Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 23, Issue 14, 2023

Breast cancer is the most common cancer among women worldwide. It is the main reason why women die from cancer. Early diagnosis due to increased public awareness and better screening helps to tackle the disease through surgical resection and curative therapies. Chemotherapies are frequently used for cancer treatment, but these have severe adverse effects due to a lack of target specificity. Formulation development scientists and clinicians are now particularly concerned with developing safe and efficient drug delivery systems for breast cancer treatment. Potentially relevant literature to get the latest developments and updated information related to properties, functionalization, toxicity and application of carbon nanotubes in breast cancer treatment has been obtained from Web of Science, Scopus, and PubMed portals. Nanomedicine has emerged as a novel tool for target-specific delivery systems and other biomedical applications. Carbon nanotubes (CNTs) are gaining popularity due to their unique mechanical and physiochemical properties for the diagnosis and treatment of cancer. It is a promising carrier that can deliver micro and macromolecules to the cancer cell. CNTs can be functionalized at the surface with different functional groups, which helps in targeting the drugs to target cancer cells. The present review has elaborated on different functionalization approaches and toxicity aspects of CNTs.

Background: Non-small cell lung cancer (NSCLC) is a common malignant cancer with high incidence and mortality. In recent decade, despite the progress in the treatment and prevention of NSCLC, its prognosis still remains poor. It is urgently needed to identify new potential mechanism and efficacious drugs for NSCLC patients. Objective: The objective of this study is to explore the potential therapeutic role of diterpenoid tanshinone (DT) against non-small cell lung cancer (NSCLC) in vitro and elucidate the molecular mechanism involved in tumor metastasis. Methods: Human NSCLC lines (A549 and NCI-H1299) were transfected with pcDNA3.1-Cavin-1 plasmids and corresponding controls. We tested the effects of DT on migration and invasion of lung cancer cells using transwell filters coated with fibronectin and Matrigel. Next, Quantitative Real-Time PCR and western blot were used to determine the transcriptional and protein levels of epithelial-mesenchymal transition (EMT) markers, transcription factors (Snail, Slug), and matrix metalloproteinases. Results: As expected, Cavin-1 related to the enhanced ability of cell migration and invasion. DT not only inhibited the migratory and invasive capacity of Cavin-1-transfected NSCLC cells but also significantly increased the expression of ZEB1 and E-cadherin and decreased the level of N-cadherin, Vimentin, Snail, and Slug. Moreover, DT treatment obviously alleviated Cavin-1 overexpression-induced high levels of MMP2, MMP7, and MMP9 at both the protein and transcriptional levels. Furthermore, overexpressed Cavin-1 upregulated ERK and Smad2 signaling pathways in NSCLC cells, which were also strongly weakened by DT administration. Conclusion: Our results suggested that DT effectively attenuates Cavin-1-mediated NSCLC metastasis via the ERK/Smad2 signaling pathway.

Background/Introduction: Prostate cancer ranks as the second leading cause of cancer death. No effective pharmacological agent is available for prostate cancer treatment. Berbamine is an alkaloid extracted from the Chinese herb berberis, which exerts an effect on inhibiting cancer cell proliferation. Objective: This study aimed to explore the mechanism of berbamine in inhibiting prostate cancer. Methods: Prostate cancer cell lines PC-3 and DU145 cells were used to evaluate the effects of berbamine. Cell viability was determined using cell-counting kit 8. The intracellular reactive oxygen species (ROS) levels were measured using a ROS assay kit. Cell apoptosis rate was examined using flow cytometry. The protein levels associated with cell proliferation, NF-ΚB pathway, and apoptosis were determined using western blot. Results: It was found that berbamine induced cell cycle arrest in the S phase and inhibited prostate cancer cell growth and proliferation. Berbamine inhibited prostate cancer cells by inhibiting the activation of the NF-ΚB pathway in vitro. Berbamine increased ROS as an upstream molecule that inhibited the NF-ΚB pathway. Conclusion: Our results demonstrated that berbamine can effectively reduce the proliferation of prostate cancer cells. The ROS/NF-ΚB axis plays a crucial role in berbamine-mediated anti-prostate cancer cell proliferation.

Background/Introduction: 4-aryl-4H-chromenes have attracted attention as potential anticancer agents. Objective: In an effort to discover effective compounds, we designed a new series of these chromenes with methoxy substitution at 2, 3, 4, 5, and 6 positions. Methods: The synthesized compounds were tested for anticancer properties against two human cancer cell lines (MCF- 7 and PC3) as well as a normal cell line. Furthermore, induction of apoptosis was explored through various methods, such as flow cytometry analysis, morphological changes, activation of caspase 3, ROS, and MMP. Results: The MTT assay showed that the 5g derivative, with methoxy groups at ortho and meta positions, exhibited the highest potency (IC50 = 40 μM) against the PC3 cell line. Our findings revealed that compound 5g induced apoptosis in the PC3 cell line, which was demonstrated by activation of caspase 3, an increase in ROS levels, and early apoptosis percentage. Conclusion: These results suggest that compound 5g holds promise as a potential therapeutic approach to cancer treatment.

Background: Combretastatin A-4 (CA-4) is a natural product isolated from the bark of the South African bush willow tree Combretum caffrum, which exerts tubulin inhibition, but its clinical application is limited due to poor stability and water solubility. 2-aryl benzimidazoles are excellent pharmacological skeletons with many activities, especially in tumor inhibition, and better pharmacokinetic properties. Several scaffold CA-4 analogs have been synthesized to date possessing antitumor activities. Objective: The benzimidazole was applied as the core moiety to replace the B ring and unstable linkage of CA-4, and the 5-aryl acetenyl group was introduced to improve the antitumor activity. MCF-7, A549, Caco-2, Siha, and Eca-109 tumor cell lines were used to study inhibition by these agents in vitro. Methods: The benzimidazole structure was constructed from the oxidation of o-nitroaniline and aldehyde and the following schemes, and the structural characterization was carried out. The antitumor effects were evaluated in vitro through MTT assay, cell cycle arrest, and apoptosis assay. Molecular docking with tubulin (Protein ID: 1SA0) was analyzed for the structure-activity relationship. Results: Among these derivatives, 4a-4h series (with 6-methoxy group) compounds inhibited the tumor cell lines much stronger than the CA-4 and cisplatin, especially compound 4f showed prominently inhibitory activity in Siha cell with IC50 value as 0.61 μmol/L. The further assay showed that the cell cycle was arrested at the G0/G1 phase as well verified in apoptosis assay. Molecular docking indicated that 4f had stronger affinity energy and hydrogen bond than CA-4. Conclusion: The compound 4f has the potency to be used as an anti-tubulin agent and the 2-trimethoxyphenyl benzimidazole skeleton deserves further study as an antitumor structure.

Background: Nanoparticles' precise targeting properties are becoming increasingly important in treating cancer and starting to outweigh cancer therapies. Methods: The in vivo anticancer activity of ethyl acetate iron oxide nanoparticles (NPS EAE) of Acalypha wilkesiana Müll. Mosaica was tested using Ehrlich ascites carcinoma cells (EAC). Results: The value of the median lethal dose LD50 limit was found to be 3000 mg/kg. The value count of EAC cells was significantly decreased to 150 ± 2.01 (10⁶) and 275 ± 2.01 (10⁶) cells for each preventive and therapeutic group related to the positive group (525 ± 4.3 (10⁶) cell. Moreover, the results of biological markers decrease in alanine amino transferase activity (ALT), aspartate amino transferase activity (AST), creatinine (CREAT), UREA, albumin, globulin, and total protein level according to the confident group by restoring the abnormal dissimilarity in the biomedical parameters to normal values. Ethyl acetate nano particles induced apoptosis in hepatic and kidney cells. This was designated by increasing the apoptosis regulator Bcl-2 associated X (BAX) level and significantly reducing antiapoptotic assay B-cell lymphoma 2 (Bcl-2) level as an antiapoptotic marker. In the apoptotic marker BAX, there was a significant rise in therapeutic activity with a change of 273.87% and a significant increase in the preventive group with a change of 144.69% according to the positive group. However, in the antiapoptotic marker, Bcl-2 highly decreases in the therapeutic group and preventive group with changes -83.20% and -87.82% according to the positive group, which has a highly significant increase with a change of 5855%. Conclusion: Histopathology tests showed anticancer activity against (EAC) in both the preventive group and therapeutic group, especially in the preventive group in kidney organs showed no pathology with normal glomeruli and normal tubules, it also showed in liver foci of lobular inflammation with mild development of a portal tract accompanied by inflammation, but in the therapeutic group showed less activity than the preventive group as in the kidney many tubules displayed appearances of slight tubular injury with mild acute tubular injury and in the liver, the therapeutic group becomes a more effective representation in normal liver architecture, with no detected lobular or portal inflammation or confluent necrosis. So the preventive group was considered as protecting agent for the kidney organ. However, the therapeutic group is supposed to be the treatment agent for the liver organ. This is due to the fact that it has a defensive effect rather than a curative effect. There is a possibility that it is a favorable anticancer agent. Green synthesis of Fe3O4- NPS was successfully done using plant extract acting as a reducing, stabilizing, and capping agent.

Background: Trillium tschonoskii Maxim (TTM) exerts antitumor effects on a variety of tumour cells. However, the antitumor mechanism of Diosgenin glucoside (DG) extracted from TTM is not clear. Objective: This study aimed to investigate the anti-tumour effects of DG-induced osteosarcoma MG-63 cells and their molecular mechanism. Methods: CCK-8 assay, HE staining, and flow cytometry were used to detect the effects of DG on the proliferation, apoptosis, and cell cycle of osteosarcoma cells. Wound healing and Transwell invasion assays were used to observe the effect of DG on the migration and invasion of osteosarcoma cells. The anti-tumour mechanism of DG on osteosarcoma cells was investigated by immunohistochemistry, Western blot, and RT-PCR. Results: DG significantly inhibited osteosarcoma cell activity and proliferation, promoted apoptosis and blocked the G2 phase of the cell cycle. Both wound healing and Transwell invasion assays showed that DG inhibited osteosarcoma cell migration and invasion. Immunohistochemical and western blot results showed that DG inhibited the activation of PI3K/AKT/mTOR. We found that DG also significantly downregulated the expression of S6K1 and eIF4F, which might be associated with the inhibition of protein synthesis. Conclusion: DG may inhibit proliferation, migration, invasion, and cell cycle G2 phase arrest of osteosarcoma MG-63 cells and promote apoptosis through the PI3K/AKT/mTOR signalling pathway.

Introduction: A variety of key human physiological processes rely on angiogenesis, ranging from reproduction and fetal growth to wound healing and tissue repair. Furthermore, this process significantly contributes to tumor progression, invasion, and metastasis. As the strongest inducer of angiogenesis, Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) are targets of therapeutic research for blocking pathological angiogenesis. Objective: Preventing the interaction between VEGF and VEGFR2 by a peptide is a promising strategy for developing antiangiogenic drug candidates. This study was aimed at designing and evaluating VEGF-targeting peptides using in silico and in vitro techniques. Methods: The VEGF binding site of VEGFR2 was considered a basis for peptide design. The interaction of VEGF and all three peptides derived from VEGFR2 were analyzed using ClusPro tools. In a complex with VEGF, the peptide with a higher docking score was evaluated to confirm its stability using molecular dynamics (MD) simulation. The gene coding for the selected peptide was cloned and expressed in E. coli BL21. The bacterial cells were cultured on a large scale, and the expressed recombinant peptide was purified using Ni-NTA chromatography. Refolding of the denatured peptide was carried out by the stepwise removal of the denaturant. The reactivity of peptides was confirmed using western blotting and enzyme-linked immunosorbent assay (ELISA) assays. Finally, the inhibition potency of the peptide on human umbilical vein endothelial cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay. Results: Among three peptides, the peptide with the best docking pose and the highest affinity for VEGF was selected for further studies. Then the stability of the peptide was confirmed over the 100 ns MD simulation. After in silico analyses, the selected peptide was presented for in vitro analysis. Expression of the selected peptide in E. coli BL21 resulted in a pure peptide with a yield of approximately 200 μg/ml. Analysis by ELISA revealed the high reactivity of the peptide with VEGF. Western blot analysis confirmed the specific reactivity of selected peptides with VEGF. The MTT assay revealed the growth inhibitory effect of the peptide on human umbilical vein endothelial cells with an IC50 value of 247.8 μM. Conclusion: In summary, the selected peptide demonstrated a promising inhibitory effect on human umbilical vein endothelial cells that could be a valuable anti-angiogenic candidate for further assessment. Additionally, these in silico and in vitro data provide new insights into peptide design and engineering.

Background: The polysaccharide extract of C. sinensis, Isaria felina (IF), has antitumor effects. Selenium (Se) can improve disease prevention and reduce the toxicity of toxic elements, but the effect of Se-enriched IF on hepatoma remains unknown. Objective: To determine the organic transformation of Se and compare the antitumor effects between Se-enriched IF (IF-Se) and IF on xenograft H22 hepatoma-bearing mice. Methods: Se was added to the solid-state culture medium, and the organic Se content was detected by HPLC-ICP-MS. Forty-two Kunming mice were randomly divided into seven groups to test the antitumor effects of low- (300 mg/kg) and high- (600 mg/kg) doses of IF-Se and IF through xenograft. Huai’er granules were administered as the positive control. In addition, interleukin (IL)-2 and vascular endothelial growth factor (VEGF) expressions were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry method. Results: The conversion rate in the IF-Se70, IF-Se140, and IF-Se280 groups were 91.5%, 93.4%, and 89.3%, respectively. Therefore, IF-Se140 was used to carry out the subsequent experiments. The tumor inhibition rates of IF-Se were significantly higher compared with IF (P < 0.05). Moreover, the spleen coefficient, IL-2, and VEGF expression levels significantly decreased (all Ps < 0.05), and the thymus coefficient significantly increased (P < 0.05) in the high-dose IF-Se group compared with the model control group. Conclusion: The inhibitory effects of IF on H22 hepatoma-bearing mice were enhanced after Se enrichment. Therefore, Se-enriched IF might be a new strategy for treating hepatoma.

The present application reports a series of novel Arcyriaflavin-A derivatives as PIM kinase inhibitors for the effective treatment of cancer. The application also describes the synthesis of compounds in detail, use, pharmaceutical composition, pharmaceutically acceptable salts, and treatment.