Showing papers on "Cancer research published in 2019"

Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands.

Abstract: Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.

Patient-Derived Glioma Models: From Patients to Dish to Animals

Abstract: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults associated with a poor survival. Current standard of care consists of surgical resection followed by radiation and chemotherapy. GBMs are highly heterogeneous, having a complex interaction among different cells within the tumor as well as the tumor microenvironment. One of the main challenges in the neuro-oncology field in general, and GBM in particular, is to find an optimum culture condition that maintains the molecular genotype and phenotype as well as heterogeneity of the original tumor in vitro and in vivo. Established cell lines were shown to be a poor model of the disease, failing to recapitulate the phenotype and harboring non-parental genotypic mutations. Given the growing understanding of GBM biology, the discovery of glioma cancer stem-like cells (GSCs), and their role in tumor formation and therapeutic resistance, scientists are turning more towards patient-derived cells and xenografts as a more representative model. In this review, we will discuss the current state of patient-derived GSCs and their xenografts; and provide an overview of different established models to study GBM biology and to identify novel therapeutics in the pre-clinical phase.

Overexpressed ITGA2 promotes malignant tumor aggression by up-regulating PD-L1 expression through the activation of the STAT3 signaling pathway.

Abstract: Recent studies have reported that Integrin alpha 2 (ITGA2) plays an essential role in tumor cell proliferation, invasion, metastasis, and angiogenesis. An abnormally expressed ITGA2 correlates with unfavorable prognoses in multiple types of cancer. However, the specific mechanism of how ITGA2 contributes to tumorigenesis remains unclear. The GEPIA web tool was used to find the clinical relevance of ITGA2 in cancer, and this significance was verified using Western blotting analysis of paired patient tissues and immunohistochemistry of the pancreatic cancer tissue. Functional assays, such as the MTS assay, colony formation assay, and transwell assay, were used to determine the biological role of ITGA2 in human cancer. The relationship between ITGA2 and programmed death-ligand 1 (PD-L1) was examined using Western blot analysis, RT-qPCR assay, and immunohistochemistry. The protein-protein interaction between ITGA2 and STAT3 was detected via co-immunoprecipitation. Our study showed that ITGA2 was markedly overexpressed in several malignant tumor cells and clinical tissues. Blocking ITGA2 inhibited the proliferation and invasion ability of cancer cells significantly, whereas overexpressed ITGA2 increased the degree of those processes considerably. Additionally, the RNA-seq assay indicated that ITGA2 transcriptionally regulated the expression of PD-L1 in pancreatic cancer. We also demonstrated that ITGA2 interacted with STAT3 and up-regulated the phosphorylation of STAT3; this interaction might involve the mechanism of ITGA2 inducing PD-L1 expression in cancer cells. Our results suggest that ITGA2 plays a critical role in cancer cell progression and the regulation of PD-L1 by activating the STAT3 pathway. We identified a novel mechanism by which ITGA2 plays a critical role in modulating cancer immune response by transcriptionally increasing the expression of PD-L1 in cancer cells. Thus, targeting ITGA2 is an effective method to enhance the efficacy of checkpoint immunotherapy against cancer.

Lung inflammatory environments differentially alter mesenchymal stromal cell behavior

Abstract: Mesenchymal stromal (stem) cells (MSCs) are increasingly demonstrated to ameliorate experimentally induced lung injuries through disease-specific anti-inflammatory actions, thus suggesting that dif...

Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis.

Abstract: Background: Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. Methods: COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. Results: COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. Conclusions: Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor’s stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.

Early detection of pre-malignant lesions in a KRASG12D-driven mouse lung cancer model by monitoring circulating free DNA.

Abstract: Lung cancer is the leading cause of cancer-related death. Two-thirds of cases are diagnosed at an advanced stage that is refractory to curative treatment. Therefore, strategies for the early detection of lung cancer are urgently sought. Total circulating free DNA (cfDNA) and tumour-derived circulating tumour DNA (ctDNA) are emerging as important biomarkers within a ‘liquid biopsy’ for monitoring human disease progression and response to therapy. Owing to the late clinical diagnosis of lung adenocarcinoma, the potential for cfDNA and ctDNA as early detection biomarkers remains unexplored. Here, using a Cre-regulated genetically engineered mouse model of lung adenocarcinoma development, driven by Kras G12D (the Kras LSL-G12D mouse), we serially tracked the release of cfDNA/ctDNA and compared this with tumour burden as determined by micro-computed tomography (CT). To monitor ctDNA, a droplet digital PCR assay was developed to permit discrimination of the Kras Lox-G12D allele from the Kras LSL-G12D and Kras WT alleles. We show that micro-CT correlates with endpoint histology and is able to detect pre-malignant tumours with a combined volume larger than 7 mm 3 . Changes in cfDNA/ctDNA levels correlate with micro-CT measurements in longitudinal sampling and are able to monitor the emergence of lesions before the adenoma-adenocarcinoma transition. Potentially, this work has implications for the early detection of human lung adenocarcinoma using ctDNA/cfDNA profiling. A video abstract for this article is available at https://youtu.be/Ku8xJJyGs3U. This article has an associated First Person interview with the joint first authors of the paper.

Genetic alteration of histone lysine methyltransferases and their significance in renal cell carcinoma.

Abstract: Background Histone lysine methyltransferases (HMTs), a category of enzymes, play essential roles in regulating transcription, cellular differentiation, and chromatin construction. The genomic landscape and clinical significance of HMTs in renal cell carcinoma (RCC) remain uncovered. Methods We conducted an integrative analysis of 50 HMTs in RCC and discovered the internal relations among copy number alterations (CNAs), expressive abundance, mutations, and clinical outcome. Results We confirmed 12 HMTs with the highest frequency of genetic alterations, including seven HMTs with high-level amplification, two HMTs with somatic mutation, and three HMTs with putative homozygous deletion. Patterns of copy number and expression varied among different subtypes of RCC, including clear cell renal cell carcinoma, papillary cell carcinoma, and chromophobe renal carcinoma. Kaplan-Meier survival analysis and multivariate analysis identified that CNA or mRNA expression in some HMTs were significantly associated with shorter overall patient survival. Systematic analysis identified six HMTs (ASH1L, PRDM6, NSD1, EZH2, WHSC1L1, SETD2) which were dysregulated by genetic alterations as candidate therapeutic targets. Discussion In summary, our findings strongly evidenced that genetic alteration of HMTs may play an important role in generation and development of RCC, which lays a solid foundation for the mechanism for further research in the future.

P57-mediated autophagy promotes the efficacy of EGFR inhibitors in hepatocellular carcinoma.

Abstract: Background & aims Resistance to EGFR-targeted therapy is a major obstacle in hepatocellular carcinoma (HCC) treatment, but its underlying mechanism remains unclear. Autophagy plays a vital role in antitumour treatment. Our previous study suggested that p57 is associated with autophagy and cisplatin resistance. The present study aimed to investigate whether p57 can enhance the sensitivity of HCC cells to Erlotinib (Er)/Cetuximab(C-225) and further explore the potential mechanisms of Er/C-225 resistance. Methods HCC cells were transfected with pIRES2-EGFP-p57 and pIRES2-EGFP-nc, accompanied by Er/C-225 treatment. Cell viability was detected by an Annexin apoptosis kit and MTT assay. Xenograft experiments were performed to study the function of p57 in the treatment of Er/C-225 in vivo. The level of autophagy was determined by analysis of the appearance of autophagic vacuoles. Western blotting was used to investigate the potential pathways involved. Results Up-regulation of p57 decreased the level of Er/C-225-induced autophagy and enhanced the decrease in Er/C-225-induced cell viability. P57 overexpression combined with CQ treatment further enhanced the therapeutic efficiency of Er/C-225. The xenograft experiment verified that p57 up-regulation sensitizes HCC cells to Er/C-225. Moreover, a mechanistic investigation demonstrated that the up-regulation of p57 resulted in a decrease of LC3B-II and beclin-1, and an increase in p-PI3K, p-AKT and p-mTOR protein expressions. Conclusions Through activating the PI3K/AKT/mTOR signalling pathway, p57 can reverse Er/C-225-induced autophagy, and thereby increase the therapeutic efficiency of Er/C-225 treatment. Given these results, p57 up-regulation may be applicable as a therapeutic strategy to improve EGFR-targeted therapy in HCC.

The Prognostic Significance of EIF3C Gene during the Tumorigenesis of Prostate Cancer

Abstract: Prostate cancer (PCa) is the most common malignant tumor for men. But the mechanism is unclear. EIF3C was shown to be overexpressed in PCa tissues and cell lines. EIF3C overexpression was correlated to age and tumor stage in PCa patients and indicated poor survival. The proliferation, migration, and invasiveness of PC3 cells were all inhibited after EIF3C knockdown. Additionally, the phosphorylation level of PI3K and Akt was downregulated while total NF-κB and Myc decreased after EIF3C knockdown. But the expression of IκB increased reversely. Therefore, EIF3C at least partially regulates the activity of PI3K/Akt/NF-κB signaling pathway in PC3 cells.

GABRQ expression is a potential prognostic marker for patients with clear cell renal cell carcinoma.

Abstract: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Novel biomarkers of ccRCC may provide crucial information on tumor features and prognosis. The present study aimed to determine whether the expression of γ-aminobutyric acid (GABA) A receptor subunit θ (GABRQ) could serve as a novel prognostic marker of ccRCC. GABA is the main inhibitory neurotransmitter in the brain that activates the receptor GABAA, which is comprised of three subunit isoforms: GABRA3, GABRB3 and GABRQ. A recent study reported that GABRQ is involved in the initiation and progression of hepatocellular carcinoma; however, the role of GABRQ in ccRCC remains unknown. In the present study, clinical and transcriptomic data were obtained from cohorts of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Differential GABRQ expression levels among early (TI and II), late (TIII and IV), nonmetastatic (M0) and metastatic (M1, primary tumor) stages of ccRCC samples were then identified. Furthermore, the use of GABRQ as a prognostic gene was analyzed using Uno's C-index based on the time-dependent area under the curve (AUC), the AUC of the receiver operating characteristic curve at 5 years, the Kaplan-Meier survival curve and multivariate analysis. The survival curve analysis revealed that low GABRQ mRNA expression was significantly associated with a poor prognosis of ccRCC (P<0.001 and P=0.0012 for TCGA and ICGC data, respectively). In addition, analyses of the C-index and AUC values further supported this discriminatory power. Furthermore, the prognostic value of GABRQ mRNA expression was confirmed by multivariate Cox regression analysis. Taken together, these results suggested that GABRQ mRNA expression may be considered as a novel prognostic biomarker of ccRCC.

Stromal and epithelial mechanisms of chemotherapeutic resistance in pancreatic cancer

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of less than 8 %. Hallmarks of pancreatic cancer are extensive desmoplasia and strong resistance to standard chemotherapeutic agents, e.g. gemcitabine. In this context, impaired drug delivery and drug metabolism pathways might play a crucial role in mediating this pronounced chemoresistance. In this study, I investigated tumor cell intrinsic and extrinsic mechanisms of chemotherapeutic resistance in PDAC. Pharmacokinetic characteristics of gemcitabine (dFdC) were analyzed in the widely used LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model by liquid chromatography tandem mass-spectrometry (LC-MS/MS). Surprisingly, the levels of gemcitabine were elevated in the primary, stroma-rich and hypovascular tumor samples compared with matched normal liver samples and samples from liver metastases. A more detailed analysis by our group revealed an increased ratio of cancer-associated fibroblasts (CAFs) in primary tumors compared to liver metastases. Notably, gemcitabine metabolizing enzymes were highly expressed in epithelial but not stromal cells. The inactivating enzymes cytidine deaminase (CDA), deoxycytidylate deaminase (DCTD), and cytosolic 5’-nucleotidase 1A (NT5C1A) were hardly expressed in the stromal compartment of murine and human PDAC samples in vivo. In contrast, these enzymes were robustly expressed in the epithelial compartment. Consequently, the cytotoxic gemcitabine metabolite dFdCTP accumulated in murine CAFs, as the phosphorylated metabolites are unable to cross the cell membrane. Drug scavenging of CAFs was confirmed in conditioned medium (CM) assays. Incubation of tumor cells with CM of gemcitabine treated CAFs reduced the available amount of gemcitabine for tumor cells in vitro. Due to the low proliferation rate of CAFs in vivo, these cells might have exhibited intrinsic resistance to the increased amounts of dFdCTP. Further experiments were aimed to characterize NT5C1A, a previously unrecognized gemcitabine inactivating enzyme in pancreatic cancer that reverses the initial phosphorylation step of gemcitabine. Immunohistochemical staining of tissue microarrays (TMAs) with more than 400 tumor samples, from two independent cohorts of resected PDAC patients, were used to study the expression pattern of NT5C1A in PDAC. We found robust protein expression in the epithelial compartment of 64-70 % of PDAC patients, whereas robust stromal expression of NT5C1A was detectable in less than 20 % of these patients. A prognostic role of NT5C1A was not observed in both patient cohorts. Recombinant expression of this enzyme was used to elucidate its impact on chemotherapeutic resistance. Re-expression of NT5C1A in pancreatic stellate cells (PSCs) reduced the intracellular levels of the active gemcitabine metabolite dFdCTP, suggesting NT5C1A as novel target for stromal reprogramming. Gemcitabine response in tumor cells overexpressing NT5C1A was investigated using standard biochemical assays and orthotopic transplantation of the modified tumor cells into mice. Indeed, cells overexpressing NT5C1A showed higher resistance towards gemcitabine and had decreased levels of intracellular dFdCTP and of cleaved caspase 3 (CC3) levels following treatment with gemcitabine. Tumor weights were increased in mice that were transplanted with NT5C1A expressing cells compared to control cells upon gemcitabine treatment, showing the relevance of this enzyme in therapeutic effectiveness. Given its role in dephosphorylation of nucleoside monophosphates, NT5C1A overexpression in pancreatic cancer cells did not reduce chemosensitivity towards paclitaxel, a standard chemotherapeutic agent that acts independently of intracellular phosphorylation. In conclusion, our study gave new insight into the impact of drug metabolizing enzymes on chemotherapeutic resistance in PDAC. We demonstrated that alterations in drug metabolism and not impaired drug delivery mainly determine the response to gemcitabine in PDAC. Our results further demonstrated NT5C1A as target for stromal reprogramming. Most importantly, our findings pave the way for a more detailed stratification of patients for treatments and suggest NT5C1A to be considered as a possible predictor of treatment response to gemcitabine in PDAC patients.

Interplays and feedback loops of oncogenic signaling pathways in B cell non-Hodgkin lymphoma

Abstract: The B cell receptor (BCR) signaling, required for the survival and maturation of B cells, is one major deregulated pathway in B cell lymphomas. Several mutations are known to enhance the tonic BCR signal in Burkitt lymphomas (BL) or to mimic an activated receptor in some diffuse large B cell lymphomas (DLBCL). While the proximal events and kinases of the BCR signaling are well studied, less is known about the interactions of downstream effector pathways. As the signaling interplays and feedback loops can influence the therapeutic success, this thesis aims for a better understanding of signaling interplays and for an improvement of oncogenic network models of B cell lymphomas. For this purpose, BCR-related pathway interplays were examined by analyzing several protein phosphorylations with a multiplex immunoassay. Our investigations of pathway activations after thirteen defined perturbations revealed positive as well as negative interplays of pathways downstream of the BCR in BLs. During the tonic and active BCR signaling, the PI3K-AKT pathway, essential for many B cell lymphomas, enhanced its own activation probably through a positive feedback to kinases in close proximity of the BCR. We proposed that the positive feedback loop is one explanation for the potent effects of PI3K, AKT and mTOR inhibitors on BL proliferation. Furthermore, two negative feedbacks on the MEK-ERK pathway were detected after BCR activation. Beside ERK1/2 itself, p38 MAPK negatively influenced upstream kinases of ERK1/2. Interestingly, further fine-tuning of the p38 MAPK and ERK1/2 activation was assumed due to the ERK-mediated upregulation of MKK6 which could contribute to p38 MAPK activation. The mentioned feedbacks were generally identified downstream of the BCR signaling in all examined BL and DLBCL cell lines except for the p38 MAPK-dependent attenuation of the MEK-ERK pathway which was not observed in the DLBCL cell line OCI-LY3. In a second approach, the NF-κB and JAK-STAT-dependent proliferation of B cell lymphomas was investigated. Therefore, the signaling network following TLR9 and IL10R stimulation was analyzed by a phosphoproteom analysis. Our results revealed that the simultaneous activation of TLR9 and IL10R changed over 200 protein phosphorylations influencing cell cycle, metabolism and migration. The direct phosphorylation of CDK2 and JNK was suggested to contribute to the proliferative effect after TLR9 and IL10R activation. The signaling interplays and feedbacks identified in this study provide a deeper insight and refinement of the signaling network structure in lymphomas. Additional improvements of computational network models are advantageous to predict signaling alterations by external influences as well as therapeutic responses.

High expression of GLO1 indicates unfavorable clinical outcomes in glioma patients.

Abstract: Backgrounds Glyoxalase I (GLO1), a ubiquitous enzyme involved in the process of detoxification of methylglyoxal in the cellular glycolysis pathway, was reported to be highly expressed in human tumor. It has also been found that GLO1 is associated with tumor cell survival and proliferation in some types of cancer, such as pancreatic cancer, hepatocellular carcinoma and gastric cancer. However, the role of GLO1 in glioma has not been clarified. The purpose of present study is to explore the expression pattern of GLO1 and whether the expression level of GLO1 is associated with the unfavorable clinical outcomes of patients with glioma. Methods Quantitative RT-PCR and immunohistochemistry staining were used to investigate the mRNA and protein level of GLO1 in glioma tissues together with normal brain tissues. The prognostic role of GLO1 in glioma patients was assessed using univariate and multivariate analyses. Clinical outcomes were estimated by using the Kaplan-Meier analysis and the log-rank test. The function of GLO1 in glioma cell lines were investigated by in vitro experiments. Results Expression level of GLO1 was higher in glioma tissues than that in normal brain tissues. High GLO1 expression was significantly correlated with WHO grade and the poor overall survival time in glioma patients. Moreover, GLO1 was also defined as an unfavorable prognosis factor. Overexpression of GLO1 in the glioma cell line U87 can enhance the tumor cell proliferation, migration and invasion. Whereas, knockdown of GLO1 can suppress those abilities. Conclusions Our studies demonstrated that GLO1 was highly expressed in glioma tissues and significantly correlated with the poor prognosis of glioma patients. It indicated that GLO1 might serve as a new prognostic predictor and therapeutic target for glioma treatment.

[Advances on the anti-inflammatory and protective effect of AMPK activators].

Abstract: AMP-activated protein kinase (AMPK) is a key enzyme in the regulation of cellular energy homeostasis. Recent studies demonstrated that AMPK also plays an important role in the modulation of inflammation, an energy-intensive molecular response. The commonly used AMPK activators include 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and A-769662. In addition, the biological activities of metformin and adiponectin are closely related to activation of AMPK. Numerous studies have shown that these AMPK activators play an effectively protective role in animal models of acute lung injury, asthma, colitis, hepatitis, atherosclerosis and other inflammatory diseases. Therefore, AMPK activators may have promising potential for the prevention and treatment of inflammation related diseases.

Role of stromal SPARC in PDAC tumorigenesis and drug delivery

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors in humans. Median survival is around 12 months and is due to late diagnosis, early metastatic spread, and a high resistance towards available chemotherapeutic regimens. The desmoplastic reaction is a key feature of PDAC which contributes to disease progression and has also been reported to confer to chemoresistance and impaired drug delivery. Secreted protein acidic and rich in cysteine (SPARC) is an important matricellular protein that regulates collagen deposition and ECM remodeling. In human PDAC, SPARC is expressed by peritumoral fibroblasts and high expression is associated with a poor prognosis. In several other cancer entities, SPARC has been shown to play either tumor promoting or tumor suppressing roles. However, the functional role of SPARC in PDAC is unclear. In my thesis, I investigated the expression of SPARC and its role during tumor progression from preneoplastic lesions to frank carcinomas in genetically engineered mouse models (GEMMs) of PDAC. In order to achieve this, I generated SPARCwt, SPARC-/-, KC-SPARCwt and KC-SPARC-/- mice with a global SPARC knock-out for in vivo studies. Furthermore, primary epithelial and fibroblast cell lines were derived from preneoplastic murine tissues and murine pancreas tumors for in vitro experiments. The in vivo results showed that the development of the murine pancreas was unaffected by germ- line SPARC knock-out. Immunohistochemical and western blot analysis revealed that SPARC is not expressed in the normal pancreas with a marked increase of SPARC in activated fibroblasts during preneoplastic stages and tumor progression. However, loss of SPARC in KC-SPARC-/- mice resulted in a significant reduction of intratumoral collagen deposition. Notably, SPARC and subsequent collagen depletion did not alter pancreatic intraepithelial neoplasia (PanIN) progression, tumor incidence or metastatic frequency to the liver. Both KC-SPARCwt and KC-SPARC-/- tumors exhibited similar tumor characteristic including proliferation, apoptosis and mean vessel density. Primary epithelial and fibroblast cell lines from both genotypes showed comparable morphology and proliferation rates. However, tumor bearing KC-SPARC-/- mice lived significantly shorter than of KC-SPARCwt mice, a finding that was most likely due to more severe clinical complications such as ascites, diarrhea and bile duct obstruction in KC-SPARC-/- mice. Interestingly, SPARC mediated collagen deposition did not impede the delivery and metabolism of gemcitabine in pre-neoplastic lesions and tumors as determined by LC-MS/MS. Strikingly, the amount of gemcitabine increased from normal pancreas tissues to pancreatic tumors questioning the drug delivery hypothesis for gemcitabine in PDAC.

Investigating the Anti-Cancer Properties of Novel Hybrid 1,4-Dihydropyridine Derivatives in U-87MG Glioblastoma Cell

Abstract: Glioblastoma is the most devastating of brain cancers with a very high death rate and a low survival rate of less than 15 months after diagnosis. Glioblastoma is a cancer of astrocytes which are the majority of the brain glial cells that support neurons and help create the blood-brain barrier among other functions. The current approach to treating this disease is surgical removal of the main tumor, followed by radiotherapy and limited chemical intervention by the use of temozolomide (TMZ). This disease is characterized by high invasion and recurrence after surgical removal of the main tumor as a result of cancerous astrocytes migrating from the main tumor site to other parts of the brain. Novel dihydropyridines were synthesized and their effects tested on glioblastoma cell line U-87MG to screen for their anti-cancer activities. Cell viability assays were performed to establish the (lethal concentration) LC50 of these compounds. The novel hybrid dihydropyridines reduced the cell viability of U-87MG cells, with the substituted aromatic compounds being more potent than substituted heteroaromatic compounds.