Current Cancer Drug Targets - Volume 20, Issue 1, 2020

The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway is one of the most important pathways responsible for tumor angiogenesis. Currently, two monoclonal antibodies, anti-VEGF-A antibody Bevacizumab and anti-VEGFR2 antibody Ramucizumab, have been approved for the treatment of solid tumors. At the same time, VEGF/VEGFR2 signaling is involved in the regulation of immune responses. It is reported that the inhibition of this pathway has the capability to promote vascular normalization, increase the intra-tumor infiltration of lymphocytes, and decrease the number and function of inhibitory immune cell phenotypes, including Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2 macrophages. On this basis, a number of clinical studies have been performed to investigate the therapeutic potential of VEGF/VEGFR2-targeting antibodies plus programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) inhibitors in various solid tumor types. In this context, VEGF/VEGFR2- targeting antibodies, Bevacizumab and Ramucizumab are briefly introduced, with a description of the differences between them, and the clinical studies involved in the combination of Bevacizumab/ Ramucizumab and PD-1/PD-L1 inhibitors are summarized. We hope this review article will provide some valuable clues for further clinical studies and usages.

Cancer and infectious diseases are one of the greatest challenges of modern medicine. An unhealthy lifestyle, the improper use of drugs, or their abuse are conducive to the increase of morbidity and mortality caused by these diseases. The imperfections of drugs currently used in therapy for these diseases and the increasing problem of drug resistance have forced a search for new substances with therapeutic potential. Throughout history, plants, animals, fungi and microorganisms have been rich sources of biologically active compounds. Even today, despite the development of chemistry and the introduction of many synthetic chemotherapeutics, a substantial part of the new compounds being tested for treatment are still of natural origin. Natural compounds exhibit a great diversity of chemical structures, and thus possess diverse mechanisms of action and molecular targets. Nucleic acids seem to be a good molecular target for substances with anticancer potential in particular, but they may also be a target for antimicrobial compounds. There are many types of interactions of small-molecule ligands with DNA. This publication focuses on the intercalation process. Intercalators are compounds that usually have planar aromatic moieties and can insert themselves between adjacent base pairs in the DNA helix. These types of interactions change the structure of DNA, leading to various types of disorders in the functioning of cells and the cell cycle. This article presents the most promising intercalators of natural origin, which have aroused interest in recent years due to their therapeutic potential.

Targeted drug delivery systems gave newer dimensions for safer and more effective use of therapeutic drugs, thus helping in circumventing the issues of toxicity and unintended drug accumulation. These ongoing developments in delivery systems can, in turn, bring back drugs that suffered various limitations, Ellipticine (EPT) being a candidate. EPT derivatives witnessed entry into clinical settings but failed to survive in clinics citing various toxic side effects. A large body of preclinical data deliberates the potency of drug delivery systems in increasing the efficiency of EPT/derivatives while decreasing their toxic side effects. Recent developments in drug delivery systems provide a platform to explore EPT and its derivatives as good clinical candidates in treating tumors. The present review deals with delivery mechanisms of EPT/EPT derivatives as antitumor drugs, in vitro and in vivo, and evaluates the suitability of EPT-carriers in clinical settings.

Background: Graphene oxide (GO) has unique physical and chemical properties that can be used in anticancer therapy - especially as a drug carrier. Graphene oxide, due to the presence of several hybrid layers of carbon atoms (sp2), has a large surface for highly efficient drug loading. In addition, GO with a large number of carboxyl, hydroxyl and epoxy groups on its surface, can charge various drug molecules through covalent bonds, hydrophobic interactions, hydrogen bonds and electrostatic interactions. Objective: The aim of our work was to evaluate the possibility of future use of graphene oxide as an anticancer drug carrier. Methods: In this paper, we present GO synthesis and characterization, as well as a study of its biological properties. The cytotoxic effect of well-defined graphene oxide was tested on both carcinoma and non-malignant cells isolated from the same organ, which is not often presented in the literature. Results: The performed research confirmed that GO in high concentrations (> 300 μgmL-1) selectively decreased the viability of cancer cell line. Additionally, we showed that the GO flakes have a high affinity to cancer cell nucleus which influences their metabolism (inhibition of cancer cell proliferation). Moreover, we have proved that GO in high concentrations can cause cell membrane damage and generate reactive oxygen species on a low level mainly in cancer cells. Conclusion: The proposed GO could be useful in anticancer therapy. A high concentration of GO selectively causes the death of tumor cells, whereas GO with low concentration could be a potential material for anticancer drug loading.

Background: Forkhead box C1 (FOXC1) is an important cancer-associated gene in tumor. PPAR-γ and C/EBPα are both transcriptional regulators involved in tumor development. Objective: We aimed to clarify the function of PPAR-γ, C/EBPα in hepatocellular carcinoma (HCC) and the relationship of PPAR-γ, C/EBPα and FOXC1 in HCC. Methods: Western blotting, immunofluorescent staining, and immunohistochemistry were used to evaluate protein expression. qRT-PCR was used to assess mRNA expression. Co-IP was performed to detect the protein interaction. And ChIP and fluorescent reporter detection were used to determine the binding between protein and FOXC1 promoter. Results: C/EBPα could bind to FOXC1 promoter and PPAR-γ could strengthen C/EBPα’s function. Expressions of C/EBPα and PPAR-γ were both negatively related to FOXC1 in human HCC tissue. Confocal displayed that C/EBPα was co-located with FOXC1 in HepG2 cells. C/EBPα could bind to FOXC1 promoter by ChIP. Luciferase activity detection exhibited that C/EBPα could inhibit FOXC1 promoter activity, especially FOXC1 promoter from -600 to -300 was the critical binding site. Only PPAR-γ could not influence luciferase activity but strengthen inhibited effect of C/EBPα. Further, the Co-IP displayed that PPAR-γ could bind to C/EBPα. When C/EBPα and PPAR-γ were both high expressed, cell proliferation, migration, invasion, and colony information were inhibited enormously. C/EBPα plasmid combined with or without PPAR-γ agonist MDG548 treatment exhibited a strong tumor inhibition and FOXC1 suppression in mice. Conclusion: Our data establish C/EBPα targeting FOXC1 as a potential determinant in the HCC, which supplies a new pathway to treat HCC. However, PPAR-γ has no effect on FOXC1 expression.

Background: Brefeldin A (BFA) has been known to induce endoplasmic reticulum stress (ERS) and Golgi body stress in cancer cells. ERGIC3 (endoplasmic reticulum-Golgi intermediate compartment 3) is a type II transmembrane protein located in the endoplasmic reticulum and Golgi body. ERGIC3 over-expression is frequently observed in cancer cells. Objective: In this study, we aim to explore whether BFA administered concurrently with ERGIC3 silencing would work additively or synergistically inhibit cancer cell growth. Methods: ERGIC3-siRNA was used to knock-down the expression of ERGIC3 and BFA was used to induce ERS in lung cancer cell lines GLC-82 and A549. Q-RT-PCR and Western Blot analysis were used to detect the expression of ERGIC3 and downstream molecules. GraphPad Prism 6 was used to quantify the data. Results: We demonstrated that silencing of ERGIC3 via siRNA effectively led to down-regulation of ERGIC3 at both mRNA and protein levels in GLC-82 and A549 cells. While BFA or ERGIC3- silencing alone could induce ERS and inhibit cell growth, the combination treatment of lung cancer cells with ERGIC3-silencing and BFA was able to additively enhance the inhibition effects of cell growth through up-regulation of GRP78 resulting in cell cycle arrest. Conclusion: ERGIC3 silencing in combination with BFA treatment could additively inhibit lung cancer cell growth. This finding might shed a light on new adjuvant therapy for lung adenocarcinoma.

Background: Src associated with mitosis of 68 kDa (Sam68), is often highly expressed in human cancers. Overexpression of Sam68 has been shown to be correlated with poor survival prognosis in some cancer patients. However, little is known whether Sam68 plays a role in promoting metastasis in breast cancer. Materials and Methods: The expression of Sam68 protein in breast cancer tissue was detected by immunohistochemistry. Trans-well assay, wound-healing, real-time PCR and Western blotting analysis were used to detect the effect of Sam68 on promoting EMT or metastasis of breast cancer. Next-generation RNA sequencing was used to analyze genes that may be regulated by Sam68. Results: Sam68 plays a positive role in promoting breast cancer metastasis. Sam68 was found to be overexpressed in breast cancer along with lymph node metastasis. MMP-9 was also found to be overexpressed in breast cancer tissue and was correlated to the expression of Sam68 (P<0.01). Xenograft in NOD/SCID mice and in vitro experiments confirmed that the invasion and metastatic ability of breast cancer cells were regulated by Sam68. And EPHA3 could be up-regulated by Sam68 in breast cancer. Conclusion: High expression of Sam68 participates in breast cancer metastasis by up-regulating the EPHA3 gene.