Current Cancer Drug Targets - Volume 21, Issue 1, 2021

Brain tumors are responsible for high morbidity and mortality worldwide. Several factors such as the presence of blood-brain barrier (BBB), sensitive location in the brain, and unique biological features challenge the treatment of brain tumors. The conventional drugs are no longer effective in the treatment of brain tumors, and scientists are trying to find novel therapeutics for brain tumors. In this way, identification of molecular pathways can facilitate finding an effective treatment. c-Myc is an oncogene signaling pathway capable of regulation of biological processes such as apoptotic cell death, proliferation, survival, differentiation, and so on. These pleiotropic effects of c-Myc have resulted in much fascination with its role in different cancers, particularly brain tumors. In the present review, we aim to demonstrate the upstream and down-stream mediators of c-Myc in brain tumors such as glioma, glioblastoma, astrocytoma, and medulloblastoma. The capacity of c-Myc as a prognostic factor in brain tumors will be investigated. Our goal is to define an axis in which the c-Myc signaling pathway plays a crucial role and to provide direction for therapeutic targeting in these signaling networks in brain tumors.

CYP1A1 and CYP1B1 are extrahepatic P450 family members involved in the metabolism of procarcinogens, such as PAHs, heterocyclic amines and halogen-containing organic compounds. CYP1A1/1B1 also participate in the metabolism of endogenous 17-β-estradiol, producing estradiol hydroquinones, which are the intermediates of carcinogenic semiquinones and quinones. CYP1A1 and CYP1B1 proteins share approximately half amino acid sequence identity but differ in crystal structures. As a result, CYP1A1 and CYP1B1 have different substrate specificity to chemical procarcinogens. This review will introduce the general molecular biology knowledge of CYP1A1/1B1 and the metabolic processes of procarcinogens regulated by these two enzymes. Over the last four decades, a variety of natural products and synthetic compounds which interact with CYP1A1/1B1 have been identified as effective chemo-preventive agents against chemical carcinogenesis. These compounds are mainly classified as indirect or direct CYP1A1/1B1 inhibitors based on their distinct mechanisms. Indirect CYP1A1/1B1 inhibitors generally impede the transcription and translation of CYP1A1/1B1 genes or interfere with the translocation of aryl hydrocarbon receptor (AHR) from the cytosolic domain to the nucleus. On the other hand, direct inhibitors inhibit the catalytic activities of CYP1A1/1B1. Based on the structural features, the indirect inhibitors can be categorized into the following groups: flavonoids, alkaloids and synthetic aromatics, whereas the direct inhibitors can be categorized into flavonoids, coumarins, stilbenes, sulfur containing isothiocyanates and synthetic aromatics. This review will summarize the in vitro and in vivo activities of these chemo-preventive agents, their working mechanisms, and related SARs. This will provide a better understanding of the molecular mechanism of CYP1 mediated carcinogenesis and will also give great implications for the discovery of novel chemo-preventive agents in the near future.

Lung cancer is the leading type of cancer worldwide today. Kinases play a crucial role in mediating the signaling pathways, and it directs to control several necessary cellular processes. Conversely, the deregulation of tyrosine kinases leads to oncogenic conversion, uncontrolled cell proliferation and tumorigenesis. Tyrosine kinases are largely deregulated in lung cancer and specifically in non-small cell lung cancer (NSCLC). Therefore, the inhibition of pathogenic kinases is a breakthrough development in cancer research, treatment and care, which clinically improve the quality of life. In the last decades, various single or combination inhibitors are approved by U.S Food and Drug Administration (FDA) and commercially available in clinics, and currently, several preclinical studies are ongoing and examining the kinase inhibitors. However, many gaps remain in understanding the mechanisms of kinase inhibitors and their selectivity. In this analysis, we focus on a class of receptor and non-receptor tyrosine kinase inhibitors and their novel role in lung cancer.

Background: Conjugation to clinical-grade tumor penetrating iRGD peptide is a widely used strategy to improve tumor homing, extravasation, and penetration of cancer drugs and tumor imaging agents. The C domain of the extracellular matrix molecule Tenascin-C (TNC-C) is upregulated in solid tumors and represents an attractive target for clinical-grade single-chain antibody- based vehicles for tumor delivery drugs and imaging agents. Objective: To study the effect of C-terminal genetic fusion of the iRGD peptide to recombinant anti- TNC-C single-chain antibody clone G11 on systemic tumor homing and extravasation. Methods: Enzyme-linked immunosorbent assay was used to study the interaction of parental and iRGD-fused anti-TNC-C single-chain antibodies with C domain of tenascin-C and αVβ3 integrins. For systemic homing studies, fluorescein-labeled ScFV G11-iRGD and ScFV G11 antibodies were administered in U87-MG glioblastoma xenograft mice, and their biodistribution was studied by confocal imaging of tissue sections stained with markers of blood vessels and Tenascin C immunoreactivity. Results: In a cell-free system, iRGD fusion to ScFV G11 conferred the antibody has a robust ability to bind αVβ3 integrins. The fluorescein labeling of ScFV G11-iRGD did not affect its target binding activity. In U87-MG mice, iRGD fusion to ScFV G11 antibodies improved their homing to tumor blood vessels, extravasation, and penetration of tumor parenchyma. Conclusion: The genetic fusion of iRGD tumor penetrating peptide to non-internalizing affinity targeting ligands may improve their tumor tropism and parenchymal penetration for more efficient delivery of imaging and therapeutic agents into solid tumor lesions.

Background: Abnormal spindle-like microcephaly-associated protein (ASPM) has been implicated in the aggressive behavior of several malignant tumors. However, its potential effects on diffuse large B-cell lymphoma (DLBCL) still remain unknown. Methods: ASPM levels were determined by immunohistochemically in DLBCL tissues from 54 patients and 15 reactive lymphoid hyperplasia (RLH) tissues as control, and its association with clinical features and overall survival were evaluated. The effects of ASPM on cell growth, cell apoptosis and cell cycle of DLBCL cells were assessed. Bioinformatics, quantitative RT-PCR and western blotting were conducted for mechanic investigation. Results: ASPM expression was upregulated in DLBCL tissues compared with RLH tissues. Its high expression was correlated with inferior clinicopathological characteristics and poor outcomes of DLBCL patients. Multivariate analysis revealed that high ASPM expression emerged as an independent factor for poor prognosis. In DLBCL cell lines, silencing of ASPM suppressed cell growth, induced cell apoptosis and arrested the cell cycle. Mechanically, effects of ASPM knockdown on DLBCL cells were partially dependent on its block of the Wnt/β-catenin pathway. Conclusion: Collectively, our results suggested that ASPM potentially served as a predictive biomarker of DLCBL tumorigenesis and prognosis, representing a potential therapeutic target for DLCBL.