Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 20, 2023

According to a 2020 WHO study, cancer is responsible for one in every six fatalities. One in four patients die due to side effects and intolerance to chemotherapy, making it a leading cause of patient death. Compared to traditional tumor therapy, emerging treatment methods, including immunotherapy, gene therapy, photothermal therapy, and photodynamic therapy, have proven to be more effective. The aim of this review is to highlight the role of gold nanoparticles in advanced cancer treatment. A systematic and extensive literature review was conducted using the Web of Science, PubMed, EMBASE, Google Scholar, NCBI, and various websites. Highly relevant literature from 141 references was chosen for inclusion in this review. Recently, the synergistic benefits of nano therapy and cancer immunotherapy have been shown, which could allow earlier diagnosis, more focused cancer treatment, and improved disease control. Compared to other nanoparticles, the physical and optical characteristics of gold nanoparticles appear to have significantly greater effects on the target. It has a crucial role in acting as a drug carrier, biomarker, anti-angiogenesis agent, diagnostic agent, radiosensitizer, cancer immunotherapy, photodynamic therapy, and photothermal therapy. Gold nanoparticle-based cancer treatments can greatly reduce current drug and chemotherapy dosages.

Background: Many ceramidase inhibitors have been developed and identified as potential treatment agents for various types of tumors in the last several decades. In recent years, their therapeutic potential against tumors has gained great attention. Inhibition of ceramidase is r eportedly related to apoptosis and cytotoxicity in macrophages, which are closely related to tumor development and progression. However, whether and how ceranib-2, a novel ceramidase inhibitor, can exert its cytotoxic and apoptotic effects on RAW 264.7, a macrophage cell line established from a tumor in a male mouse induced with the Abelson murine leukemia virus, remains unknown.Objective: In this study, we aimed to investigate whether and how ceranib-2 can exert cytotoxic, antiproliferative, and apoptotic effects on the RAW264.7 macrophages.Methods: We performed the MTT assay, Annexin V staining assay, and confocal microscopy to detect the cytotoxicity, apoptosis, and morphological changes, respectively, in the RAW264.7 cells.Results: The viability of RAW264.7 cells treated with ceranib-2 was decreased as the doses of ceranib-2 increased at 24 h and 48 h due to apoptosis resulting from ceranib-2-reduced integrity of the mitochondrial membrane. Moreover, morphological changes were observed in these ceranib-2 exposed cells, further indicating the role of ceranib-2 in inducing apoptosis in these cells.Conclusion: Ceranib-2 is cytotoxic to RAW 264.7 macrophages and can induce apoptosis in these cells.

Background: Green synthesis is an efficient and eco-friendly method that has been used frequently in silver nanoparticle production in recent years. This method facilitates the production of nanoparticles using various organisms, such as plants, and is also cheaper and easier to apply than the other techniques.Aims: This study aims to find possible mechanisms and pharmacological effects of cubic silver nanoparticles (AgNPs).Objectives: This study characterizes cubic AgNPs and describes in detail their anticancer, antimicrobial, and anti- Trichomonas vaginalis abilities.Methods: Silver nanoparticles were produced by green synthesis using Juglans regia (walnut) leaf aqueous extract. We validated the formation of AgNPs by UV-vis spectroscopy, FTIR analysis, and SEM micrographs. To determine the pharmacological effects of the AgNPs, we conducted anti-cancer, anti-bacterial, and anti-parasitic activity experiments.Results: Cytotoxicity data revealed that AgNPs have cellular inhibitory properties on cancerous MCF7 (breast), HeLa (cervix), C6 (glioma), and HT29 (colorectal) cell lines. Similar results are also obtained with anti-bacterial and anti- Trichomonas vaginalis activity experiments. At certain concentrations, AgNPs displayed stronger anti-bacterial activities than the sulbactam/cefoperazone antibiotic combination in five bacteria species. Furthermore, the 12-h AgNPs treatment exhibited satisfactory anti-Trichomonas vaginalis activity similar to the FDA-approved metronidazole.Conclusion: Consequently, AgNPs produced by the green synthesis method by Juglans regia leaves showed remarkable anti-carcinogenic, anti-bacterial, and anti-trichomonas vaginalis activities. We propose the potential usefulness of green synthesized AgNPs as therapeutics.

Background: Circular RNA, as a member of noncoding RNA, plays an important role in the occurrence, development and metastasis of tumor cells. So far, the correlation between circular RNA and malignant melanoma remains obscure.Methods: RNA expression of circFAT1 and miR-375 in malignant melanoma (MM) tissues and cell lines was detected by RT-PCR. The proliferation, cloning, migration and invasion of SK-Mel-28 and A375 cells were assessed using CCK-8 test, clone formation and Transwell assay, respectively. CircRNA immunoprecipitation was used to validate the relationship between circFAT1 and miR-375. The binding between circFAT1 and miR-375, as well as SLC7A11 and miR-375 were verified by luciferase assay.Results: In our study#140;the circFAT1 was significantly overexpressed in the MM tissue than melanocytic nevi. Conversely, the expression of miR-375 in MM tissue was lower than in melanocytic nevi tissue. The underexpression of circFAT1 with siRNA plasmids significantly suppressed the proliferation, invasion and clone formation of MM cell line. Mechanistically, circFAT1 positively regulates the expression level of SLC7A11 by sponging miR-375. The promotive effects of circFAT1 on the proliferation and invasion ability of MM cells were reversed by the upregulation of miR-375.Conclusion: circFAT1 promotes the proliferation, invasion and clone formation of malignant melanoma cells by improving the expression level of SLC7A11 via sponging miR-375.

Background: Osteosarcoma is the most common malignant bone tumor, with highly proliferative and metastatic properties. Previous studies have reported that arctigenin (Arc), a bioactive lignin compound, showed excellent anti-tumor activities in a variety of human cancers. However, its role in osteosarcoma has not been studied.Objective: We aimed to investigate the anti-tumor effects of Arc on osteosarcoma cell proliferation, migration, invasion, apoptosis, and cell cycle.Methods: Effects of Arc on osteosarcoma cell proliferation were detected by MTT and colony formation assay. Flow cytometry analysis was performed to assess the cell apoptosis and cycle arrest. Transwell assay was used to evaluate the capability of migration and invasion. qRT-PCR and Western blot were employed to determine the changes in mRNA and protein levels.Results: Arc could significantly suppress the proliferation, colony formation, and induce cell apoptosis and S phase cycle arrest of MG63 and U-2 OS cells in a dose-dependent manner. In addition, we also observed an inhibitory effect of Arc treatment on osteosarcoma cell invasion, migration, and epithelial-mesenchymal transition (EMT). HMOX1, encoding enzyme heme oxygenase-1, was predicted to be a candidate target of Arc using STITCH. Arc treatment significantly reduced the mRNA and protein levels of HMOX1. Furthermore, overexpression of HMOX1 could partly reverse the inhibitory effects of Arc on osteosarcoma cell malignant phenotypes.Conclusion: Our results suggest that Arc inhibits the proliferation, metastasis and promotes cell apoptosis and cycle arrest of osteosarcoma cells by downregulating HMOX1 expression.

Background: Neuroblastoma (NB) remains associated with a low overall survival rate over the long term. Abnormal activation of the Hedgehog (HH) signaling pathway can activate the transcription of various downstream target genes that promote NB. Both arsenic trioxide (ATO) and itraconazole (ITRA) can inhibit tumor growth.Objective: To determine whether ATO combined with ITRA can be used to treat NB with HH pathway activation, we examined the effects of ATO and ITRA monotherapy or combined inhibition of the HH pathway in NB.Methods: Analysis of CCK8 and flow cytometry showed cell inhibition and cell cycle, respectively. Real-time PCR analysis was conducted to assess the mRNA expression of HH pathway.Results: We revealed that as concentrations of ATO and ITRA increased, the killing effects of both agents on SK-N-BE(2) cells became more apparent. During G2/M, the cell cycle was largely arrested by ATO alone and combined with ITRA, and in the G0/G1 phase by ITRA alone. In the HH pathway, ATO inhibited the transcription of the SHH, PTCH1, SMO and GLI2 genes, however, ITRA did not. Instead of showing synergistic effects in a combined mode, ITRA decreased ATO inhibitory effects.Conclusion: We showed that ATO is an important inhibitor of HH pathway but ITRA can weaken the inhibitory effect of ATO. This study provides an experimental evidence for the clinical use of ATO and ITRA in the treatment of NB with HH pathway activation in cytology.

Background: TRAIL has emerged as a promising therapeutic target due to its ability to selectively induce apoptosis in cancer cells while sparing normal cells. Autophagy, a highly regulated cellular recycling mechanism, is known to play a cell survival role by providing a required environment for the cell. Recent studies suggest that autophagy plays a significant role in increasing TRAIL resistance in certain cancer cells. Thus, regulating autophagy in TRAIL-mediated cancer therapy is crucial for its role in cancer treatment.Objective: Our study explored whether the antidepressant drug desipramine could enhance the ability of TRAIL to kill cancer cells by inhibiting autophagy.Methods: The effect of desipramine on TRAIL sensitivity was examined in various lung cancer cell lines. Cell viability was measured by morphological analysis, trypan blue exclusion, and crystal violet staining. Flow cytometry analysis was carried out to measure apoptosis with annexin V-PI stained cells. Western blotting, rtPCR, and immunocytochemistry were carried out to measure autophagy and death receptor expression. TEM was carried out to detect autophagy inhibition.Results: Desipramine treatment increased the TRAIL sensitivity in all lung cancer cell lines. Mechanistically, desipramine treatment induced death receptor expression to increase TRAIL sensitivity. This effect was confirmed when the genetic blockade of DR5 reduced the effect of desipramine in enhanced TRAIL-mediated cell death. Further investigation revealed that desipramine treatment increased the LC3 and p62 levels, indicating the inhibition of lysosomal degradation of autophagy. Notably, TRAIL, in combination with either desipramine or the autophagy inhibitor chloroquine, exhibited enhanced cytotoxicity compared to TRAIL treatment alone.Conclusion: Our findings revealed the potential of desipramine to induce TRAIL-mediated cell death by autophagy impairment. This discovery suggests its therapeutic potential for inducing TRAIL-mediated cell death by increasing the expression of death receptors, which is caused by impairing autophagy.

Background: Indenoisoquinoline-based compounds have shown promise as topoisomerase-I inhibitors, presenting an attractive avenue for rational anticancer drug design. However, a detailed QSAR study on these derivatives has not been performed till date.Objective: This study aimed to identify crucial molecular features and structural requirements for potent topoisomerase- 1 inhibition.Methods: A comprehensive two-dimensional (2D) QSAR analysis was performed on a series of 49 indenoisoquinoline derivatives using TSAR3.3 software. A robust QSAR model based on a training set of 33 compounds was developed achieving favorable statistical values: r² = 0.790, r²CV = 0.722, f = 36.461, and s = 0.461. Validation was conducted using a test set of nine compounds, confirming the predictive capability of the model (r² = 0.624). Additionally, artificial neural network (ANN) analysis was employed to further validate the significance of the derived descriptors.Results: The optimized QSAR model revealed the importance of specific descriptors, including molecular volume, Verloop B2, and Weiner topological index, providing essential insights into effective topoisomerase-1 inhibition. We also obtained a robust partial least-square (PLS) analysis model with high predictive ability (r² = 0.788, r²CV = 0.743). The ANN results further reinforced the significance of the derived descriptors, with strong r² values for both the training set (r² = 0.798) and the test set (r² = 0.669).Conclusion: The present 2D QSAR analysis offered valuable molecular insights into indenoisoquinoline-based topoisomerase- I inhibitors, supporting their potential as anti-lung cancer agents. These findings contribute to the rational design of more effective derivatives, advancing the development of targeted therapies for lung cancer treatment.

Background: Desmoid tumors have an extremely variable natural history. The uncertainty behind desmoid behavior reflects the complexity, which subtends its development and non-linear advancement. Apart from Wnt- βcatenin mutation, estrogen receptors, and COX-2 overexpression, little is known about the ability of desmoids to grow and recur while being unable to metastasize. Several tumors have been shown to express the CXCR4/CXCR7/CXCL12 axis, whose functions are essential for tumoral development.Aims: This study aimed to investigate the expression of the CXCR4/CXCR7/CXCL12 axis in primary desmoid tumors and discuss the potential role of this key-signaling as an antiangiogenic therapeutic strategy.Methods: In this study, 3 μm-thick consecutive sections from each formalin-fixed and paraffin-embedded tissue block were treated with mouse monoclonal antibodies developed against CD34, CXCR4, CXCR7, and CXCL12.Results: Two distinct vessel populations: CXCR4⁺ and CXCR4- vessels, have been found. Similarly, chemokine receptor CXCR7 expression in the entire desmoid tumor series positively stained a portion of tumor-associated vessels, identifying two distinct subpopulations of vessels: CXCR7⁺ and CXCR7- vessels. All 8 neoplastic tissue samples expressed CXCL12. Immunohistochemical positivity was identified in both stromal and endothelial vascular cells. Compared to CXCR4 and CXCR7, the vast majority of tumor-associated vessels were found to express this chemokine.Conclusion: It is the first time, as per our knowledge, that CXCR4/CXCR7/CXCL12 axis expression has been identified in a desmoid type-fibromatosis series. CXCL12 expression by neoplastic cells, together with CXCR4 and CXCR7 expression by a subgroup of tumor-associated vessels, was detected in all desmoid tumor tissue samples examined. Since chemokines are known contributors to neovascularization, CXCR4/CXCR7/CXCL12 axis may play a role in angiogenesis in this soft-tissue tumor histotype, thereby supporting its growth.