Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 1, 2023

Background: Ginseng (Panax ginseng Meyer) is a cultivated medicinal herb that has been widely available in the Asian region since the last century. Ginseng root is used worldwide in Oriental medicine. Currently, the global mortality and infection rates for lung cancer and inflammation are significantly increasing. Therefore, various preventative methods related to the activity of ginsenosides have been used for lung cancer as well as inflammation. Methods: Web-based searches were performed on Web of Science, Springer, PubMed, and Scopus. A cancer statistical analysis was also conducted to show the current ratio of affected cases and death from lung cancer around the world. Results: Ginsenosides regulate the enzymes that participate in tumor growth and migration, such as nuclear factor kappa B (NF-ΚB), mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), extracellular signalregulated kinases 1/2 (ERK1/2), the gelatinase network metalloproteinase-2 (MMP-2/9) and activator protein 1 (AP-1). In addition, ginsenosides also possess anti-inflammatory effects by inhibiting the formation of proinflammatory cytokines (tumor necrosis factor-α) (TNF-α) and interleukin-1β (IL-1β) and controlling the activities of inflammatory signalling pathways, such as NF-ΚB, Janus kinase2/signal transducer, and activator of transcription 3 (Jak2/Stat3). Conclusion: In several in vitro and in vivo models, P. ginseng showed potential beneficial effects in lung cancer and inflammation treatment. In this review, we provide a detailed and up-to-date summary of research evidence for antilung cancer and anti-inflammatory protective effects of ginsenosides and their potential molecular mechanisms.

Cyclooxygenase-2 (COX-2) is a key-type enzyme playing a crucial role in cancer development, making it a target of high interest for drug designers. In the last two decades, numerous selective COX-2 inhibitors have been approved for various clinical conditions. However, data from clinical trials propose that the prolonged use of COX-2 inhibitors is associated with life-threatening cardiovascular side effects. The data indicate that a slight structural modification can help develop COX-2 selective inhibitors with comparative efficacy and limited side effects. In this regard, secondary metabolites from natural sources offer great hope for developing novel COX-2 inhibitors with potential anticancer activity. In recent years, various nature-derived organic scaffolds are being explored as leads for developing new COX-2 inhibitors. The current review attempts to highlight the COX-2 inhibition activity of some naturally occurring secondary metabolites, concerning their capacity to inhibit COX-1 and COX-2 enzymes and inhibit cancer development, aiming to establish a structure-activity relationship.

Background: Cervical cancer is one of the leading causes of female death, with a mortality rate of over 200,000 per year in developing countries. Despite a decrease in cervical cancer occurrences in developed countries over the last decade, the frequency of the disease in developing nations continues to rise at an alarming rate, particularly when it is linked to the human papillomavirus (HPV). With just a few highly invasive conventional therapies available, there is a clear need for novel treatment options such as nanotechnology-based chemotherapeutic drug delivery. Methods: Traditional anticancer therapy is limited by poor drug potency, non-specificity, unwanted side effects, and the development of multiple drug resistance (MDR), leading to a decrease in long-term anticancer therapeutic efficacy. An ideal cancer therapy requires a personalized and specialized medication delivery method capable of eradicating even the last cancer cell responsible for disease recurrence. Results: Nanotechnology provides effective drug delivery mechanisms, allowing it to serve both therapeutic and diagnostic purposes. Nanotechnology-based formulations are widely used to accurately target the target organ, maintain drug load bioactivity, preferentially accumulate the drug at the target location, and reduce cytotoxicity. Conclusion: The key benefits of this drug delivery are that it improves pharmacological activity, solubility, and bioavailability and reduces toxicity in the target tissue by targeting ligands, allowing for new innovative treatment methods in an area that is desperately required. The goal of this review is to highlight possible research on nanotechnologybased delivery systems for cancer detection and treatment.

Background: Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Researchers are continually finding new and more effective medications to battle the diseases. Objective: The objective of this study is to identify the emerging role of Thiosemicarbazide analogs for different types of cancer targets with a glance at different novel synthetic routes reported for their synthesis. Methods: A systematic literature review was conducted from various sources over the last 15 years with the inclusion of published research and review articles that involves the synthesis and use of thiosemicarbazide analogs for different targets of cancer. Data from the literature review for synthesis and anticancer potential for specific targets for cancer studies of thiosemicarbazide analogs are summarized in the paper. Results: There are several emerging studies for new synthetic routes of thiosemicarbazide derivatives with their role in various types of cancers. The main limitation is the lack of clinical trial of the key findings for the emergence of new anticancer medication with thiosemicarbazide moiety. Conclusion: Emerging therapies exist for use of a limited number of medications for the treatment of cancer; results of the ongoing studies will provide more robust evidence in the future.

Background: Sargassum is a marine organism that, under specific conditions, drastically increases its population damaging the environment and risking other organisms. However, sargassum could represent a source of bioactive compounds to treat different diseases such as cancer. Thus, aqueous, ethanolic, and ethyl acetate extracts of sargassum from Playa del Carmen, Mexico, were subjected to metabolomic and antiproliferative assays in breast cancer cells. Objective: To evaluate the biological effect of different extracts of sargassum, its toxicity over Artemia salina and its antiproliferative effect tested in MCF-7, MDA-MB-231, and NIH3T3 cell lines. Finally, using UHPLC-MS/MS to identify the metabolites in each extract to correlate them with its antiproliferative effect. Methods: The sargassum sample collection was carried out in September at three different points in Playa del Carmen, Quintana Roo, Mexico. The aqueous, ethanolic, and ethyl acetate extracts of Mexican sargassum were obtained by evaporation of solvent and lyophilization. Then, these extracts were evaluated in the cytotoxicity bioassay of Artemia salina. Next, its antiproliferative effect was assessed in MCF-7, MDA-MB-231, and NIH3T3 cell lines. Using UHPLC-MS/MS, the metabolites present in each extract were identified. Finally, docking studies on sphingosine kinase 1 (PDB ID: 3VZB) of sphingosine were carried out. Results: The extracts from sargassum showed a greater effect in the antiproliferative assays in cells than in cytotoxic assays in Artemia salina. The ethanolic extract obtained from sargassum showed the best antiproliferative activity in MCF7 and MDA-MB-231 cells. Despite its antiproliferative effect on NIH3T3 cells, an additional extract is required indicating that this extract has compounds that could have a better effect on cancer cells in fibroblast (NIH3T3). The UHPLC-MS/MS of ethanolic and the ethyl acetate extract showed that these extracts have compounds such as sphinganine C16, N, N-Dimethylsphingosine compound, and that it could be possible that the effect observed is due to their metabolites which could be ligands for the sphingosine kinase 1 as demonstrated by docking studies. Conclusion: The ethanolic extract obtained from sargassum has better antiproliferative activity, despite not having a cytotoxic effect in Artemia salina. The antiproliferative effect could be related to the sphinganine C16, N,NDimethylphingosine identified with more abundance by UHPLC-MS/MS. In addition, these metabolites could be targets of sphingosine kinase 1.

Background: Both AKT and Aurora inhibitors are a potential therapeutic agent for the treatment of malignant tumors. However, the role of combined inhibition of AKT and Aurora in colon cancer and its underlying mechanism have yet to be fully investigated. Objective: To investigate the role of combined AKT and Aurora inhibitors in colon cancer and its underlying mechanisms. Methods: CCK8 assay, colony formation assay, and flow cytometry were performed to analyze the proliferation and apoptosis of colon cancer cell line SW480 treated with combined AKT inhibitor MK2206 and Aurora inhibitor Alisertib, respectively. And tumor formation and growth were measured in tumor allograft model mice administered with the combined inhibitors. Western blot analysis was used to examine the expression levels of apoptosis-related proteins and signal transduction pathway components. The PI3K agonist 740Y-P and Overexpression of AKT are used to verify whether the PI3K/AKT pathway plays an anti-tumor effect when combined with inhibitory administration. Results: Aurora A inhibitor Alisertib and AKT inhibitor MK2206 displayed consistent and synergistic antiproliferation and proapoptotic effects. Combined inhibition of Aurora A and AKT down-regulated the expression of Bcl-2/Bax and up-regulated the expression of cleaved-caspase-3 and cleaved-PARP. While single-drug treatment can significantly inhibit the expression of P-PI3K and P-AKT as well as increase the expression of P53 and H2A.X, the combined drugs had a more significant inhibitory effect than the single drug. Moreover, administration of PI3K agonist 740Y-P and AKT1 overexpression in experiments proved that the combined drugs exert an anticancer effect by inhibiting the PI3K/AKT pathway. Meanwhile, we showed that the combined administration had an anti-colon cancer effect on tumor allograft mice, and the underlying mechanism involved inhibition of the PI3K/AKT pathway. Conclusion: Combined administration of Aurora A inhibitor Alisertib and AKT inhibitor MK2206 can inhibit the proliferation of colon cancer cells and induce apoptosis, while inhibiting tumor growth in vivo. The underlying mechanism may involve the PI3K/AKT pathway and DNA damage pathway.

Background: Melanoma is a highly invasive and metastatic malignant tumor originating from melanocytes and is associated with a poor prognosis. Surgical resection and chemotherapy are currently the main therapeutic options for malignant melanoma; however, their efficacy is poor, highlighting the need for the development of new, safe, and effective drugs for the treatment of this cancer. Objective: To investigate the effects of alantolactone (ALT) on the proliferative, migratory, invasive, and apoptotic ability of malignant melanoma cells and explore its potential anticancer mechanism. Methods: Melanoma cells (A375 and B16) were treated with different concentrations (4, 6, 8, and 10 μmol/L) of ALT, with DMSO and no treatment serving as controls. The effects of the different concentrations of the drug on cell proliferation were assessed by crystal violet staining and CCK-8 assay. The effects on cell migration and invasion were detected by wound healing and Transwell assays, respectively. Flow cytometry was used to evaluate the effects of the drug on apoptosis and the cell cycle. ALT target genes in melanoma were screened using network pharmacology. Western blotting was used to measure the expression levels of the proliferation-related protein PCNA; the apoptosisrelated proteins Bax, Bcl-2, and caspase-3; the invasion and metastasis-related proteins MMP-2, MMP-7, MMP-9, vimentin, E-cadherin, and N-cadherin; and the canonical Wnt signaling pathway-related proteins β-catenin, c-Myc, and p-GSK3β. In addition, an l model of melanoma was established by the subcutaneous injection of A375 melanoma cells into nude mice, following which the effects of ALT treatment on malignant melanoma were determined in vivo. Results: Compared with the controls, the proliferative, migratory, and invasive capacity of ALT-treated melanoma cells was significantly inhibited, whereas apoptosis was enhanced (P<0.01), showing effects that were exerted in a dose-dependent manner. The expression levels of the pro-apoptotic proteins Bax and caspase-3, as well as those of the interstitial marker E-cadherin, were upregulated in melanoma cells irrespective of the ALT concentration (P<0.05). In contrast, the expression levels of the anti-apoptotic protein Bcl-2, the proliferation-related protein PCNA, and the invasion and metastasis-related proteins MMP-2, MMP-7, MMP-9, N-cadherin, and vimentin were downregulated (P<0.05). The network pharmacology results indicated that GSK3β may be a key ALT target in melanoma. Meanwhile, western blotting assays showed that ALT treatment markedly suppressed the expression of β-catenin as well as that of its downstream effector c-Myc, and could also inhibit GSK3β phosphorylation. Conclusion: ALT can effectively inhibit the culture viability, migration, and invasion of A375 and B16 melanoma cells while also promoting their apoptosis. ALT may exert its anti-melanoma effects by inhibiting the Wnt/β-catenin signaling pathway. Combined, our data indicate that ALT has the potential as an effective and safe therapeutic drug for the treatment of melanoma.

Background: Non-small cell lung cancer (NSCLC) accounts for about 80% of lung cancers. Cisplatin is a broad-spectrum anti-cancer drug and is often used in combination with other drugs. Research suggests that dendrobine, a pyrrolizidine derivative alkaloid, exhibits antitumor activity in various cancers. This study explores the effect of dendrobine combined with cisplatin on NSCLC and its underlying molecular mechanism. Methods: The effects of dendrobine combined with cisplatin on tumor progression were evaluated by xenograft model (in vivo) and clonogenic survival assay (in vitro) using H1299 cell line. Annexin V staining was used for detecting apoptotic cells. The population of T cells, B cells and other subpopulations in the peripheral blood was determined by flow cytometry. Results: Dendrobine combined with cisplatin prolonged the survival of mice implanted with H1299 cells and reduced tumor volume compared with single drug application. However, dendrobine exhibited no effect on H1299 cells in clonal survival assays with or without cisplatin treatment and did not promote cisplatin-induced apoptosis in vitro. Importantly, dendrobine suppressed the regulatory T cells (Treg cells) and enhanced the T helper 17 cells (Th17 cells). Treatment of dendrobine significantly reduced Foxp3, and increased the level of IL-17 in serum. Conclusion: Dendrobine displayed a synergistic effect with cisplatin to exert anti-tumor effect in vivo, which might be achieved by modulating the balance of Treg/Th17 cells rather than regulating cell apoptosis.

Background: Src family tyrosine kinases play a potential role in Bcr-Abl-induced leukemogenesis. Src kinase inhibitors are reported as selective inhibitors of chronic myeloid leukemia. Objective: Since Src kinase inhibitors have an inhibitive effect on chronic myeloid leukemia, indole derivatives (C-1, C-2, C-3) previously found as potent inhibitors of Src kinase were tested against chronic myeloid leukemia in this study. Methods: Cell viability of K562 and R/K562 cells, antiproliferative and antioxidant effects, and inhibition profiles of Bcr-Abl kinase of indole derivatives were determined compared to dasatinib and imatinib. Results: The results showed that compounds affected cell proliferation and decreased the levels of Bcr/Abl. These results confirmed that the antileukemic activity of compounds was related to Bcr/Abl expression. Docking studies also presented that compounds are inhibitors of both Src and Abl kinases. Calculation of drug-like properties showed that compounds could be potential drug candidates. Conclusion: Among indole-2-on derivatives, previously identified as Src kinase inhibitors, C-2 has been discovered to be a strong anticancer drug that is active against susceptible and resistant K562 cell lines and induces apoptosis.