We demonstrate, for the first time, that the transcription factor NF-jB is constitutively activated during human cervical cancer progression. Immunohistochemical analysis was done using 106 paraffin-embedded cervical tissue specimens of different histological grades. In normal cervical tissue and low-grade squamous intraepithelial lesions, p50, RelA and IjB-a were mainly localized in the cytosol, whereas in high-grade lesions and squamous cell carcinomas, p50-RelA heterodimers translocated into the nucleus with a concurrent decrease in IjB-a protein. By Western blot analysis, p50 and RelA were detectable mainly in the cytosolic and nuclear extracts in normal and cancer tissues, respectively, and cytosolic IjB-a expression was detectable in normal but not in cancer cervical tissues. NF-jB DNA-binding activity increased during cervical cancer progression and the binding complex was mainly composed of the p50-RelA heterodimers as revealed by electrophoretic mobility shift assays. Semiquantitative RT-PCR analysis, however, showed increased levels of IjB-a mRNA in cancer samples presumably because of feedback regulation as a result of enhanced NF-jB DNA-binding activity and a consequent functional activation of NF-jB. Further immunohistochemical analysis with an antibody to phospho IjB-a revealed that phosphorylation occurs mainly in squamous intraepithelial lesions, suggesting that the IjB-a gets phosphorylated initially and degraded as the tumor progressed.
This review provides an overview of the clinical relevance of chemosensitization, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity. We also give a brief summary of all the clinical trials related to the important phytochemicals that emerge as chemosensitizers. The mode of action of these phytochemicals in regulating the key players of the death receptor pathway and multidrug resistance proteins is also abridged. Rigorous efforts in identifying novel chemosensitizers and unraveling their molecular mechanism have resulted in some of the promising candidates such as curcumin, genistein, and polyphenon E, which have gone into clinical trials. Even though considerable research has been conducted in identifying the salient molecular players either contributing to drug efflux or inhibiting DNA repair and apoptosis, both of which ultimately lead to the development of chemoresistance, the interdependence of the molecular pathways leading to chemoresistance is still the impeding factor in the success of chemotherapy. Even though clinical trials are going on to evaluate the chemosensitizing efficacy of phytochemicals such as curcumin, genistein, and polyphenon E, recent results indicate that more intense study is required to confirm their clinical efficacy. Current reports also warrant intense investigation about the use of more phytochemicals such as quercetin, emodin, and resveratrol as chemosensitizers, as all of them have been shown to modulate one or more of the key regulators of chemoresistance.
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