Abstract: We have previously demonstrated that important regulatory elements responsible for regulated expression of the humanGLUT4 promoter are located between −1154 and −412 relative to transcription initiation (Olson, A. L., and Pessin, J. E. (1995)
J. Biol. Chem. 270, 23491–23495). Through further analysis of this promoter regulatory region, we have identified a perfectly conserved
myocyte enhancer factor 2 (MEF2)-binding domain (-CTAAAAATAG-) that is necessary, but not sufficient, to support... Show More
Article · Jun 1998 · Journal of Biological Chemistry
Abstract: We have previously demonstrated that important regulatory elements responsible for regulated expression of the human GLUT4 promoter are located between -1154 and -412 relative to transcription initiation (Olson, A. L., and Pessin, J. E. (1995) J. Biol. Chem. 270, 23491-23495). Through further analysis of this promoter regulatory region, we have identified a perfectly conserved myocyte enhancer factor 2 (MEF2)-binding domain (-CTAAAAATAG-) that is necessary, but not sufficient, to support... Show More
Article · Jul 1998 · Journal of Biological Chemistry
Abstract: Retinoic acid analogues, called retinoids, have shown promise in clinical trials in preventing breast and ovarian cancers. Classic retinoids bind to retinoic acid receptors, which regulate cell growth. Some novel retinoids, such as fenretinide, i.e., N-(4-hydroxyphenyl)retinamide (4-HPR), induce apoptosis through retinoic acid receptor-independent mechanisms; however, they appear to do so only at concentrations above those achieved in clinical chemoprevention trials. At lower concentrations... Show More
Full-text available · Article · Apr 2001 · JNCI Journal of the National Cancer Institute
Abstract: To better define determinants of survival and optimal management strategies for patients with ovarian cancer and brain metastases.
A review of literature using Medline identified 15 case series of ovarian cancer patients with brain metastases (OBM). Each article was abstracted for survival data, and in all cases, the intervals between ovarian cancer diagnosis and brain metastasis identification, and between brain metastasis identification and last follow-up were recorded. Cases were... Show More
Abstract: Regulation of growth, differentiation, and apoptosis by synthetic retinoids can occur through mechanisms that are dependent and independent of their ability to bind and activate nuclear retinoic acid receptors. The objective of this study was to determine if increasing flexibility of the heteroarotinoid structure would affect the specificity of the synthetic retinoids for the receptors and for their regulation of cancerous and nonmalignant cells. Methods were developed to produce the first... Show More
Full-text available · Article · Mar 2004 · Journal of Medicinal Chemistry
Abstract: Current therapy for cervical cancer includes radiation therapy. Retinoic acid (RA) can increase the sensitivity of cervical cancer cell lines to radiation. The mechanism of this sensitization may not involve the p53 protein because the human papillomavirus (HPV) E6 protein, which is present in the majority of cervical cancers, promotes p53 degradation. The objective of this study was to determine if p53 is involved in the mechanism of RA radiosensitization.
The effects of radiation on... Show More
Abstract: The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea... Show More
Abstract: Treatment of ovarian cancer with cisplatin-based chemotherapy is highly toxic and is often followed by cancer recurrence. Repeated treatments with cisplatin frequently result in the development of resistance to this drug. Drugs with low toxicity that could enhance the tumor cell killing effects of cisplatin could potentially reduce the toxicity and enhance the efficacy of cisplatin. The mechanism of cell kill by cisplatin is partially due to induction of apoptosis through the p53 pathway.... Show More
Article · Apr 2006 · American journal of pharmacology and toxicology
Abstract: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by formation of cysts from tubular epithelial cells. Previous studies indicate that secretion of prostaglandin E2 (PGE2) into cyst fluid and production of cAMP underlie cyst expansion. However, the mechanism by which PGE2 directly stimulates cAMP formation and modulates cystogenesis is still unclear, because the particular E-prostanoid (EP) receptor mediating the PGE2 effect has not been characterized. Our goal is to... Show More
Article · Dec 2007 · American journal of physiology. Renal physiology
Abstract: S-adenosyl L-methionine (SAM) is a universal methyl group donor to various intermediary metabolites, hormones, proteins, neurotransmitters, phospholipids and nucleic acids. Deficiency of folate, which plays a role in the synthesis of SAM leads to increased risk for colon cancer. This study tested the effectiveness of SAM supplementation in protecting against azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. We also tested the effect of SAM on cyclooxygenase-2 (COX-2) in a... Show More
Full-text available · Article · Jan 2008 · International Journal of Cancer
Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation initiated by dedifferentiation and proliferation of renal tubular epithelial cells. Renal tubular epithelial cells (RTC, derived from normal kidney tissue) in primary cultures exhibit both homogeneous expression of gamma-glutamyl transferase and low molecular weight cytokeratin, two different markers for proximal and distal renal epithelial cells, respectively. RTC in cultures also abnormally express the... Show More
Abstract: Colorectal cancer is the leading cause of cancer related deaths in the United States. Although it is preventable, thousands of lives are lost each year in the U.S. to colorectal cancer than to breast cancer and AIDS combined. In colon cancer, the formation and progression of precancerous lesions like aberrant crypt foci and polyps is associated with the up-regulation of cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and hydroxy methyl glutaryl CoA reductase (HMG-CoA... Show More
Full-text available · Article · May 2008 · Gene regulation and systems biology
Abstract: Tumor suppressor p53 plays a major role in colorectal cancer development. The present study explores the effects of p53-modulating agent CP-31398 alone and combined with celecoxib on azoxymethane-induced aberrant crypt foci (ACF) and colon adenocarcinomas in F344 rats. Maximum tolerated doses were 400 and 3,000 ppm for CP-31398 and celecoxib, respectively. ACF and tumor efficacy endpoints were carried out on azoxymethane-treated 7-week-old rats (48 per group) fed the control AIN-76A diet.... Show More
Full-text available · Article · Oct 2009 · Cancer Research
Abstract: Progression of colon cancer is associated with the up-regulation of cyclooxygenase-2 (COX-2) and hydroxymethyl glutaryl CoA reductase (HMG-R). Clinical and preclinical evidence shows that a combination of COX-2 and HMG-R inhibitors provide additive/synergistic chemopreventive effects against colorectal cancer. However, the mechanism by which statins and NSAIDs inhibit cancer growth is not yet fully understood. We aimed to identify critical molecules and signal pathways modulated by a... Show More
Article · Nov 2009 · International Journal of Oncology
Abstract: Clinical and preclinical studies suggest that NSAIDs and cyclooxygenase (COX)-2 inhibitors such as celecoxib, reduce the risk of colorectal cancer. However, at high doses celecoxib causes gastrointestinal toxicity and an increased cardiovascular risk. Inducible nitric oxide synthase (iNOS), similar to COX-2, is overexpressed in colon tumors, and nitric oxide is shown to stimulate COX-2 activity and contributes to the tumor invasiveness. Thus, in the present study we tested a novel... Show More
Abstract: The occurrence of intestinal polyps in people at high risk for developing colorectal cancer provides an opportunity to test the efficacy of chemoprevention agents. In this situation of treating otherwise healthy people, the potential for toxicity must be minimal. The small molecule flexible heteroarotinoid (Flex-Het), called SHetA2, has chemoprevention activity in organotypic cultures in vitro and lack of toxicity at doses capable of inhibiting xenograft tumor growth in vivo. The objective... Show More
Full-text available · Article · Jul 2013 · Cancer Prevention Research
The ratio of Bax to Bcl-2 has been shown to be a key determinant that can drive the initiation of apoptosis. SHetA2 reduces the expression of Bcl-2, but not Bax in cancer cells in vitro [7, 13, 26] and tumors in vivo leading to induction of the intrinsic apoptosis pathway, while mortalin can prevent reduction of Bcl-2 and conformational changes in Bax leading to inhibition of the intrinsic apoptosis pathway444546.
[Show abstract] [Hide abstract] ABSTRACT: SHetA2 is a small molecule flexible heteroarotinoid (Flex-Het) with promising cancer prevention and therapeutic activity. Extensive preclinical testing documented lack of SHetA2 toxicity at doses 25 to 150 fold above effective doses. Knowledge of the SHetA2 molecular target(s) that mediate(s) the mechanism of SHetA2 action is critical to appropriate design of clinical trials and improved analogs. The aim of this study was to develop a method to identify SHetA2 binding proteins in cancer cells. A known metabolite of SHetA2 that has a hydroxyl group available for attachment was synthesized and conjugated to a linker for attachment to a magnetic microsphere. SHetA2-conjugated magnetic microspheres and unconjugated magnetic microspheres were separately incubated with aliquots of a whole cell protein extract from the A2780 human ovarian cancer cell line. After washing away non-specifically bound proteins with the protein extraction buffer, SHetA2-binding proteins were eluted with an excess of free SHetA2. In two independent experiments, an SDS gel band of about 72 kDa was present at differential levels in wells of eluent from SHetA2-microspheres in comparison to wells of eluent from unconjugated microspheres. Mass spectrometry analysis of the bands (QStar) and straight eluents (Orbitrap) identified mortalin (HSPA9) to be present in the eluent from SHetA2-microspheres and not in eluent from unconjugated microspheres. Co-immunoprecipitation experiments demonstrated that SHetA2 interfered with mortalin binding to p53 and p66 Src homologous-collagen homologue (p66shc) inside cancer cells. Mortalin and SHetA2 conflictingly regulate the same molecules involved in mitochondria-mediated intrinsic apoptosis. The results validate the power of this protocol for revealing drug targets.
Electronic supplementary material
The online version of this article (doi:10.1007/s10637-013-0041-x) contains supplementary material, which is available to authorized users.
Elevated production of endogenous PGI 2 enhanced PPARa translocation from the cytosol to the nucleus which could protect renal tubular cells from I/R induced apoptosis (Chen et al., 2009). Therefore, it is suggested that protective effects of APN on the kidney post I/R injury may include: (1) PGE 2 possess anti-apoptotic or anti-inflammatory effects on renal tubular cells (Elberg et al., 2007); (2) PGI 2 not only inhibits renal apoptosis but may influence PPARa translocation to attenuate cytokine production via NFkB pathway (Chen et al., 2009); and (3) up-regulation of the protective gene, HO-1, by APNinduced PPARa pathway may contribute significantly to their anti-inflammatory or anti-apoptosis properties. In addition, (4) AMPK kinase pathway has demonstrated its protective effect against inflammation induced chronic renal injury and lastly (Ouchi et al., 2004; Li et al., 2010), (5) APNR1 and APNR2 adaptor protein (APPL1) protein has implicated its regulation on APN transduction to activate ERK1/2 MAP kinase and Ca 2þ / calmodulin-dependent protein kinase kinase (CaMKK) pathway (Mao et al., 2006; Zhou et al., 2009).
It is noteworthy that HPV, a major risk factor for vulvar cancer [4, 66], requires p63 for its late viral functions . While SW962 cells are HPV negative , almost 40% of our FFPE samples were demonstrated to be HPV positive. However, no association between p63 expression and HPV status was achieved.
[Show abstract] [Hide abstract] ABSTRACT: MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation (p < 0.01) and migration (p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified (p < 0.004). In silico search indicated that miR-223-5p targets TP63, member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients (p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion (p = 0.0491) and lower patient overall survival (p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.
In contrast, WT1 is expressed not only in renal precursors, but also in mature podocytes in the adult kidney (Kann et al., 2015;Kreidberg, 2010). Other markers like paired box (PAX)2, which are widely expressed in vivo during many stages of renal development, but not in mature renal cells, become re-expressed in mature renal cells under in vitro conditions (Elberg et al., 2008). Therefore, the state of PSC-derived cells cannot be reliably identified by their marker expression patterns only, and it is important to test also other properties of the obtained structures and cell types.
[Show abstract] [Hide abstract] ABSTRACT: The global rise in the numbers of kidney patients and the shortage in transplantable organs have led to an increasing interest in kidney-specific regenerative therapies, renal disease modelling and bioartificial kidneys. Sources for large quantities of high-quality renal cells and tissues would be required, also for applications in in vitro platforms for compound safety and efficacy screening. Stem cell-based approaches for the generation of renal-like cells and tissues would be most attractive, but such methods were not available until recently. This situation has drastically changed since 2013, and various protocols for the generation of renal-like cells and precursors from pluripotent stem cells (PSC) have been established. The most recent breakthroughs were related to the establishment of various protocols for the generation of PSC-derived kidney organoids. In combination with recent advances in genome editing, bioprinting and the establishment of predictive renal screening platforms this results in exciting new possibilities. This review will give a comprehensive overview over current PSC-based protocols for the generation of renal-like cells, precursors and organoids, and their current and potential applications in regenerative medicine, compound screening, disease modelling and bioartificial organs.
All of the above mentioned findings let us to think that CAV-1 has an important role to generate new capillary networks in tumor- igenesis .Table 2  demonstrated in cell culture setup that CAV-1 inhibition caused a distinct decline in the cell viability in terms of mRNA expressions. Other similar studies have pointed out the possibilities for CAV-1 inhibition to lead the development of new chemotherapeutic agents by using these findings [26,29,30]. Nimri et al. determined that CAV-1 expression was absent in high metastatic cell series, whereas CAV-1 expression was shown in weak metastatic cell series in cytosolic cell fractions .
Similar results regarding pAMPK were found in epitrochlearis muscle (not shown). AMPK regulates GLUT4 abundance by increasing the activity of the transcription factor Mef2A (Thai et al., 1998). Both GLUT4 total content and Mef2A nuclear content was similar in soleus muscle from BHE/cdb and CD rats (Fig. 4B, C).
[Show abstract] [Hide abstract] ABSTRACT: The BHE/cdb rat has a mutation in adenosine triphosphate (ATP) synthase that impairs insulin secretion. However, male BHE/cdb rats have normal circulating glucose and enhanced glucose tolerance. The aim of the current study was to identify mechanisms of enhanced glucose tolerance. The respiratory exchange ratio was increased, indicating increased oxidation of carbohydrate in BHE/cdb rats, consistent with increases in liver pyruvate dehydrogenase activity and muscle citrate synthase activity. Liver also exhibited diminished phosphoenol pyruvate carboxykinase content, which correlated with a decreased counter-regulatory response in the insulin tolerance test. Signaling via Akt or AMP-dependent kinase pathways in the liver could not account for lower blood glucose. We conclude that chronically low insulin secretion leads to adaption in glucose metabolism primarily in liver to maintain euglycemia.
However, in vivo-based experiments with p53 SMWC agents showed that they had only a noticeable but not significant impact on tumor-free survival in the MCA mouse tumor model. This lack of efficacy in the MCA model is in marked contrast to the well-documented efficacy of these p53 SMWC in several other primary murine tumor model systems . Importantly, their modest effect in vivo on MCA mice was not due to the outgrowth of p53 SMWC resistant tumor cells, since our in vitro-based analysis indicated that early passage cell lines derived from tumors induced in these mice were highly sensitive to p53 SMWC.
[Show abstract] [Hide abstract] ABSTRACT: Cancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH).
Thus, ALDHbright tumor cells represent targets for developing novel cancer prevention/
treatment interventions. Loss of p53 function is a common genetic event during cancer
development wherein small molecular weight compounds (SMWC) that restore p53
function and reverse tumor growth have been identified. Here, we focused on two widely
studied p53 SMWC, CP-31398 and PRIMA-1, to target ALDHbright CSC in human breast,
endometrial and pancreas carcinoma cell lines expressing mutant or wild type (WT)
p53. CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation by
these cell lines in vitro. In addition, these agents were more effective in vitro against
CSC compared to cisplatin and gemcitabine, two often-used chemotherapeutic agents.
We also tested a combinatorial treatment in methylcholantrene (MCA)-treated mice
consisting of p53 SMWC and p53-based vaccines. Yet using survival end-point analysis,
no increased efficacy in the presence of either p53 SMWC alone or with vaccine compared
to vaccine alone was observed. These results may be due, in part, to the presence of
immune cells, such as activated lymphocytes expressing WT p53 at levels comparable
to some tumor cells, wherein further increase of p53 expression by p53 SMWC may alter
survival of these immune cells and negatively impact an effective immune response.
Continuous exposure of mice to MCA may have also interfered with the action of these
p53 SMWC, including potential direct interaction with MCA. Nonetheless, the effect of
p53 SMWC on CSC and cancer treatment remains of great interest.
As reported before, statins can be used as co-adjuvants of classic chemotherapeutic drugs, as well as of more recent small molecules targeting tyrosine kinase receptors, often linked to resistance mechanisms induction. In this context, in vitro collected evidence reported the synergistic anticancer effects of statins with chemotherapeutic drugs able to induce apoptosis, such as 5-fluoruracil and cisplatin  , with cetuximab showing antiproliferative effects in K-Ras mutant cells , with doxorubicin via NFkB pathway [65,66], or with the anti-inflammatory celecoxib responsible for the inhibition of invasiveness properties by the suppression of caveolin-1 . The anti-proliferative effects of statins in head and neck squamous cell carcinoma (HNSCC) cell lines and in primary cells derived from patients, tested alone or in combination with the chemotherapeutic drugs cisplatin and docetaxel, appeared to be more potent in co-administration than alone  .
[Show abstract] [Hide abstract] ABSTRACT: Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed towards the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.
ACF have been widely used to study the potential anti-cancer properties of dietary factors or nutritional supplements against colon carcinogenesis in rodent models and may be important to help understand the earliest events of colon carcinogenesis [57, 69]. For example, bioactive compounds, such as naringin and limonin found in grapefruits, have been shown to reduce the number of ACF, in particular HMACF in azoxymethane (AOM)-treated rodent model .
[Show abstract] [Hide abstract] ABSTRACT: Globally colon cancer strikes more than one million people annually and is responsible for more than half a million cancer deaths. Recent evidence suggests that the majority of malignancies, including colon cancer are driven by cancer stem cells (CSCs) that are resistant to current chemotherapeutic approaches leading to cancer relapse. Wnt signaling plays a critical role in colon stem cell (SC) renewal and carcinogenesis. Leucine-rich repeat-containing G-protein-coupled receptor 5(LGR5), a Wnt target gene, and aldehyde dehydrogenase 1B1 (ALDH1B1) are good markers for normal and malignant human colon stem cells. Diet contributes to 20-42% of all human cancers and 50-90% of colon cancer. Recent evidence shows that Western diet has a causative link to colon cancer; however, mechanisms of action are not fully elucidated. Western diet-induced obesity elevates systemic insulin-like growth factor-1 (IGF-1) and insulin levels, which could lead to elevated proliferation and suppressed apoptosis of CSCs through PI3K/AKT/Wnt pathway. Although conventional chemotherapy targets the PI3K/AKT pathways and can significantly reduce tumor size, it fails to eliminate CSCs and has serious side effects. Dietary bioactive compounds such as grape seed extract, curcumin, lycopene, and resveratrol have promising chemopreventive effects, without serious side effects on various types of cancers due to their direct and indirect actions on CSC self-renewal pathways such as the Wnt pathway. Understanding the role of CSCs in diet-induced colon cancer will aid in development of evidence-based dietary chemopreventive strategies and/or therapeutic agents targeting CSCs.
Some reports have indicated that Glut-4 levels are low in diabetes mellitus  hence, upregulation of Glut-4 transcription is seen as a means to alleviate type 2 diabetes . Glut-4 gene is regulated by myocyte enhancing (Mef2) transcription factor which binds to its cis-elements as a hetero-dimer (Mef2a/D) resulting in Glut-4 expression [55,56]. Recent studies showed that Glut-4 expression is also regulated by nuclear respiratory factor (Nrf-1), a mitochondrial transcription factor, which controls Mef2a gene to regulate Glut-4 [57,58].
[Show abstract] [Hide abstract] ABSTRACT: Diabetes mellitus is a metabolic disease that threatens and reduces the quality of life. Eight hybrids (1a-h) of thiosemicarbozone and triazole were screened for their effects on genes related to type 2 diabetes as well as their antioxidant activity. The influence of the hybrids on glucose transport genes (Glut-4, Mef2a and Nrf-1) was carried out using quantitative real time polymerase chain reaction (PCR). Antioxidant assays were carried out using established techniques. Hybrids 1b, 1d, 1e and 1g exhibited high expression of Glut-4 gene relative to insulin and control. All the hybrids tested except 1h and 1f expressed the Nrf-1 while only 1h did not express Mef-2a relative to control. Among all the compounds, 1b showed the highest 1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging ability and Trolox Equivalent Antioxidant Capacity (TEAC) values. In terms of Ferric Reducing Antioxidant Power (FRAP) and Oxygen Radical Absorbance Capacity (ORAC), 1c and 1d had the highest values, respectively. In all the antioxidant assays carried out, 1a was shown to have the lowest antioxidant activities. Hybrids 1d and 1g showed consistent pattern of glucose transport pathway gene transcription with all the hybrids showing antioxidant potentials though at varying extents. These hybrids could be potential candidates eliciting antidiabetic and antioxidant effects.
[Show abstract] [Hide abstract] ABSTRACT: Background:
The management of patients with recurrent gynecological malignancy is complex, and often contentious. While historically, patients with metastases in the lungs, liver or brain have been treated with palliative intent, surgery is proving to have an increasing role in the management of such patients.
In this review article, the surgical management of lung, liver and brain metastases from gynecological cancers is examined. A search of the English language literature over the last 25 years was conducted using the Medline and PubMed databases.
The results for management of metastases from the endometrium, ovary and cervix to the lung, brain and liver show that surprisingly good long-term survival results can be achieved for resection of metastases from all three organs. Patient selection is critical, and surgery is often used in conjunction with other treatment modalities.
From this review, it is apparent that surgery should play an increasing role in the management of patients with parenchymal metastases from gynecological cancers. The surgery should ideally be performed in high volume, tertiary centers where there is a committed multi-disciplinary team with the necessary infrastructure to achieve the best possible outcomes in terms of both survival and morbidity.