. The docking grid was centered around Arg 33 , Arg 35 , Tyr 36 , Glu 39 , and Arg 187 , as they were deemed critical for ligand and DNA binding (22).…”

Cancer and diet: How are they related?

“…This NF-κB suppression leads to the down-regulation of its regulated gene products, including COX-2, MMP-9 and cyclin D1. Nutraceuticals derived from various kinds of ginger, such as crotepoxide [30], zerumbone [31], 1′-acetoxychavicol acetate [32] and [6]-gingerol [33], have been reported to suppress the NF-κB signalling pathway and induce apoptosis in a variety of human cancer cell lines. Recently, zerumbone has been shown to suppress the receptor activator of NF-κB ligand (RANKL)-induced NF-κB activation and osteoclastogenesis induced by RANKL and tumour cells, thus decreasing osteolysis in MDA-MB-231 breast cancer tumour-bearing athymic nude mice [34].…”