Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 7, 2023

Purpose: The Warburg effect is an important metabolic feature of tumours, and hexokinase is the first ratelimiting enzyme of the glycolytic pathway during tumour metabolism. Among hexokinase subtypes, hexokinase 2 (HK2) is increasingly proving to be a key target for cancer treatment. This study presents the challenges and potential strategies for developing HK2 inhibitors by systematically summarising the characteristics of HK2 inhibitors reported in the literature and patents. Methods: In this study, we analysed the HK2 active site using molecular docking and evaluated the structure, biochemical and physiological function, activity, and action mechanism of reported HK2 inhibitors using databases (Science, SCI Finder, CNKI, and WANFANG DATA). Results: In total, 6 natural inhibitors of HK2, 9 synthetic inhibitors of HK2, and 3 compounds with patent-pending HK2 inhibitory effects were obtained by searching 87 articles. These inhibitors have poor efficacy and specificity when used alone and have numerous side effects; therefore, there is an urgent need to develop HK2 inhibitors with improved activity and high selectivity. Conclusion: HK2 has received much attention in anticancer drug development, but most previous studies have focused on elucidating the action mechanism of HK2 in carcinogenesis, whereas the development of its small-molecule inhibitors has rarely been reported. In this study, we analysed and illustrated the eutectic structure of small molecules with the catalytic structural domain of HK2 to develop highly selective and low-toxicity HK2 inhibitors.

Bakuchiol is a meroterpene natural product distributed in various plants. It possesses several biological activities particularly anticancer. A large number of analogs have been prepared by various researchers by targeting several positions such as phenolic –OH, ethenyl and isopropylidene groups present in the bakuchiol to develop potent therapeutic agents with improved pharmaceutical properties. The present review describes the isolation, organic synthetic schemes, chromatographic study, and biological activities of bakuchiol reported till date. Further, the review also provides an insight into the skin care effects of bakuchiol and structure-activity relationship studies of reported derivatives. Moreover, the biosynthetic pathway of bakuchiol has also been described. All the articles published on bakuchiol revealed that bakuchiol and its analogs possess a remarkable potential for the development of potent anticancer and several other therapeutic agents. The reported synthetic schemes can be utilized for the industrial production of bakuchiol. Finally, we believe that this review will provide important information to the researchers interested in the chemistry and biology of Bakuchiol.

Historically, natural plant-derived drugs received a great impact of consideration in the treatment of several human-associated disorders. Cancer is a devastating disease and the second most cause of mortality. Sanguinarine (SANG), a naturally isolated plant alkaloidal agent, possesses chemo-preventive effects. Several studies have revealed that SANG impedes tumor metastasis and development by disrupting a wide range of cell signaling pathways and its molecular targets, such as BCL-2, MAPKs, Akt, NF-ΚB, ROS, and microRNAs (miRNAs). However, its low chemical stability and poor oral bioavailability remain key issues in its use as a medicinal molecule. A novel method (e.g., liposomes, nanoparticles, and micelles) and alternative analogs provide an exciting approach to alleviate these problems and broaden its pharmacokinetic profile. Cancer-specific miRNA expression is synchronized by SANG, which has also been uncertain. In this critical study, we review the utilization of SANG mimics and nano-technologies to improve its support in cancer. We focus on recently disclosed studies on SANG anti-cancer properties.

Background: Cancer is associated with metabolic changes from increased cell proliferation and growth. Compared to normal differentiated cells, MM cells use the glycolytic pathway even when adequate oxygen is present triggering “Glutamine addiction”. Objective: To investigate the single and combined effects of epigallocatechin-3-gallate (EGCG) and telaglenastat, a glutaminase inhibitor, on the proliferation and apoptosis of the multiple myeloma cell line KM3/BTZ. Methods: KM3/BTZ cells were treated with different concentrations of telaglenastat and EGCG alone or in combination to investigate their effect on proliferation and apoptosis using the CCK8 assay, flow cytometry, and western blotting. The Chou-Talalay combination index analysis was used to explore the effect of telaglenastat combined with EGCG, while the Combination Index (CI) was calculated to analyze whether the combination of the two drugs had a synergistic effect. Results: Telaglenastat and EGCG alone as well as in combination (5 μmol/L telaglenastat + 120 μmol/L EGCG) significantly inhibited the proliferation of KM3/BTZ cells compared to the inhibition effect of the control. Additionally, the combined treatment increased the proportion of KM3/BTZ cells in the G2 phase and decreased the proportion of cells in the G1 phase. The apoptosis rate of EGCG alone and the combined treatment was significantly higher than that of the control group. Bax protein expression was highest in the combined treatment group, whereas Bcl-2 expression was lowest, with the combined treatment group having the highest ratio of Bax/Bcl-2. Conclusion: Telaglenastat and EGCG act synergistically to inhibit cell proliferation and promote apoptosis in KM3/BTZ cells, possibly by targeting glutamine metabolism and glycolysis.

Purpose: The study aims to investigate the suppressing tumor-promoting effects via multi-anti-angiogenesis activity of the copper chelator (ammonium tetrathiomolybdate, TM) combined with lenvatinib for hepatocellular carcinoma. Methods: A total of 55 C57 mice were injected subcutaneously with Hepa1-6 hepatoma cell suspensions into the right posterior thigh. After 7 days, the subcutaneous tumors were formed, and the mice were randomly divided into five groups: TM (G1), Lenvatinib (G2), TM+Lenvatinib (G3), Control (G4), and Copper (II) Gluconate (G5). The copper concentrations in serum and tumors were measured at the predetermined time points. After 14 days of treatments, tumor weight and volumes were analyzed, histology was observed, and the expressions of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor tissues were measured by immunohistochemistry. Results: The median concentration of copper in serum was 401.70, 469.40, and 665.35 μg/L in normal mice, in mice 7 days after implantation, and in the control group, respectively. The intratumoral copper concentrations were higher in G4 mice than in mice 7 days after implantation (P < 0.05). The serum concentration of copper was higher in G5 than all the other groups (P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G2, P = 0.013; G2 vs. G3, P = 0.018; G1 vs. G3, P = 0.903. The intratumoral copper concentrations were 608.40, 980.00, 539.31, and 2938.90 μg/L in G1, G2, G3, and G5, respectively. The average tumor weight was 0.55, 0.44, 0.08, 1.37, and 3.11 in G1, G2, G3, G4, and G5, respectively. G5 vs. other groups, P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05; G1 vs. G2, P > 0.05. Furthermore, the expression levels of VEGF were significantly lower in G1, G2, and G3 than in G4 and G5 (P < 0.05). A similar trend was observed for MVD in the five groups, but no significant difference was detected in G1 and G2. Conclusion: The study showed a significant positive correlation between tumor load and copper. Copper promotes tumor progression, but copper chelating suppresses tumor growth. The combination of TM with lenvatinib reduces tumor angiogenesis and improves the effect of antitumor treatment.These findings underlie the clinical application of combination therapy.

Background: As epigenetic readers, Bromodomain and extraterminal domain (BET) proteins have attracted immense interest in developing novel therapies targeting this family to inhibit cancer progression. Although the impact of BRD4 in the carcinogenesis of various tumors has been widely investigated, little is known about the potential roles of the BET family in gastric cancer. Methods: In this cohort study, we have screened the expression profile of the BET protein family, including three members, BRD2, BRD3 and BRD4, in fresh gastric cancer (GC), adjacent non-tumor and normal gastric tissues, as well as the anti-cancer effects and molecular mechanisms of BET inhibition in GC cell lines. Results: Among GC patients, BRD2, BRD3 and BRD4 showed overexpression, 48.07% (25/52), 61.5% (32/52) and 63.46% (33/52), respectively. The overexpression of BRD3 and BRD4 were remarkably associated with unfavorable outcomes (HR = 2.023, P = 0.038; HR = 3.874, P = 0.001, respectively). However, multivariate Cox regression analysis indicated that BRDs mRNA expression could not be used as an independent prognostic factor for GC patients after adjustment with other variables. I-BET151, a potent pan-inhibitor, suppressing the BET family, decreased cell growth, migration and invasion of GC cells. Interestingly, I-BET151 induced G1 cell cycle arrest through down-regulation of c-Myc and its target, CDK2/Cyclin D1 complex. Conclusions: Our data provide insights into the prognostic role of the BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.

Background: Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system with a high recurrence rate and easy metastasis. Current clinical drugs for renal cell carcinoma include immunotherapies and targeted drugs. Axitinib is a clinically targeted drug for treating renal cell carcinoma, which has shortcomings such as unstable efficacy and easy drug resistance. Therefore, this study aims to determine whether embelin can enhance the sensitivity of renal cancer cells to axitinib and explore its regulatory pathways. Methods: The enhancing effect of embelin on axitinib was detected using MTT, crystal violet staining, and annexin VFITC staining in two renal cancer cell lines. Western blot was performed to detect the expression of autophagy-related proteins under different conditions. Bioinformatic tools were used to predict the pathways through which embelin may act on renal cancer cells, and pharmacological methods were used to verify the results. Results: Embelin enhanced the sensitivity of renal cancer cells to axitinib in the following aspects: enhancing the inhibition of cell proliferation by axitinib, and the induction of cell apoptosis. HIF was a potential pathway for embelin’s action. After IOX2 regulated the HIF-1α pathway, the enhancing effect of embelin on axitinib was weakened. Moreover, after PT2977 regulated the HIF-2α pathway, the enhancing effect of embelin on axitinib was weakened. Conclusions: Embelin enhanced the sensitivity of A498 and 786-O renal cancer cells to axitinib by inhibiting the HIF pathway.

Aims: The aim of this study was to sensitize the resistant breast adenocarcinoma cells towards Tumour Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced apoptosis. Background: Breast cancer is a heterogeneous disease involving complex mechanisms. TRAIL is a potential anticancer candidate for targeted treatment due to its selective killing effects on neoplastic cells. Nonetheless, resistance occurs in many cancers either intrinsically or after multiple treatments. Objective: Therefore, this research investigated whether the combination of Trichostatin A (TSA) and Zebularine (Zeb) (TZ) followed by TRAIL (TZT) could sensitize the human breast adenocarcinoma cells towards apoptosis. Methods: The breast adenocarcinoma cells, MDA-MB-231, MCF-7 and E-MDA-MB-231 (E-cadherin re-expressed MDA-MB-231) were treated with TSA, Zeb, TZ, TRAIL and TZT. The cells were subjected to hematoxylin and eosin (H & E) staining and FITC-Annexin V/Propidium Iodide apoptosis detection prior to proteome profiling. Results: Based on morphological observation, apoptosis was induced in all cells treated with all treatment regimens though it was more evident for the TZT-treated cells. In the apoptosis detection analysis, TZ increased early apoptosis significantly in MDA-MB-231 and MCF-7 while TRAIL induced late apoptosis significantly in E-MDA-MB-231. Based on the proteome profiling on MDA-MB-231, TRAIL R2 and Fas expression was increased. For E-MDA-MB- 231, down-regulation of catalase, paraoxonase-2 (PON2), clusterin, an inhibitor of apoptosis proteins (IAPs) and cell stress proteins validated the notion that E-cadherin re-expression enhances TZT anti-cancer efficacy. Similar trend was observed in MCF-7 whereby TZT treatment down-regulated the anti-apoptotic catalase and PON2, increased the proapoptotic, B cell lymphoma 2 (Bcl-2)-associated agonist of cell death (Bad) and Bcl-2-associated X (Bax), second mitochondria-derived activator of caspase (SMAC) and HtrA serine peptidase 2 (HTRA2) as well as TRAIL receptors (TRAIL R1 and TRAIL R2). Conclusion: TZ treatment serves as an efficient treatment regimen for MDA-MB-231 and MCF-7, while TRAIL serves as a better treatment option for E-MDA-MB-231. Therefore, future studies on E-cadherin’s positive regulatory role in TRAIL-induced apoptosis are warranted.

Background: Various natural products have been demonstrated for their anti-tumor activities. As a natural triterpenoid, the effects of ganoderic acid A on oxaliplatin chemotherapy for cancer treatment remain unclear. Methods: A xenograft mouse model of colon cancer was constructed using the HT-29 cells. Ganoderic acid A was intravenously administered with or without oxaliplatin. The CCK-8 method was performed to assess cell viability. Flow cytometry was used to determine cell apoptosis and subtyping of T cells. Cytotoxicity of the T cells was assayed using a lymphocyte-tumor co-culture system in vitro. Results: Ganoderic acid A enhanced tumor suppression of oxaliplatin in the xenograft model, while single administration showed no obvious anti-tumor effect. Ganoderic acid A didn’t affect cell proliferation and apoptosis of HT-29 cells treated by oxaliplatin in vitro. Additionally, ganoderic acid A co-administered with oxaliplatin didn’t impact T cell subtyping in the xenograft model. Cytotoxicity of T cells in co-administered mice was remarkably enhanced compared with oxaliplatin-treated mice. Conclusion: Our findings reveal that ganoderic acid A synergistically enhances tumor suppression of oxaliplatin possibly via increasing the cytotoxicity of T cells.

Background: Rhodanine derivatives have a proven wide range of biological activities. Objective: The aim of this study was to evaluate the cytotoxic effect of a series of rhodanine derivatives and investigate the quantitative structure-activity relationships, as well as binding modes to tyrosine kinase. Methods: Cytotoxic effect on cell proliferation (CaCo-2, HeLa, MDCK-1, Hut-78, K562) in vitro was evaluated by the MTT viability assay. QSAR analysis was performed with Dragon descriptors using QSARINS software. Molecular docking was performed on the tyrosin kinase (c-Src) (PDB ID: 3G6H) using iGEMDOCK. Results: Compounds with the best inhibiting activity toward all cell lines were the ones possessing only one group in the C2 of the phenyl ring. QSAR study on the cytotoxic activity against Human T cell lymphoma achieved the model that satisfies the fitting and internal cross-validation criteria (R² = 0.75; Q²LOO = 0.64). Descriptors included in the model (MATS2e, MATs7e, RDF060p) revealed the importance of the presence of atoms with higher polarizability in the outer region of molecules. The findings of the molecular docking study performed on the c-Src are in accordance with the results of the QSAR study. The key interactions with binding site residues were achieved through oxygen atoms from phenoxy and rhodanine groups and rhodanine sulphur atoms. Conclusion: Rhodanine derivatives could be developed as novel tyrosine kinase inhibitors in the treatment of leukemia.

Background: Galangin is one of the flavonoids in Alpinia officinarum. It has various anti-tumor activities, but its anti-bladder cancer effect is unclear. Objective: To investigate the mechanism of action of galangin against bladder cancer using a network pharmacology approach. Methods: The TCM Systematic Pharmacology Database and Analysis Platform (TCMSP), SwissTargetPrediction database, and the Targetnet database were used to predict the targets of action of galangin. Bladder cancer-related targets were obtained through the GeneCards database. The intersection of the two was taken as the target of galangin's action against bladder cancer. The intersecting targets were screened for core targets using the STRING database and Cytoscape 3.9.0 software to build a protein-protein interaction (PPI) network of targets. The core targets were subjected to gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using the online annotation and visual integration analysis tool DAVIDBioinformaticsResources (2021Update). A drug-disease-target-pathway network was constructed using Cytoscape 3.9.0 software. The antibladder cancer effect of galangin was observed by cell proliferation, and plate cloning assay; apoptosis of bladder cancer cells induced by galangin was detected by Hoechst33342 staining and flow cytometry; protein immunoblotting (Western-blot) was used to detect the effect of galangin on apoptosis-related proteins Bax, Bcl-2, Cleaved-PARP, p53 signaling pathway p53 and cytc. Results: A total of 115 genes were obtained from galangin against bladder cancer, and 16 core targets were screened. The kEGG pathway enrichment analysis included Pathways in cancer, PI3K-AKT signaling pathway, p53 signaling pathway, etc. In vitro experiments showed that galangin could inhibit bladder cancer cell proliferation, induce apoptosis, upregulate the expression of apoptosis-related proteins Bax and Cleaved-PARP and downregulate the expression of Bcl-2; meanwhile, galangin could promote the upregulation of the expression of p53 and cytc proteins by activating the p53 signaling pathway. Conclusion: Galangin induced apoptosis in bladder cancer cells by activating the p53 signaling pathway.