zearalenone and Uterine-Cervical-Neoplasms

Aberrant activation of nuclear factor-κB (NF-κB) allows cancer cells to escape chemotherapy-induced cell death and acts as one of the major mechanisms of acquired chemoresistance in cervical cancer. TAK1, a crucial mediator that upregulates NF-κB activation in response to cellular genotoxic stress, is required for tumor cell viability and survival. Herein, we examined whether TAK1 inhibition is a potential therapeutic strategy for treating cervical cancer. We found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of Dox in a panel of cervical cancer cell lines. Treatment with 5Z-7-oxozeaenol hindered Dox-induced NF-κB activation and promoted Dox-induced apoptosis in cervical cancer cells. Moreover, 5Z-7-oxozeaenol showed similar effects in both positive and negative human papillomavirus-infected cervical cancer cells. Taken together, our results provide evidence that TAK1 inhibition significantly sensitizes cervical cancer cells to chemotherapy-induced cell death and supports the use of TAK1 inhibitor with current chemotherapies in the clinic for patients with refractory cervical cancer.

Topics: Antibiotics, Antineoplastic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Doxorubicin; Drug Synergism; Female; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; NF-kappa B; Signal Transduction; Uterine Cervical Neoplasms; Zearalenone

As part of an on going investigation of novel anticancer agents from natural origin, the biological and cellular effects of (5Z)-7-oxozeaenol on cancer cells were investigated.. The expression of nuclear factor kappa B (NF-κB), IκB kinase (IKKα), IKKβ and caspase-3 were analyzed by western blot. Reactive oxygen species (ROS) fluorescence and caspase luminescent assays were used to assess the intracellular effects in HeLa cervical and HT-29 colon cancer cell lines. The mitochondrial transmembrane potential (MTP) was analyzed by fluorescence-activated cell sorting (FACS).. Cells treated with (5Z)-7-oxozeaenol exhibited down-regulation of NF-κB in a dose-dependent manner. Treatment with (5Z)-7-oxozeaenol significantly enhanced the levels of ROS in HeLa and HT-29 cells. MTP was reduced in HT-29 cells. The expression of caspase-3 and -7 was induced in (5Z)-7-oxozeaenol treated HeLa cells, in comparison with those treated with paclitaxel.. Our findings suggest that (5Z)-7-oxozeaenol is a potent inhibitor of the NF-κB pathway and potentiates the production of ROS, as well as induces caspase-3 and -7 in HeLa and HT-29 cancer cells. Thus, (5Z)-7-oxozeaenol represents a new lead compound for drug development, particularly as a new cancer chemotherapeutic agent, since programmed cell death might be mediated through the activation of a caspase-arbitrated pathway.

Topics: Caspase 3; Caspase 7; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Flow Cytometry; HeLa Cells; HT29 Cells; Humans; Immunoblotting; Membrane Potential, Mitochondrial; NF-kappa B; Oxidation-Reduction; Reactive Oxygen Species; Uterine Cervical Neoplasms; Zearalenone

Zearalenone (6-[10-hydroxy-6-oxo-trans-1-undecenyl]-beta-resorcylic acid-p-lactone), a mycotoxin produced in corn, is able to adopt a conformation which sufficiently resembles 17beta-oestradiol to allow it to bind to the oestrogen receptor in target cells of the body and exert (agonist) oestrogenic action. We adopted an analytical approach to isolate and quantify the mycotoxin and its derivatives using high-performance liquid chromatography and gas chromatography-mass spectrometry. In this study, the quantity of zearalenone and its congeners (alpha-zearalenol and beta-zearalenol) present in the plasma of patients with breast (n = 28) and cervical carcinoma (n=54) were compared with levels in patients presenting with other diagnoses (n = 26) and healthy volunteers (n = 24). There were no significant differences between the groups in the levels of zearalenone and its congeners, using analysis of covariance (0.2 < p < 0.6). These results suggest that the presence of this mycotoxin in blood does not indicate causal relationship between exposure to this exogenous myco-oestrogen and the subsequent biological effect in our study population but may be used as an indicator of exposure. The presence of zearalenone in the study groups is, however, of growing concern, due to the possible effects of cumulative long-term exposure of oestrogenic target organs to this compound.

Topics: Analysis of Variance; Breast Neoplasms; Chromatography, High Pressure Liquid; Female; Gas Chromatography-Mass Spectrometry; Humans; Uterine Cervical Neoplasms; Zearalenone