Current Cancer Drug Targets - Volume 19, Issue 11, 2019

Src homolog and collagen homolog (Shc) proteins have been identified as adapter proteins associated with cell surface receptors and have been shown to play important roles in signaling and disease. Shcbp1 acts as a Shc SH2-domain binding protein 1 and is involved in the regulation of signaling pathways, such as FGF, NF-ΚB, MAPK/ERK, PI3K/AKT, TGF-β1/Smad and β -catenin signaling. Shcbp1 participates in T cell development, the regulation of downstream signal transduction pathways, and cytokinesis during mitosis and meiosis. In addition, Shcbp1 has been demonstrated to correlate with Burkitt-like lymphoma, breast cancer, lung cancer, gliomas, synovial sarcoma, human hepatocellular carcinoma and other diseases. Shcbp1 may play an important role in tumorigenesis and progression. Accordingly, recent studies are reviewed herein to discuss and interpret the role of Shcbp1 in normal cell proliferation and differentiation, tumorigenesis and progression, as well as its interactions with proteins.

Background: The solute carrier family 7 (SLC7) can be categorically divided into two subfamilies, the L-type amino acid transporters (LATs) including SLC7A5-13, and SLC7A15, and the cationic amino acid transporters (CATs) including SLC7A1-4 and SLC7A14. Members of the CAT family transport predominantly cationic amino acids by facilitating diffusion with intracellular substrates. LAT1 (also known as SLC7A5), is defined as a heteromeric amino acid transporter (HAT) interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide to uptake not only large neutral amino acids, but also several pharmaceutical drugs to cells. Methods: In this review, we provide an overview of the interaction of the structure-function of LAT1 and its essential role in cancer, specifically, its role at the blood-brain barrier (BBB) to facilitate the transport of thyroid hormones, pharmaceuticals (e.g., I-DOPA, gabapentin), and metabolites into the brain. Results: LAT1 expression increases as cancers progress, leading to higher expression levels in highgrade tumors and metastases. In addition, LAT1 plays a crucial role in cancer-associated reprogrammed metabolic networks by supplying tumor cells with essential amino acids. Conclusion: The increasing understanding of the role of LAT1 in cancer has led to an increase in interest surrounding its potential as a drug target for cancer treatment.

Complex nature of the tumor is depicted at the cellular landscape by showing heterogeneity in the presence of cancer cells, cancer-associated stromal cells, mesenchymal stem cells and cancer stem cells (CSCs). One of the plausible views in cancer formation is suggested as the theory of cancer CSCs that is known as a source of initiation of tumorigenesis. In essence, these powerful CSCs are equipped with high Sonic Hedgehog (SHH) signaling and epigenetic memory power that support various tumor hallmarks. Truly, nature justifies its intent by limiting these stem cells with a potential to turn into CSCs and in turn suppressing the high risk of humans and other organisms. In short, this mini-review addresses the contribution of SHH signaling to allow reprogramming of epigenetic memory within CSCs that support tumor hallmarks. Besides, this paper explores therapeutic approaches to mitigate SHH signaling that may lead to a blockade of the pro-tumor potential of CSCs.

Background: Diabetes Mellitus (DM) accelerates progress of lung cancer. Hyperglycemia, a critical feature of DM, promotes lung cancer metastasis. Mogroside V is a triterpenoid glycoside from Siraitia grosvenorii. Interestingly, mogroside V not only plays an anti-diabetic role, but also has anti-tumor effects. Objective: In this study, we investigated the metastatic efficiency of mogroside V in lung cancer cells cultured in hyperglycemia. Methods: Two lung cancer cell lines-A549 and H1299 were cultured in normoglycemia (5.5mM glucose) and hyperglycemia (25mM glucose). Cellular proliferation was tested by MTT, invasion was examined by transwell assay, migration was measured by wound healing assay, cytoskeleton was stained by Phalloidin-TRITC and the expressions of EMT markers and Rho-GTPase family protein were detected by western blot. Results: Hyperglycemia promoted the invasion and migration of A549 and H1299 cells compared with normoglycemia. Mogroside V inhibited the hyperglycemia-induced invasion and migration. Hyperglycemia promoted epithelial-mesenchymal transition (EMT), while mogroside V could reverse this process through up-regulating E-Cadherin expression and down-regulating N-Cadherin, Vimentin, Snail expressions. Furthermore, mogroside V fractured microfilaments and reduced Rho A, Rac1, Cdc42 and p-PAK1 expressions under hyperglycemic conditions. Conclusion: These results suggest that mogroside V inhibits hyperglycemia-induced lung cancer cells migration and invasion through reversing EMT and damaging cytoskeleton.

Background: The expression of programmed cell death ligands on tumor cells has a role in the suppression of antitumor immunity, resulting in tumor immune evasion. Objective: In this study, we evaluated the prognostic value of the soluble form of programmed death-ligand1 (sPD-L1) in Egyptian hepatocellular carcinoma (HCC) patients. Methods: This prospective cohort study was performed between November 2016 to November 2018 on 85 individuals (25 HCC patients, 25 HCC with vascular invasion and/or extrahepatic metastasis, 25 patients with liver cirrhosis, 10 healthy controls). The levels of sPD-L1 were determined in all subjects and compared in different groups and stages of cirrhosis and HCC. The association between sPD-L1 levels and overall survival (OS) was assessed. Results: Significant statistical difference in sPD-L1 was detected between different study groups. The cut-off value for normal sPD-L1 was defined by high sPD-L1 levels determined in a healthy control cohort. It was 2.522 ng/ml. In HCC patients, cut-off value was 7.42 ng/ml (sensitivity 88%, specificity 100%). In HCC with vascular invasion or metastasis, cut–off value was 9.62 ng/ml (sensitivity 88%, specificity 88%). Patients with high serum sPD-L1 or serum bilirubin concentrations had an increased risk of mortality. Conclusion: High sPD-L1 level could be a possible prognostic indicator for a poor outcome in liver cirrhosis and HCC patients. The predictive value of sPD-L1 levels for a successful anti- PD1/PD-L1 therapy should be investigated in the future.

Background: Intestinal β-glucuronidase enzyme has a significant importance in colorectal carcinogenesis. Specific inhibition of the enzyme helps prevent immune reactivation of the glucuronide- carcinogens, thus protecting the intestine from ROS (Reactive Oxidative Species) mediatedcarcinogenesis. Objectives: Advancement in In-silico based techniques has provided a broad range of studies to carry out the drug design and development process smoothly using SwissADME and BOILED-Egg tools. Methods: In our designed case study, we used SwissADME and BOILED-Egg predictive computational tools to estimate the physicochemical, human pharmacokinetics, drug-likeness, medicinal chemistry properties and membrane permeability characteristics of our recently In-vitro evaluated novel β-Glucuronidase inhibitors. Results: Out of the eleven screened potent inhibitors, compound (8) exhibited excellent bioavailability radar against the six molecular descriptors, good (ADME) Absorption, Distribution, Metabolism and Excretion along with P-glycoprotein, CYP450 isozymes and membranes permeability profile. On the basis of these factual observations, it is to be predicted that compound (8) can achieve in-vivo experimental clearance efficiently, Therefore, in the future, it can be a drug in the market to treat various disorders associated with the overexpression of β-Glucuronidase enzyme such as various types of cancer, particularly hormone-dependent cancer such as (breast, prostate, and colon cancer). Moreover, other compounds (1-7, & 9-11), have also shown good predictive pharmacokinetics, medicinal chemistry, BBB and HIA membranes permeability profiles with slight lead optimization to obtain improved results. Conclusion: In consequence, in-silico based studies are considered to provide robustness for a rational drug design and development approach to avoid the possibility of failures of drug candidates in the later stages of drug development phases. The results of this study effectively reveal the possible attributes of potent β-Glucuronidase inhibitors, for further experimental evaluation.

Background: Lung cancer is the most common cancer with a high mortality rate. The diagnosis only at advanced stages and lack of effective treatment are the main factors responsible for high mortality. Tobacco smoke is the major responsible factor for inflammation and tumor development in lungs. Objective: The present study was carried out to identify differentially expressed proteins and elucidate their role in carcinogenesis. Methods: The lung cancer was developed in Wistar rats by using NNK as carcinogen and cancer development was confirmed by histopathological examination. The 2D SDS PAGE was used to analyse total proteins and find out differentially expressed proteins in NNK treated lung tissue vis-a-vis control tissue. The findings of proteomic analysis were further validated by quantification of corresponding transcripts using Real Time PCR. Finally, Cytoscape was used to find out protein-protein interaction. Results: The histopathological examinations showed neoplasia at 9th month after NNK treatment. The proteomic analysis revealed several differentially expressed proteins, four of which were selected for further studies. (TOM34, AL1A1, PADI2 and KLRBA) that were up regulated in NNK treated lung tissue. The real time analysis showed over expression of the genes coding for the selected proteins. Thus, the proteomic and transcriptomic data corroborate each other. Further, these proteins showed interaction with the members of NF-ΚB family and STAT3. Conclusion: We conclude that these proteins play a substantial role in the induction of lung cancer through NF-ΚB and STAT3 pathway. Therefore, these may have the potential to be used as therapeutic targets and for early detection of lung cancer.