Current Cancer Drug Targets - Volume 23, Issue 5, 2023

Background: In the last decade, cancer has been a leading cause of death worldwide. Despite the impressive progress in cancer therapy, firsthand treatments are not selective to cancer cells and cause serious toxicity. Thus, the design and development of selective and innovative small molecule drugs is of great interest, particularly through in silico tools. Objective: The aim of this review is to analyze different subsections of computer-aided drug design (CADD) in the process of discovering anticancer drugs. Methods: Articles from the 2008-2021 timeframe were analyzed and based on the relevance of the information and the JCR of its journal of precedence, were selected to be included in this review. Results: The information collected in this study highlights the main traditional and novel CADD approaches used in anticancer drug discovery, its sub-segments, and some applied examples. Throughout this review, the potential use of CADD in drug research and discovery, particularly in the field of oncology, is evident due to the many advantages it presents. Conclusion: CADD approaches play a significant role in the drug development process since they allow a better administration of resources with successful results and a promising future market and clinical wise.

Gastrointestinal cancers are prevalent cancers in the world with a poor prognosis, causing about one-half of all cancer deaths in the world. Unfortunately, there is no effective treatment for GI cancers. GHRH and GHRH receptors (GHRH-R) are expressed in various tumoral tissues and cell lines. The inhibition of GHRH-R is a new area of research because it provides a possible means of treating several types of cancer. Recent publications have reported GHRH and GHRH-R expressions in breast, pancreatic, prostate, colon, gastric, ovarian, and lung cancers, along with promising data about the use of GHRH antagonists in the treatment of different cancers. This review aims to summarize the recent studies on the relationship between GHRH and GI cancers and assess whether this hormone can be our target for therapy or used as a prognostic marker for GI cancers.

Immunotherapy has completely changed the treatment pattern of lung cancer and significantly prolonged the overall survival of patients, especially for advanced patients. However, a large number of lung cancer patients are unable to benefit from immunotherapy, which forces us to find new therapeutic targets to overcome drug resistance to immunotherapy. Cyclical GMP-AMP synthetase (cGAS) recognizes cytoplasmic DNA and promotes the formation of cyclical GMP-AMP (cGAMP), activates stimulator of interferon genes (STING), then induces the expression of varieties proinflammatory cytokines and chemokines, and then promotes the cross-presentation of dendritic cells (DCs) and initiates tumor-specific CD8+T cell response, showing great potential to overcome resistance and enhance antitumor immunity. In this review, we describe recent advances in the biological function,activation mode, and current applications of cGAS-STING pathway in lung cancer therapy. We also describe the mechanisms of the inactivation of cGAS-STING pathway in lung cancer cells, hoping to promote the progress of immunotherapy of lung cancer by targeting cGAS-STING pathway.

Background: The mechanism of metastasis-associated lung adenocarcinoma transcript 1 (Malat1) in triple-negative breast cancer (TNBC) is still unclear. Objective: This study aimed to investigate the role of miR-141-3p and Malat1 in autophagy in TNBC under hypoxia. Methods: The expression levels of Malat1 and miR-141-3p were detected via quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression levels of hypoxia-inducible factor 1α (HIF-1α), HIF-2α, MMP9, p62 and LC3 were determined via western blotting. A Cell Counting Kit-8 assay was used to detect cell viability, while a Transwell assay to detect cell proliferation and invasion. A luciferase assay was used to confirm the relationship between Malat1 and miR-141-3p. Results: A significant increase was observed in the expression level of Malat1 and the autophagic activity in TNBC tissues and cells. The expression level of Malat1 was higher in a hypoxic environment, which can significantly promote the proliferation, migration, and invasion of TNBC cells by activating autophagy. HIF-1α, but not HIF-2α, was identified to induce the upregulation of Malat1 in TNBC cells. The dual-luciferase assay results identified a miR-141-binding site in Malat1. Malat1 knockdown and miR-141-3p overexpression were demonstrated to significantly inhibit autophagy, thereby inhibiting cell proliferation, invasion, and migration. Moreover, hypoxia can inhibit the effect of miR-141-3p on TNBC cells. Conclusion: miR-141-3p could suppress autophagy and inhibit proliferation, migration, and invasion by targeting Malat1 in TNBC cells under hypoxia. The existence of the HIF-1α/Malat1/miR-141 axis plays a vital role in the development of TNBC and may be a target for the diagnosis and treatment of TNBC.

Background: Geiparvarin (GN) is a natural compound isolated from the leaves of Geijera parviflora and exhibits anticancer activity. Nevertheless, little is known about its anticancer mechanism and anti-osteosarcoma (OS) effects. Aim: This study explored whether GN effectively inhibits the growth and metastasis of osteosarcoma (OS) through a series of in vitro and in vivo experiments. Methods: Cell proliferation was measured by colony formation and MTT assays, and cell invasion was detected by Transwell assay. Flow cytometry and caspase-3 activity assays were carried out to examine cell apoptosis, and western blot analysis was performed to assess protein expression. In the animal experiments, the changes in relevant indexes were determined by immunohistochemistry and tumor vessel imaging. Results: Animal experiments showed that GN treatment significantly inhibited the growth and lung metastasis of OS, accompanied by increased apoptosis. In addition, GN treatment notably diminished COX2 expression and angiogenesis in OS. Moreover, COX2 overexpression nullified GN-induced decline in angiogenesis, growth, and lung metastasis and increased apoptosis in OS. Of note, the body weight of mice was enhanced after GN treatment, and the pathological examination manifested that GN treatment did not cause any damage to major organs. Conclusion: Our data indicated that GN might depress the growth, metastasis, and angiogenesis of OS by decreasing COX2 expression, suggesting GN is a favorable candidate drug for OS treatment without side effects. Hence, it can be concluded that geiparvarin inhibits OS progression by reducing COX2 expression.

Background: Bacterial pore-forming toxins, BinA and BinB together known as the binary toxin are potent insecticidal proteins, that share structural homology with antitumor bacterial parasporin-2 protein. The underlying molecular mechanism of Bin toxin-induced cancer cell cytotoxicity requires more knowledge to understand whether the toxin induced human cytotoxic effects occur in the same way as that of parasporin-2 or not. Methods: In this study, anticancer properties of Lysinibacillus sphaericus derived Bin toxin on HK1 were evaluated through MTT assay, morphological analysis and lactate dehydrogenase efflux assay. Induction of apoptosis was determined from RT-qPCR, caspase activity and cytochrome c release assay. Internalization pattern of Bin toxin in HK1 cells was studied by confocal laser-scanning microscopic analysis. Results: Activated Bin toxin had strong cytocidal activity to HK1 cancer cell line at 24 h postinoculation. Both BinA and BinB treated HK1 cells showed significant inhibition of cell viability at 12 μM. Induction of apoptotic mediators from RT-qPCR and caspase activity analyses indicated the activation of programmed cell death in HK1 cells in response to Bin toxin treatment. Internalization pattern of Bin toxin studied by using confocal microscopy indicated the localization of BinA on cell surface and internalization of BinB in the cytoplasm of cancer cells as well as colocalization of BinA with BinB. Evaluation of cytochrome c release also showed the association of BinB and BinA+BinB with mitochondria. Conclusion: Bin toxin is a cytotoxic protein that induces cytotoxic and apoptotic events in HK1 cells, and may have high therapeutic potential as an anti-cancer agent.

Background: Stromal cells in the tumor microenvironment play crucial roles in glioma development. Current methods for isolating tumor-associated stromal cells (such as neutrophils) are inefficient due to the conflict between tissue dissociation and cell surface protein protection, which hampers the research on patient-derived stromal cells. Our study aims to establish a novel method for isolating glioma-associated neutrophils (GANs). Methods: To observe neutrophil-like polymorphonuclear cells, we performed Hematoxylin-Eosin staining on glioma tissues. For isolating single cells from glioma tissues, we evaluated the efficiency of tissue dissociation with FastPrep Grinder-mediated homogenization or proteases (trypsin or papain) digestion. To definite specific markers of GANs, fluorescence-activated cell sorting (FACS) and immunofluorescence staining were performed. FACS and Ficoll were performed for the separation of neutrophils from glioma tissue-derived single-cell or whole blood pool. To identify the isolated neutrophils, FACS and RT-PCR were carried out. Results: Neutrophil-like cells were abundant in high-grade glioma tissues. Among the three tissue dissociation methods, papain digestion produced a 5.1-fold and 1.7-fold more living cells from glioma mass than physical trituration and trypsin digestion, respectively, and it preserved over 97% of neutrophil surface protein markers. CD66B could be adopted as a unique neutrophil surface protein marker for FACS sorting in glioma. Glioma-derived CD66B+ cells specifically expressed neutrophil marker genes. Conclusion: A combination of papain-mediated tissue dissociation and CD66B-mediated FACS sorting is an effective novel method for the isolation of GANs from glioma tissues.

Background: Treatment with immune checkpoint inhibitors has improved both progressionfree survival and overall survival in a subset of patients with tumors. However, the selection of patients who benefit from immune checkpoint inhibitor treatment remains challenging. Positron Emission Tomography (PET) is a non-invasive molecular imaging tool that offers a promising alternative to the current IHC for detecting the PD-L1 expression in malignant cells in vivo, enabling patient selection and predicting the response to individual patient immunotherapy treatment. Objectives: Herein, we report the development of novel [¹⁸F]labeled pyridine-2-carboxamide derivatives [¹⁸F]2 and [¹⁸F]3 as small-molecule probes for imaging immune checkpoint (PD-1/PD-L1) in cancer using PET. Methods and Results: [¹⁸F]2 and [¹⁸F]3 were prepared by a one-step radiofluorination in 44 ± 5% and 30 ± 4% radiochemical yield and > 98% radiochemical purity for a potential clinical translation. The total synthesis time, including HPLC purification, was less than 45 min. [¹⁸F]2 and [¹⁸F]3 showed excellent stability in injection solution and a significant accumulation and retention in PD-1/PD-L1 expressing MDA-MB-231 breast cancer and in HeLa cervix carcinoma cells (2- 5 cpm/1000 cells). In addition, autoradiographic analysis and inhibition experiments on tumor slices confirm the potential of both compounds as specific imaging probes for the PD-1/PD-L1 axis in tumors. Conclusion: The in vitro evaluation in PD-L1 expressing cells together with results from autoradiographic analysis in PD-L1 positive tumor sections, suggest that [¹⁸F]2 and [¹⁸F]3 could be potential imaging probes for assessing PD-L1 expression in tumors and warrant further biological evaluations in vivo.