Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.
The Wilms' tumor gene WT1 is overexpressed in leukemias and various types of solid tumors, and the WT1 protein was demonstrated to be an attractive target antigen for immunotherapy against these malignancies. Here, we report the outcome of a phase I clinical study of WT1 peptide-based immunotherapy for patients with breast or lung cancer, myelodysplastic syndrome, or acute myeloid leukemia. The WT1 gene was isolated as a gene responsible for Wilms' tumor, a pediatric renal cancer, and encodes a zinc finger transcription factor, which is involved in cell proliferation and differentiation, apoptosis, and organ development (3-6). Although the WT1 gene was first categorized as a tumor suppressor gene, we have proposed that the wild-type WT1 gene functions as an oncogene rather than a tumor-suppressor gene on the basis of the following findings. The first is high expression of the wild-type WT1 gene in both leukemias and solid tumors (7-18), the second is growth inhibition of leukemic and solid tumor cells by treatment with WT1 antisense oligomers (14,19), and the third is block of differentiation, but induction of proliferation, of wild-type WT1 gene-transfected myeloid progenitor cells in response to granulocyte colony-stimulating factor (20, 21). The last two are block of thymocyte differentiation but induction of thymocyte proliferation in the transgenic mice with the lck promoter-driven WT1 gene (22), and WT1 gene expression in the majority of dimethylbenzanthracene-induced erythroblastic leukemia and a stronger tendency of the cells with high levels of WT1 to develop into leukemias (23).Expression of the wild-type WT1 gene has been found in most cases of acute myelocytic leukemia (AML), acute lymphocytic leukemia, chronic myelocytic leukemia, and myelodysplastic syndrome (MDS) at higher levels than those in normal bone marrow (BM) or peripheral blood (7-13). Furthermore, various types of solid tumors, including lung, breast, thyroid, and colorectal cancers, expressed the wild-type WT1 gene at higher levels compared to those in corresponding normal tissues (15-18). These results indicated that the wild-type WT1 gene product may be a promising target for cancer immunotherapy (24,25).We tested the potential of the WT1 gene product to serve as a target antigen for tumor-specific immunotherapy. Human WT1-specific CTLs have been found to induce lysis of endogenously WT1-expressing tumor cells in vitro, but not to cause damage to physiologically WT1-expressing normal cells (24,(26)(27)(28). We used a mouse in vivo system to demonstrate that immunization of mice with either MHC class I-restricted WT1 peptide or WT1 cDNA induced WT1-specific CTLs. We also showed that the immunized mice rejected challenges of WT1-expressing tumor cells, whereas the induced CTLs did not affect normal healthy tissues that physiologically expressed WT1 nor damaged the normal tissues (25, 29). These results indicated that the WT1 protein could be a novel tumor rejection antigen for cancer immunotherapy (24)(25)(26)(27)(28)(29)(30)(31)(32).In...
Purpose: Breast cancer stem cells have been shown to be associated with resistance to chemotherapy in vitro, but their clinical significance remains to be clarified. The aim of this study was to investigate whether cancer stem cells were clinically significant for resistance to chemotherapy in human breast cancers. Experimental Design: Primary breast cancer patients (n = 108) treated with neoadjuvant chemotherapy consisting of sequential paclitaxel and epirubicin-based chemotherapy were included in the study. Breast cancer stem cells were identified by immunohistochemical staining of CD44/CD24 and aldehyde dehydrogenase 1 (ALDH1) in tumor tissues obtained before and after neoadjuvant chemotherapy. CD44 + /CD24-tumor cells or ALDH1-positive tumor cells were considered stem cells. Results: Thirty (27.8%) patients achieved pathologic complete response (pCR). ALDH1-positive tumors were significantly associated with a low pCR rate (9.5% versus 32.2%; P = 0.037), but there was no significant association between CD44 + /CD24 -tumor cell proportions and pCR rates. Changes in the proportion of CD44 + /CD24 -or ALDH1-positive tumor cells before and after neoadjuvant chemotherapy were studied in 78 patients who did not achieve pCR. The proportion of ALDH1-positive tumor cells increased significantly (P < 0.001) after neoadjuvant chemotherapy, but that of CD44 + /CD24 -tumor cells did not. Conclusions: Our findings suggest that breast cancer stem cells identified as ALDH1-positive, but not CD44
We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator-activated response-␥ coactivator-1␣ (PGC-1␣) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPK␣1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1␣ completely blocked the hyperglycemiainduced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative-AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1␣ pathway. Diabetes 55:120 -127, 2006
Purpose: LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle. Methylation status of the promoter regions of these genes as well as its correlation with their mRNA levels were studied in human breast cancers. Correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics of breast tumors were also studied.Experimental Design: Methylation status of promoter regions of LATS1 and LATS2 was studied by a methylationspecific PCR and mRNA expression levels of LATS1 and LATS2 were determined by a real-time PCR assay in 30 breast cancers. In addition, correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics was studied in 117 breast cancers.Results: Methylation-specific PCR showed that of 30 tumors, LATS1 promoter region was hypermethylated in 17 tumors (56.7%) and LATS2 promoter region was hypermethylated in 15 (50.0%) tumors. LATS1 mRNA levels in breast tumors with hypermethylation (2.15 F F 0.37, mean F F SE) were significantly (P < 0.01) lower than those without hypermethylation (6.09 F F 1.38), and LATS2 mRNA levels in breast tumors with hypermethylation (1.42 F F 0.66) were also significantly (P < 0.01) lower than those without hypermethylation (3.10 F F 1.00). The decreased expression of LATS1 or LATS2 mRNA was significantly associated with a large tumor size, high lymph node metastasis, and estrogen receptor and progesterone receptor negativity. Furthermore, the decreased expression of LATS1 mRNA, but not LATS2 mRNA, was significantly (P < 0.05) associated with a poor prognosis.Conclusions: Hypermethylation of the promoter regions of LATS1 and LATS2 likely plays an important role in the down-regulation of their mRNA levels in breast cancers, and breast cancers with a decreased expression of LATS1 or LATS2 mRNA levels have a biologically aggressive phenotype.
Recently, aldehyde dehydrogenase (ALDH) 1 has been identified as a reliable marker for breast cancer stem cells. E vidence has recently been accumulating to support the cancer stem cell hypothesis for solid tumors, including breast cancer, which holds that cancers are driven by a small subpopulation of stem cells that are capable of self-renewal and give rise to multipotent progenitor cells that ultimately differentiate into all cell types within the tumor.(1) Al-Hajj et al. were the first to distinguish tumorigenic from non-tumorigenic cancer cells by using the cell surface markers CD44 and CD24.(2) They have shown that cancer stem cells in a population of tumor cells are enriched with the CD44 + and CD24 -phenotype because as few as 100 tumor cells with this phenotype were able to produce tumors in immunodeficient mice, whereas tumor cells with other CD44 and CD24 phenotypes were unable or rarely able to produce tumors even when as many as 10 5 -10 6 tumor cells were inoculated into such mice. + cancer stem cells may well be clinically useful for patient prognosis. In the study reported here, we therefore investigated the clinicopathological characteristics of breast cancers with ALDH1 + cancer stem cells and also compared ALDH1 expression in primary tumors and axillary metastases. In addition, the ER, Ki67, and HER2 status of ALDH1 + tumor cells was investigated on a cell-by-cell basis by means of double immunohistochemical staining for further characterization of the phenotype of breast cancer stem cells. Materials and MethodsPatients and breast tumor tissues. Tumor tissue samples were obtained from 203 primary breast cancer patients (mean age, 52.6 years; range, 32-86 years) who underwent mastectomy or breast-conserving surgery between January 1993 and December 1997 at Osaka University Hospital, Osaka, Japan. Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. This study protocol was approved by the Ethics Committee of Osaka University.For adjuvant therapy, 85 patients were treated with hormonal therapy (tamoxifen, n = 74; toremifene, n = 7; gosereline, n = 3; or gosereline + tamoxifen, n = 1), 22 with chemotherapy (fluoropyrimidine, n = 8; cyclophosphamide + methotrexate + 5-fluorouracil, n = 7; cyclophosphamide + adriamycin + 5-fluorouracil, n = 4; or high-dose chemotherapy, n = 3), and 84 with chemohormonal therapy (fluoropyrimidine, n = 37; cyclophosphamide + methotrexate + 5-fluorouracil, n = 25; cyclophosphamide + adriamycin + 5-fluorouracil, n = 20; or high-dose chemotherapy, n = 2; plus tamoxifen, n = 78; toremifene, n = 1; gosereline, n = 3; or gosereline + tamoxifen, n = 2). Twelve patients received no adjuvant therapy.
Methylglyoxal is a highly reactive dicarbonyl degradation
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