Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 13, 2023

Despite the substantial progress that has been made in cancer therapy over the past few decades, there has been a discernible rise in the number of reported instances of carcinoma over the past few decades. Breast cancer especially triple-negative breast cancer (TNBC), being the most common cancer found in females account for extensive research. This type of cancer, which is responsible for more than 15% to 20% of all breast cancers, is particularly interesting for research since it is difficult to treat due to its poor response to treatment and extremely aggressive nature. In clinical practice, triple-negative breast cancer is characterized by a relatively high risk of disease recurrence and distant metastasis, as well as a poor prognosis regarding overall survival. The goal of this review is to provide the recent advancement of the therapeutic potential of N-heterocycles covering in vitro and in vivo activities for the treatment of triple-negative breast cancer.

Germacrone, a kind of natural sesquiterpenoid compound, has been reported to exhibit many pharmacological properties, especially the anticancer effect. Many in vitro experiments have been performed on various cancer cell lines, trying to explore their anticancer mechanism. Aiming at investigating the anticancer effect of germacrone, this article reviews the extant information on existing literature about germacrone-related studies. The anticancer mechanisms and clinical usages of germacrone are summarized. Literature databases (such as PubMed and CNKI) are used to search the current studies and experimental research about the anticancer effect information of germacrone. Anticancer mechanism of germacrone includes cell cycle arrest inducing, programmed cell death (apoptosis, autophagy, pyroptosis and ferroptosis) inducing, and estrogen-related genes mediating. Structural modification and analogue design are worthy of further study in the future.

Nature is the chief source of various remedies which are used to cure various diseases. Boswellic acid (BA) is a secondary metabolite from the pentacyclic terpenoid compound groups that are derived from the plant genus Boswellia. The oleo gum resins of these plants are primarily composed of polysaccharides, with the remaining amounts of resin (30-60%) and essential oils (5-10%) soluble in organic solvents. BA and its analogs are also reported to exhibit various in vivo and biological responses for example anti-inflammatory, anti-tumor, free radical scavenging activity, etc. Among all analogs, 11-keto-β-boswellic acid (KBA) and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) has been demonstrated to be the most effective at reducing cytokine production and inhibiting the inflammatory responsecausing enzymes. In this review, we summarized the computational ADME prediction via the SwissADME computational tool and the structure-activity relationship of the Boswellic acid scaffold for the aspect of anticancer and antiinflammatory potency. In addition to these research findings which are associated with the therapy of acute inflammation and some cancers, the potential of boswellic acids against other disorders was also discussed.

Gastric cancer is a severe malignant tumor with high morbidity and mortality, which seriously affects people’s health. At present, the most common treatment for gastric cancer is chemotherapy. However, chemotherapy is very harmful to the human body, and some of the injuries caused by chemotherapy are irreversible. Natural products have low toxicity and anti-cancer activity, so they are currently widely studied at present. Natural products are a large variety of compounds naturally found in fruits, vegetables, spices, and medicinal plants. It is reported that natural products have different anti-cancer properties. This review has summarized the study of natural products in inducing gastric cancer cell apoptosis, inhibiting gastric cancer cell metastasis, and inhibiting gastric cancer cell proliferation. The relevant references on gastric cancer and natural products were obtained from scientific databases, including Pub- Med, Web of Science, and Science Direct. This paper records dozens of natural products with anti-gastric tumor activity and describes the potential living anti-cancer chemical compounds, their element targets, and their underlying mechanism. This review may lay the foundation for future researchers to treat gastric cancer.

Silybum marianum (SM) belongs to the family Asteraceae, which holds therapeutic significance in medicinal chemistry. Phytochemistry analysis revealed an abundance of active constituents, particularly silymarin, composed of polyphenols and flavonolignans. Silymarin is majorly found in leaves, seeds, and fruits and is comprised of seven flavonolignans. Silymarin derivatives, specifically silybin, were reported for their medicinal properties. This review summarizes the studies conducted to evaluate SM’s pharmacological properties and proposed mechanisms. SM exhibited anticancer properties due to being capable of modifying the induction of apoptosis, inhibiting the STAT3 pathway, decreasing the transcription of various growth factors, impeding the growth of 4T1 cells and inducing cell cycle arrest in various types of cancers, i.e., skin cancer, liver cancer, breast cancer, ovarian cancer etc. Silymarin and its derivatives protect the liver and ameliorate various immune-mediated and autoimmune hepatic diseases. Moreover, antimicrobial, antidiabetic, cardioprotective, nephroprotective, and neuroprotective activities were also reported. Based on testified in vitro and in vivo studies, SM can serve as an alternative to cure various pathological ailments.

Background: Long non-coding RNAs (LncRNAs) are identified as pivotal regulators and biomarkers for glioblastoma (GBM). However, the role of a novel LncRNA LINC00324 in regulating GBM progression has not been fully studied in the existing publications. Objective: In this study, we evidenced LINC00324 to act as an oncogene to facilitate GBM development, and the underlying mechanisms have also been uncovered. Methods: Clinicopathology and follow-up data of GBM patients were retrospectively studied, LINC00324 expression in clinical tissue or cell lines of GBM was measured by Real-time qPCR, and the role of LINC00324 in cell proliferation and migration was investigated by loss-of-function experiments in vitro and in vivo. The targeting genes of LINC00324 were predicted and verified by bioinformatic analysis and dual luciferase reporter gene system, respectively. Results: LINC00324 was found to be significantly upregulated in GBM tissues and cells in contrast to normal counterparts, and the GBM patients with high-expressed LINC00324 tended to have a worse prognosis. Further, loss-offunction experiments showed that the silencing of LINC00324 suppressed cell proliferation, colony formation and migration, and promoted cell apoptosis in GBM cells in vitro. Consistently, the in vivo experiments supported that LINC00324 ablation also restrained tumorigenesis in nude mice models. The following mechanism studies showed that LINC00324 sponged miR-16-5p to upregulate SEPT2 in a competing endogenous RNA-dependent manner, and the inhibitory effects of LINC00324 downregulation on the malignant characteristics of GBM cells were abrogated by both miR-16-5p ablation and SEPT2 overexpression. Conclusion: LINC00324 promotes the malignant phenotypes in GBM via targeting the miR-16-5p/SEPT2 axis, and the study provides novel biomarkers for GBM diagnosis and therapy.

Background: Medicinal plants are known to contain numerous phytometabolites with suggested pharmacological value. Literature suggests that the medicinal use of phytometabolites in its natural state has limited success due to poor absorption rates. Currently, the focus lies on synthesizing phytometabolites extracted from medicinal plants and silver ions to generate nano-scale carriers with specialized properties. Thus, the nano-synthesis of phytometabolites with silver (Ag⁺) ions is proposed. The use of silver is promoted due to its known antibacterial and antioxidant effectiveness, among many. Nanotechnology allows for the green generation of nano-scaled particles that are able to penetrate target areas due to its size and unique structure. Therefore, this study aimed to generate a novel protocol for the synthesis of AgNP’s using the leaf and stembark extracts of C. erythrophyllum. In addition, the biological activity of the generated nanoparticles was evaluated. Objectives: To synthesis silver nanoparticles (AgNP’s) using the leaf and stembark extracts of Combretum erythrophyllum. The relative shape, size, distribution, and zeta potential of the synthesised particles were characterized using transmission electron microscopy (TEM), scanning electron microscopy (SEM), Energy-dispersive X-ray (EDX), Nanoparticle tracking analysis (NTA), and UV Spectrophotometry (UV -vis). To screen the synthesised particles for its potential antibacterial, apoptotic and cytotoxic properties. Methods: A novel protocol for the synthesis of silver nanoparticles (AgNP’s) using the leaf and stembark extracts of Combretum erythrophyllum was established. The generated AgNP’s were characterised using transmission electron microscopy (TEM), scanning electron microscopy (SEM), Energy-dispersive X-ray (EDX), Nanoparticle tracking analysis (NTA), and UV Spectrophotometry (UV -vis). Furthermore, the AgNP’s were evaluated for their antibacterial, cytotoxic and apoptotic activity against a range of bacterial strains and cancer cells. Characterisation was based upon particle size, shape and elemental silver composition. Results: Within the stembark extract, synthesised nanoparticles were large, spherical in shape and dense in elemental silver composition. While synthesised nanoparticles of the leaf extract were small to medium in size, varied in shape established and contained minimal quantities of silver (substantiated by the TEM and NTA results). Furthermore, it was established that the synthesized nanoparticles exhibited high antibacterial properties due to the conducted antibacterial assay. The FTIR analysis revealed the presence of numerous functional groups within active compounds found in the synthesised extracts. Functional groups found varied between the leaf and stembark extracts, each with proposed pharmacological activity. Conclusion: Presently, antibiotic-resistant bacteria are continuously evolving thus, posing as a threat to conventional drug delivery systems. Nanotechnology provides a platform that enables the formulation of a low-toxicity and hypersensitive drug delivery system. Further studies evaluating the biological activity of extracts of C. erythrophyllum synthesized with silver nanoparticles could enhance its proposed pharmaceutical value.

Aim: This study aims to provide in vitro experimental evidence that wild mushrooms have the potential to be used as a pharmaceutical that could be effective against various types of cancer. Background: Throughout human history, besides food, traditional medicine and natural poisons obtained from mushrooms have been used for the treatment of many diseases. Clearly, edible and medicinal mushroom preparations have beneficial health effects without the known severe adverse side effects. Objectives: This study was designed to reveal the cell growth inhibitory potential of five different edible mushrooms and the biological activity of Lactarius zonarius was shown here for the first time. Methods: The mushrooms fruiting bodies were dried and powdered then extracted with hexane, ethyl acetate, and methanol. The mushroom extracts were screened for possible antioxidant activities by the free radical scavenging activity (DPPH) method. Antiproliferative activity and cytotoxicity of the extracts were investigated in vitro on A549 (human lung carcinoma), HeLa (human cervix carcinoma), HT29 (human colon carcinoma), Hep3B (human hepatoma), MCF7 (human breast cancer), FL (human amnion cells), and Beas2B (normal human cells) cells lines by using MTT cell proliferation assay, lactate dehydrogenase (LDH) assay, DNA degradation, TUNEL, and cell migration assay. Results: Using proliferation, cytotoxicity, DNA degradation, TUNEL, and migration assay, we displayed that hexane, ethyl acetate, and methanol extracts of the Lactarius zonarius, Laetiporus sulphureus, Pholiota adiposa, Polyporus squamosus, and Ramaria flava were effective on the cells even so at low doses (< 45.0 - 99.6 µg/mL) by acting in a way that represses migration, as a negative inducer of apoptosis. It was also demonstrated that mushroom extracts with high antioxidant effect have within the acceptable cytotoxic activity of 20%-30% on the cell membrane at concentrations higher than 60 µg/mL. Overall, all of the mushroom extracts with high antioxidant effects had strong antiproliferative activity and low toxicity for cells. These findings, at least, highlight that these mushroom extracts can be used for the treatment of cancer disease, especially as a supportive therapy against colon, liver, and lung cancer.

Background: P-coumaric acid (p-CA) is a kind of phenylpropionic acid derived from aromatic amino acids, which is widely distributed in many plants and human diets. It has strong pharmacological and inhibitory effects on a variety of tumors. However, the role of p-CA in osteosarcoma, a tumor with a poor prognosis, is still unknown. Therefore, we aimed to evaluate the effect of p-CA on osteosarcoma and explore its potential mechanism. Objective: This study aimed to investigate whether p-CA has an inhibitory effect on the growth of osteosarcoma cells and explore its potential mechanism. Methods: MTT assay and clonogenic assay were used to detect the effect of p-CA on the proliferation of osteosarcoma cells. The effect of p-CA on apoptosis of osteosarcoma cells was detected by the Hoechst staining and flow cytometry. The effects of p-CA on the migration and invasion of osteosarcoma cells were detected by scratch healing assay and Transwell invasion assay. Western blot and PI3K/Akt pathway activator 740Y-P were used to detect the anti-tumor mechanism of p-CA on osteosarcoma cells. The effect of p-CA on osteosarcoma cells in vivo was verified by an orthotopic osteosarcoma tumor animal model in nude mice. Results: MTT assay and clonogenic assay showed that p-CA inhibited the proliferation of osteosarcoma cells. Hoechst stain and flow cytometry showed that p-CA could induce apoptosis of osteosarcoma cells and lead to G2 phase arrest of osteosarcoma cells. Transwell assay and scratch healing assay found that p-CA could inhibit the migration and invasion of osteosarcoma cells. Western blot showed that p-CA could inhibit the activity of the PI3K/Akt signaling pathway in osteosarcoma cells, and 740Y-P could reverse its inhibitory effect. In vivo mouse models, p-CA has an antitumor effect on osteosarcoma cells in vivo, and at the same time, it has less toxic side effects on mice. Conclusion: This study demonstrated that p-CA could effectively inhibit the proliferation, migration and invasion of osteosarcoma cells and promote apoptosis. p-CA may play an anti-osteosarcoma role by inhibiting PI3K/Akt signaling pathway.

Background: According to the WHO report of 2022, 2.21 million new cases and 1.80 million deaths were reported for lung cancer in the year 2020. Therefore, there is an urgent need to explore novel, safe, and effective therapeutic interventions for lung cancer. Objective: To find the potential targets of vincamine using a network pharmacology approach and docking studies and to evaluate the anti-cancer effect of vincamine on A549 cell line. Methods: Hence, in the present study, we explored the anti-cancer potential of vincamine by using network pharmacology, molecular docking, and in vitro approaches. Network pharmacology demonstrated that the most common targets of vincamine are G-protein coupled receptors, cytosolic proteins, and enzymes. Among these targets, two targets, ALK and ERBB2 protein, were common between vincamine and non-small cell lung cancer. Results: We discovered a link between these two targets and their companion proteins, as well as cancer-related pathways. In addition, a docking investigation between the ligand for vincamine and two targeted genes revealed a strong affinity toward these targeted proteins. Further, the in vitro study demonstrated that vincamine treatment for 72 h led to dosedependent (0-500 μM) cytotoxicity on the A549 lung cancer cell line with an IC50 value of 291.7 μ. The wound-healing assay showed that vincamine treatment (150 and 300 μM) significantly inhibited cell migration and invasion. Interestingly, acridine orange/ethidium bromide dual staining demonstrated that vincamine treatment induces apoptosis in A549 cells. Additionally, the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay showed an increased level of reactive oxygen species (ROS) after the vincamine treatment, indicating ROS-mediated apoptosis in A549 cells. Conclusion: Altogether, based on our findings, we hypothesize that vincamine-induced apoptosis of lung cancer cells via ALK and ERBB2 protein modulation may be an attractive futuristic strategy for managing lung cancer in combination with chemotherapeutic agents to obtain synergistic effects with reduced side effects.

Background: Tripterygium wilfordii Hook F provided the source of the first diterpenoid triepoxide lactone, Triptolide, identified as the primary constituent causing the anticancer activity. So far, it has not been reported whether triptolide has a therapeutic effect on cutaneous squamous cell carcinoma (cSCC). Objective: This study investigates the triptolide's therapeutic impact on cSCC both in vitro and in vivo and investigates the triptolide's potential involvement in signaling pathways. Methods: The CCK-8 assays, wound healing assays, and colony formation assays were used to assess the effects of triptolide on the proliferation and migration of cSCC cells. The alteration in gene expression following triptolide treatment was shown by RNA sequencing. Flow cytometry was then applied to evaluate cell apoptosis. Western blot was used to find the associated proteins' expressions. The effectiveness of triptolide was then evaluated in vivo using a xenograft model, and histological staining was employed to determine the visceral toxicity. Results: Triptolide greatly reduces the migratory and proliferative capacity of cSCC cells. Triptolide dramatically decreased cell viability and migration in the A431 and SCL-1 cells compared to the control group, according to the CCK8 assay, wound healing assay, and colony formation assay. Flow cytometry demonstrated that treatment with 10- 40 nM triptolide increased apoptosis in a concentration-dependent manner, with a statistically significant difference. Furthermore, mice given triptolide had smaller tumor sizes than those in the control group. Triptolide treatment drastically altered the expression of autophagic and apoptotic proteins. The considerable reduction in the proteins Akt and mTOR levels further illustrated the critical function of triptolide in cSCC. Conclusion: Triptolide caused cSCC cells to engage in autophagy and apoptosis by inhibiting the Akt/mTOR signaling pathways. Triptolide may be a possible antitumor agent for the treatment of cSCC.