Ala Abudayyeh

Oncogenic microRNA-27a is a target for anticancer agent methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate in colon cancer cells

Methyl 2‐cyano‐3,11‐dioxo‐18β‐olean‐1,12‐dien‐30‐oate (CDODA‐Me) is a synthetic derivative of glycyrrhetinic acid, a triterpenoid phytochemical found in licorice extracts. CDODA‐Me inhibited growth of RKO and SW480 colon cancer cells and this was accompanied by decreased expression of Sp1, Sp3 and Sp4 protein and mRNA and several Sp‐dependent genes including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1 or Flt‐1). CDODA‐Me also induced apoptosis, arrested RKO and SW480 cells at G2/M, and inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. CDODA‐Me decreased expression of microRNA‐27a (miR‐27a), and this was accompanied by increased expression of 2 miR‐27a‐regulated mRNAs, namely ZBTB10 (an Sp repressor) and Myt‐1 which catalyzes phosphorylation of cdc2 to inhibit progression of cells through G2/M. Both CDODA‐Me and antisense miR‐27a induced comparable responses in RKO and SW480 cells, suggesting that the potent anticarcinogenic activity of CDODA‐Me is due to repression of oncogenic miR‐27a.

Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met

The non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 muM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.

Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors.

Background: Metformin inhibits pancreatic cancer cell and tumor growth and down-regulated Sp transcription factors. Results: Inhibition of mTOR and Ras signaling by metformin is due to decreased expression of Sp-regulated insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), respectively. Conclusion: Metformin-induced down-regulation of Sp proteins affects multiple pro-oncogenic pathways. Significance: These results identify important metformin-induced anticancer activities. The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively.

Mechanism of Metformin-dependent Inhibition of mTOR and Ras Activity in Pancreatic Cancer: Role of Sp Transcription Factors

Background: Metformin inhibits pancreatic cancer cell and tumor growth and down-regulated Sp transcription factors. Results: Inhibition of mTOR and Ras signaling by metformin is due to decreased expression of Sp-regulated insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), respectively. Conclusion: Metformin-induced down-regulation of Sp proteins affects multiple pro-oncogenic pathways. Significance: These results identify important metformin-induced anticancer activities. The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (mTOR) signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R), resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively.

Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression

Survivin is overexpressed in most human cancers, including pancreatic adenocarcinoma. Expression of survivin is regulated by specificity protein (Sp) proteins and related to resistance to radiation therapy. Tolfenamic acid induces Sp protein degradation in several cancer cell lines. The purpose of this study is to investigate whether tolfenamic acid inhibits survivin expression and sensitizes pancreatic cancer cells/tumor to radiotherapy. Panc1 and L3.6pl cells have been used to study the effect of radiation on survivin expression and to investigate the efficacy of tolfenamic acid in enhancing the response to radiation therapy. In addition, an orthotopic model for human pancreatic cancer has been used to confirm the efficacy of tolfenamic acid to enhance tumor response to radiation in vivo. Pancreatic cancer cell lines express variable levels of survivin mRNA/protein, which correlate with their radiosensitivity. Radiation increased survivin promoter activity and protein expression in Panc1 and L3.6pl cells and tolfenamic acid inhibited both constitutive and radiation-induced survivin protein expression and enhanced the response of pancreatic cancer cells to radiation therapy. In vivo studies show that tolfenamic acid enhanced the radiation-induced apoptosis associated with decreased survivin expression in tumors and this correlates with the enhanced response of these tumors to the radiation. Thus, tolfenamic acid significantly enhances pancreatic cancer cells/tumor response to radiation therapy. The underlying mechanism includes tolfenamic acid-induced degradation of Sp proteins, which in tumor decreases expression of the Sp-dependent antiapoptotic protein survivin. These preclinical data suggest that tolfenamic acid has the potential to increase the response of pancreatic adenocarcinoma to radiation therapy. [Mol Cancer Ther 2009;8(3):533–42]

Nuclear receptor 4A (NR4A) family - Orphans no more

The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer.

The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression

Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic cancer cells, TA induced down-regulation of erbB2 but not Sp proteins. TA-induced erbB2 down-regulation was accompanied by decreased erbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. TA also decreased erbB2 mRNA expression and promoter activity, and this was due to decreased mRNA stability in BT474 cells and, in both cell lines, TA decreased expression of the YY1 and AP-2 transcription factors required for basal erbB2 expression. In addition, TA also inhibited tumor growth in athymic nude mice in which BT474 cells were injected into the mammary fat pad. TA represents a novel and promising new anticancer drug that targets erbB2 by decreasing transcription of this oncogene. [Mol Cancer Ther 2009;8(5):OF1–11]

5,5′-Dibromo-bis(3′-indolyl)methane induces Krüppel-like factor 4 and p21 in colon cancer cells

Bis(3′-indolyl)methane (DIM) is a metabolite of the phytochemical indole-3-carbinol, and both compounds exhibit a broad spectrum of anticancer activities. We have developed a series of synthetic symmetrical ring-substituted DIM analogues, including 5,5′-dibromoDIM, which are more potent than DIM as inhibitors of cancer cell and tumor growth. In colon cancer cells, 5,5′-dibromoDIM decreased cell proliferation and inhibited G0-G1- to S-phase progression, and this was accompanied by induction of the cyclin-dependent kinase inhibitor p21 in HT-29 and RKO colon cancer cells. Mechanistic studies showed that induction of p21 in both RKO (p53 wild-type) and HT-29 (p53 mutant) cells by 5,5′-dibromoDIM was Krüppel-like factor 4 (KLF4) dependent, and induction of p53 in RKO cells was also KLF4 dependent. Analysis of the p21 promoter in p53-dependent RKO cells showed that 5,5′-dibromoDIM activated p21 gene expression through the proximal GC-rich sites 1 and 2, and chromatin immunoprecipitation assays showed that KLF4 and p53 bound to this region of the promoter, whereas in HT-29 cells unidentified upstream cis-elements were required for induction of p21. 5,5′-DibromoDIM (30 mg/kg/d) also inhibited tumor growth and induced p21 in athymic nude mice bearing RKO cells as xenografts, showing that ring-substituted DIM such as 5,5′-dibromoDIM represent a novel class of mechanism-based drugs for clinical treatment of colon cancer. [Mol Cancer Ther 2008;7(7):2109–20]

Symptomatic BK Virus Infection Is Associated with Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause‐specific hazard of kidney function decline, and the Fine–Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft‐versus‐host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Paraprotein–Related Kidney Disease: Evaluation and Treatment of Myeloma Cast Nephropathy

Nearly 50% of patients with multiple myeloma develop renal disease, most commonly from AKI caused by cast nephropathy. Development of AKI is associated with poor 1-year survival and reduces the therapeutic options available to patients. There is a great need for more effective therapies. Cast nephropathy is caused by the interaction and aggregation of filtered free light chains and Tamm-Horsfall protein causing intratubular obstruction and damage. The key to treating cast nephropathy is rapid lowering of free light chains, because this correlates with renal recovery. Newer chemotherapy agents rapidly lower free light chains and have been referred to as renoprotective. There is additional great interest in using extracorporeal therapies to remove serum free light chains. Small trials initially showed benefit of therapeutic plasma exchange to improve renal outcomes in cast nephropathy, but a large randomized trial of therapeutic plasma exchange failed to show benefit. A newer technique is extended high-cutoff hemodialysis. This modality uses a high molecular weight cutoff filter to remove free light chains. To date, trials of high-cutoff hemodialysis use in patients with cast nephropathy have been encouraging. However, there are no randomized trials showing the benefit of high-cutoff hemodialysis when used in addition to newer chemotherapeutic regimens. Until these studies are available, high-cutoff hemodialysis cannot be recommended as standard of care.