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Matrix metalloproteinases (MMP) are a family of zinc-dependent proteases that degrade the entire component of the extracellular matrix. Our study explores the association of the MMP1gene promoter (-1607 1G/2G) polymorphisms in oral submucous fibrosis (OSMF) and head and neck squamous cell carcinoma (HNSCC) in an Indian population. The MMP1single-nucleotide polymorphism (SNP) was genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis in 412 patients with OSMF, 422 with HNSCC and 426 controls. Our results showed that the frequency of 1G/2G or 2G/2G promoter genotypes having the 2G allele is associated with higher enzymatic activity and significantly increases in OSMF (p<0.001) and HNSCC cases (p<0.00). In this study, results concluded that SNPs in the MMP1promoter region may be associated with susceptibility to OSMF as well as HNSCC in an Indian population and addiction habits such as areca nut chewing and alcohol abuse may enhance the expression of the 2G allele of MMP1genes in OSMF and HNSCC cases.

We hypothesized that plasma level of tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 may be a potential tool for diagnosis, prognosis and prediction of treatment outcome in non-small cell lung carcinoma (NSCLC). Plasma levels of TNF-α and TGF-β1 were quantified in 100 NSCLC patients and 100 controls. Association of TNF-α and TGF-β1 with response to therapy and survival was determined in 42 patients. An increased presence of TNF-α and TGF-β1 was observed in NSCLC compared with controls. TNF-α and TGF-β1 levels did not correlate with survival and response to chemotherapy. TNF-α and TGF-β1 do not appear to be reliable markers for predicting survival and response to therapy in advanced NSCLC.

Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor–κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-κB and STAT3 and if their suppression induces apoptosis. We assayed CD138+ cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-κB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-κB and STAT3 but to a variable degree (NF-κB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-κB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-κB and STAT3 were absent in cells from healthy individuals. Suppression of NF-κB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-κB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-κB and STAT3, and suppression of these transcription factors inhibits the survival of the cells. (Blood. 2004;103:3175-3184)

Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor–κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-κB and STAT3 and if their suppression induces apoptosis. We assayed CD138+cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-κB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-κB and STAT3 but to a variable degree (NF-κB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-κB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-κB and STAT3 were absent in cells from healthy individuals. Suppression of NF-κB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-κB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-κB and STAT3, and suppression of these transcription factors inhibits the survival of the cells. (Blood. 2004;103:3175-3184)

Because of the central role of the transcription factor nuclear factor–κB (NF-κB) in cell survival and proliferation in human multiple myeloma (MM), we explored the possibility of using it as a target for MM treatment by using curcumin (diferuloylmethane), an agent known to have very little or no toxicity in humans. We found that NF-κB was constitutively active in all human MM cell lines examined and that curcumin, a chemopreventive agent, down-regulated NF-κB in all cell lines as indicated by electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. All MM cell lines showed consitutively active IκB kinase (IKK) and IκBα phosphorylation. Curcumin suppressed the constitutive IκBα phosphorylation through the inhibition of IKK activity. Curcumin also down-regulated the expression of NF-κB–regulated gene products, including IκBα, Bcl-2, Bcl-xL, cyclin D1, and interleukin-6. This led to the suppression of proliferation and arrest of cells at the G1/S phase of the cell cycle. Suppression of NF-κB complex by IKKγ/NF-κB essential modulator-binding domain peptide also suppressed the proliferation of MM cells. Curcumin also activated caspase-7 and caspase-9 and induced polyadenosine-5′-diphosphate-ribose polymerase (PARP) cleavage. Curcumin-induced down-regulation of NF-κB, a factor that has been implicated in chemoresistance, also induced chemosensitivity to vincristine and melphalan. Overall, our results indicate that curcumin down-regulates NF-κB in human MM cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of MM patients with this pharmacologically safe agent.

Because of the central role of the transcription factor nuclear factor–κB (NF-κB) in cell survival and proliferation in human multiple myeloma (MM), we explored the possibility of using it as a target for MM treatment by using curcumin (diferuloylmethane), an agent known to have very little or no toxicity in humans. We found that NF-κB was constitutively active in all human MM cell lines examined and that curcumin, a chemopreventive agent, down-regulated NF-κB in all cell lines as indicated by electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. All MM cell lines showed consitutively active IκB kinase (IKK) and IκBα phosphorylation. Curcumin suppressed the constitutive IκBα phosphorylation through the inhibition of IKK activity. Curcumin also down-regulated the expression of NF-κB–regulated gene products, including IκBα, Bcl-2, Bcl-xL, cyclin D1, and interleukin-6. This led to the suppression of proliferation and arrest of cells at the G1/S phase of the cell cycle. Suppression of NF-κB complex by IKKγ/NF-κB essential modulator-binding domain peptide also suppressed the proliferation of MM cells. Curcumin also activated caspase-7 and caspase-9 and induced polyadenosine-5′-diphosphate-ribose polymerase (PARP) cleavage. Curcumin-induced down-regulation of NF-κB, a factor that has been implicated in chemoresistance, also induced chemosensitivity to vincristine and melphalan. Overall, our results indicate that curcumin down-regulates NF-κB in human MM cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of MM patients with this pharmacologically safe agent.

Almost two decades ago, tumor necrosis factor (TNF) was identified as a protein produced by the immune system that played a major role in suppression of tumor cell proliferation. Extensive research since then has revealed that TNF is a major mediator of inflammation, viral replication, tumor metastasis, transplant rejection, rheumatoid arthritis, and septic shock. As of today, 18 different members of the TNF superfamily have been identified, and most of them have been found to mediate a wide variety of diseases including cancer, arthritis, bone resorption, allergy, diabetes, atherosclerosis, myocardial infarction, graft versus host disease, and acquired immune deficiency disease. All the cytokines of the TNF superfamily mediate their effects through the activation of the transcription factor NF-κB, c-Jun N-terminal kinase, apoptosis, and proliferation. Thus, agents that can either suppress the production of these cytokines or block their action have therapeutic value for a wide variety of diseases. In this review, we have elucidated the signal transduction pathways used by the members of the TNF family and the effects of deletion of genes that mediate the pathways. Our current understanding of the signaling pathways for TNF and other family members could serve as a target for the development of therapeutics.

Nuclear factor-?B (NF-?B), a transcription factor, is present normally in the cytoplasm as an inactive heterotrimer consisting of p50, p65, and I?B? subunits. When activated, NF-?B translocates to the nucleus as a p50-p65 heterodimer. This factor regulates the expression of various genes that control apoptosis, viral replication, tumorigenesis, various autoimmune diseases, and inflammation. NF-?B has been linked to the development of carcinogenesis for several reasons. First, various carcinogens and tumor promoters have been shown to activate NF-?B. Second, activation of NF-?B has been shown to block apoptosis and promote proliferation. Third, the tumor microenvironment can induce NF-?B activation. Fourth, constitutive expression of NF-?B is frequently found in tumor cells. Fifth, NF-?B activation induces resistance to chemotherapeutic agents. Sixth, several genes involved in tumor initiation, promotion, and metastasis are regulated by NF-?B. Seventh, various chemopreventive agents have been found to down-regulate the NF-?B activation. All these observation suggest that NF-?B could mediate tumorigenesis and thus can be used as a target for chemoprevention and for the treatment of cancer. Agents that suppress NF-?B activation can suppress the expression of genes involved in carcinogenesis and tumorigenesis in vivo.