Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 22, Issue 13, 2022

The growth of nanotechnology has revolutionized the diagnosis and treatment of diseases with high precision and effectiveness. Nanoparticles (NPs) represent a major point of attention in the scientific field, with an increasing number of studies revealing promising results. The unique physicochemical properties, biocompatibility, and highly developed chemical properties of gold nanoparticles (AuNPs) have promoted breakthroughs in the cancer community, focusing on the therapeutic and diagnostic applications of cancer diagnosis and treatment. This perspective aims to summarize the latest research on multifunctional AuNPs as therapeutic, diagnostic agents in cancer diagnosis and treatment. Several nanostructured hybrid AuNPs have been reviewed, and their applications in imaging, targeting, therapy, and delivery have been discussed.

Background: A high yielding green protocol has been developed and delineated for the synthesis of 3,3- di(indolyl)indolin-2-ones, potentially bioactive compounds, involving one pot aqueous medium condensation of isatin with indole in the presence of VOSO4. The synthesized compounds were screened for their carbonic anhydrase inhibitory activity against human (h) isoforms hCA I, hCA II, hCA IX, and hCA XII. These non-sulfonamide derivatives selectively inhibited hCA II in the micromolar range. Objective: To develop a high yielding green protocol to synthesize 3,3-diindolyl oxindole derivatives using water as solvent media and screening the synthesized molecules for their carbonic anhydrase inhibitory activity. Methods: The target compound is obtained by taking isatin, indole, VOSO4, and H2O in one-pot at 70^oC. Results: The designed molecules were synthesized by using the new method. The molecules were screened for their CA inhibitory activity, which shows selective inhibition toward hCA II.The result showed an excellent yield without any loss or decrease in catalytic activity, proving the catalyst's performance and recyclability. Conclusion: An efficient, simple, and green protocol was established that provides a facile and straightforward approach for the preparation of 3,3-diindolyl oxindole derivatives (3a-r) from Isatin and Indole by using 10 mol% VOSO4 in high yields in a short period of time by a one-pot coupling reaction. Furthermore, the catalyst can also be recovered and reused for three consecutive catalytic cycles without any loss of its efficiency, which was confirmed by performing the experiment with 3a. The newly synthesized molecules (3a-r) were screened for their carbonic anhydrase inhibition potency against four isoforms, hCA I, II, IX, and XII and most of the compounds were found potent against hCA II with potency low to submicromolar range.

Glioblastoma, an aggressive brain cancer, demonstrates the least life expectancy among all brain cancers. Because of the regulation of diverse signaling pathways in cancers, the chemotherapeutic approaches used to suppress their multiplication and spread are restricted. Sensitivity towards chemotherapeutic agents has been developed because of the pathological and drug-evading abilities of these diverse mechanisms. As a result, the identification and exploration of strategies or treatments, which can overcome such refractory obstacles to improve glioblastoma response to treatment as well as recovery, is essential. Medicinal herbs contain a wide variety of bioactive compounds, which could trigger aggressive brain cancers, regulate their anti-cancer mechanisms and immune responses to assist in cancer elimination, and cause cell death. Numerous tumor-causing proteins, which facilitate invasion as well as metastasis of cancer, tolerance of chemotherapies, and angiogenesis, are also inhibited by these phytochemicals. Such herbs remain valuable for glioblastoma prevention and its incidence by effectively being used as anti-glioma therapies. This review thus presents the latest findings on medicinal plants using which the extracts or bioactive components are being used against glioblastoma, their mechanism of functioning, pharmacological description, and recent clinical studies conducted on them.

Background: Disease-modifying therapy in cancer can be defined as long-term treatment that has a beneficial outcome on the course of cancer, affecting the underlying pathophysiology of cancer. The anticancer potential of polyphenols is widely studied. However, there is a significant gap between experimental data obtained in vitro and in vitro and the current role of polyphenols in cancer therapy. Objective: In this article, the reason for this inconsistency is discussed, which might be in the design of polyphenols clinical trials. The approach of long-term polyphenol disease-modifying therapy in cancer is encouraged. Conclusion: The physiologic concentrations of polyphenols are not sufficient for reaching cytotoxic levels. Therefore, the immune modulation and effects on cancer signal transduction pathways should be considered in the design of polyphenol clinical trials. Such effects apparently can not cause the rapid regression of the disease. However, more likely, they can modulate the course of the disease, leading to favorable changes in the patient's condition in case of long-term treatment.

Microbial L-asparaginase is the most effective first-line therapy used in the treatment protocols of paediatric and adult leukemia. Leukemic cells’ auxotrophy for L-asparagine is exploited as a therapeutic strategy to mediate cell death through metabolic blockade of L-asparagine using L-asparaginase. Escherichia coli and Erwinia chrysanthemi serve as the major enzyme deriving sources accepted in clinical practice, and the enzyme has bestowed improvements in patient outcomes over the last 40 years. However, an array of side effects generated by the native enzymes due to glutamine co-catalysis and short serum stays augmenting frequent dosages intended a therapeutic switch towards developing bio better alternatives for the enzyme, including the formulations resulting in sustained local depletion of Lasparagine. In addition, the treatment with L-asparaginase in a few cancer types has proven to elicit drug-induced cytoprotective autophagy mechanisms and therefore warrants concern. Although the off-target glutamine hydrolysis has been viewed as contributing to the drug-induced secondary responses in cells deficient with asparagine synthetase machinery, the beneficial role of glutaminase-asparaginase in proliferative regulation of asparagine prototrophic cells has been looked forward. The current review provides an overview of the enzyme’s clinical applications in leukemia and possible therapeutic implications in other solid tumours, recent advancements in drug formulations, and discusses the aspects of two-sided roles of glutaminase-asparaginases and drug-induced cytoprotective autophagy mechanisms.

Background: Colon cancer is one of the most important causes of death in the entire world. New pharmacological strategies are always needed, especially in resistant variants of this pathology. We have previously reported that drugs such as menadione (MEN), D, L-buthionine-S,R-sulfoximine or calcitriol, used in combination, enhanced cell sensibility of breast and colon tumour models, due to their ability to modify the oxidative status of the cells. Melatonin (MEL), a hormone regulating circadian rhythms, has anti-oxidant and anti-apoptotic properties at low concentrations, while at high doses, it has been shown to inhibit cancer cell growth. Objective: The objective of this study is to determine the antitumoral action of the combination MEN and MEL on colon cancer cells. Methods: Caco-2 cells were employed to evaluate the effects of both compounds, used alone or combined, on cellular growth/morphology, oxidative and nitrosative stress, and cell migration. Results: MEN plus MEL dramatically reduced cell proliferation in a time and dose-dependent manner. The antiproliferative effects began at 48 h. At the same time, the combination modified the content of superoxide anion, induced the formation of reactive nitrogen species and enhanced catalase activity. Cell migration process was delayed. Also, changes in nuclear morphology consistent with cell death were observed. Conclusion: The enhanced effect of simultaneous use of MEN and MEL on Caco-2 cells suggests that this combined action may have therapeutic potential as an adjuvant on intestinal cancer acting in different oncogenic pathways.

Background: Despite the dynamic development of medicine, globally cancer diseases remain the second leading cause of death. Therefore, there is a strong necessity to improve chemotherapy regimens and search for new anticancer agents. Pyridocarbazoles are compounds with confirmed antitumor properties based on multimodal mechanisms, i.e. DNA intercalation and topoisomerase II-DNA complex inhibition. One of them, S16020, displayed a wide spectrum of activity. Objective: The aim of the study was to investigate the antitumor potency of six S16020 derivatives, synthesized according to the SAR (structure-activity relationship) method. Methods: The biological evaluation included influence on cancer cell viability, proliferation, and migration, as well as P-glycoprotein activity. NHDF, A549, MCF-7, LoVo, and LoVo/DX cell lines were used in the study. Results: All derivatives displayed low toxicity to normal (NHDF) cells at 1 and 2 μM (≤ 20% of cell growth inhibition). The highest reduction in cell viability was noted in A549 cells, which was accompanied by significant disruption of cells proliferation and motility. Compound 1 exhibited the strongest cytotoxic, antiproliferative, and antimigratory effects, higher than the reference olivacine. A significant reduction in P-glycoprotein activity was found for derivatives 6 and 1. Conclusion: S16020 derivatives could be considered as potential candidates for new anticancer drugs.

Background: Coumarin is a functional compound with a pronounced wide range of biological activities and has recently been shown to have anticancer effects on various human cancer cells. Cisplatin is widely used in treating many cancers, but its effectiveness is limited due to acquired resistance and dose-related side effects. Objective: This study aimed to reveal the chemosensitizing ability of novel synthesized coumarin-triazole hybrid compounds (3a-f) compared to the cisplatin in A549, MCF-7, and HeLa cancer cells. Methods: Cytotoxicity was determined by MTT assay. Lactate dehydrogenase (LDH), antioxidant/oxidant status, and DNA fragmentation were determined spectrophotometrically using commercial kits. Muse™ Cell Analyzer was used to assess cell cycle progression. Pro/anti-apoptotic gene expressions were determined by Real-Time qPCR. The antiangiogenic activity was determined by VEGF expression and Hen's chorioallantoic membrane model. Results: Compounds 3c, -d, -e, and -f potentiated the cisplatin-induced cytotoxicity by increasing LDH release and DNA fragmentation, inducing G2/M cell cycle arrest, overproducing oxidative stress, and decreasing cellular antioxidant levels. These compounds combined with cisplatin caused upregulation in the pro-apoptotic Bax, Bıd, caspase-3, caspase-8, caspase-9, Fas, and p53 gene expressions while downregulating anti-apoptotic DFFA, NFkB1, and Bcl2 gene expressions. These combinations caused vascular loss and a reduction in VEGF expression. Conclusion: These results suggest that a combinational regimen of coumarin compounds with cisplatin could enhance the effect of cisplatin in A549 cells. Besides, these compounds exhibit relatively low toxicity in normal cells, thus decreasing the dose requirement of cisplatin in cancer treatments.

Background: Isatin (1H-indole-2,3-dione) and its derivatives have been utilized in a variety of biological activities. Anticancer compounds were the most extensively highlighted and explored among the range of beneficial properties. Objective: Herein, we report the targeting effect of halogenated isatin derivatives on cancer cell mitochondria and their antiproliferative mechanism. Methods: A series of novel 5-halo-Isatin derivatives consisting of the 5-Amino-1,3,4-thiadiazole-2-thiol scaffold were synthesized and easily conducted in good yields through a condensation reaction between keto groups of Isatin and primary amine under alcoholic conditions, followed by S-benzylation. The compounds were fully characterized using spectroscopic methods such as ¹H-NMR, FTIR, mass spectroscopy and then tested in vitro towards three cancer cell lines HT-29 (colon cancer), MCF-7 (breast cancer), and SKNMC (neuroblastoma). Apoptosis induction was investigated through assessment of caspase 3 and mitochondrial membrane potential. Results: The most potent compounds of 5b, 5r (IC50 = 18,13 μM), and 5n (IC50 = 20,17 μM) were found to show strong anticancer activity, especially for MCF7 cells. Further anticancer mechanism studies indicated that 5b and 5r induced apoptosis through the intrinsic mitochondrial pathway. Conclusion: This research demonstrated that 5b and 5r have an anticancer property via the modulation of oxidative stress-mediated mitochondrial apoptosis and immune response, which deserves further studies on their clinical applications.

Aim: This study aimed to investigate the anticancer effect and the underlying mechanisms of organoantimony (III) fluoride on MDA-MB-231 human breast cancer cells. Methods: Five cancer and one normal cell line were treated with an organoantimony (III) compound 6-cyclohexyl-12- fluoro-5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine (denoted as C4). The cell viability was detected by MTT assay. Induction of cell death was determined by Hoechst 33342/PI staining and Annexin-V/PI staining. The effect of C4 on the necroptotic relative protein was determined by Western blot analysis. Results: Among the five cancer cell lines, C4 decreased the viability of MDA-MB-231, MCF-7 and A2780/cisR, and showed less toxicity on normal human embryonic kidney cells. In breast cancer cell line MDA-MB-231, the C4 treatment induced necrotic cell death as well as LDH release in a time- and dose-dependent manner. Moreover, C4 could increase the expression of phosphorylated RIPK3 and MLKL proteins. Overall, the C4 treatment resulted in the reduction of mitochondrial transmembrane potential and accumulation of ROS in MDA-MB-231 cells. Conclusion: C4-induced necroptosis could be ascribed to glutathione depletion and ROS elevation in MDA-MB-231 cells. Our findings illustrate C4 to be a potential necroptosis inducer for breast cancer treatment.

Background: Lung cancer is one of the leading causes of cancer-related deaths worldwide. Platycodin D (PD), a major pharmacological constituent from the Chinese medicinal herb named Platycodonis Radix, has shown potent anti-tumor activity. Also, it is reported that PD could inhibit cellular growth in the non-small-cell lung carcinoma (NSCLC) A549 cell line. However, the underlying mechanism is not fully clarified. Methods: Cell proliferation was measured by MTT assay. Annexin V and propidium iodide (PI) assay were employed to study the apoptosis effects of PD on A549 cells. Western blot analysis was used to evaluate protein expression. Also, we used a siRNA against p53, as well as a plasmid-based RRM1 over-expression to investigate their functions. Results: It is demonstrated that PD inhibited A549 cell proliferation in a dose- and time-dependent manner. Further investigations showed that PD induced cell apoptosis, which was supported by dose-dependent and time-dependent caspase-3 activation and p53/VEGF/MMP2 pathway regulation. Also, PD demonstrated the inhibition effect of ribonucleotide reductase M1 (RRM1), whose role in various tumors is contradictory. Remarkably, in this work, RRM1 overexpression in A549 cells could have a negative impact on the regulation of the p53/VEGF/MMP2 pathway induced by PD treatment. Note that RRM1 overexpression also attenuated cell apoptosis and inhibition of cell proliferation of A549 treated with PD. Conclusion: The results suggested that PD could inhibit A549 cell proliferation and induce cell apoptosis by regulating p53/VEGF/MMP2 pathway, in which RRM1 plays an important role directly.

Background: Poly (ADP-ribose) polymerase (PARP) plays a key role in DNA damage repair. A novel compound (E)-N'-(2,3-dibromo-4,5-dihydroxyphenyl)-N-(phenylcarbamothioyl)formimidamide (DDPF-20) with excellent PARP inhibitory activity was synthesized. Objective: In this study, we aimed to clarify the mechanism of the novel PARP inhibitor DDPF-20 against lung cancer by inducing DNA damage and inhibiting angiogenesis. Methods: The cytotoxic effect of DDPF-20 on the A549 cell line was determined with an MTT assay. Cell cycle and apoptosis were determined by a flow cytometer. Moreover, the γH2AX foci were detected by immunofluorescence. Capillary-like tube formation assay and chick chorioallantoic membrane (CAM) assay were used to detect the angiogenesis inhibitory effect of DDPF-20. The expressions of related proteins were detected by western blot. The anticancer activity of DDPF-20 in vivo was also detected. Results: With an IC50 value of 52.42 ± 15.13 nM, DDPF-20 inhibited the proliferation, induced G2/M cycle arrest, and induced apoptosis of human lung cancer A549 cells. Further research showed that DDPF-20 induced DNA doublestrand breaks (DSBs). Interestingly, DDPF-20 inhibited the tube formation of HUVEC cells, as well as inhibited the neovascularization of CAM, proving the angiogenesis inhibitory ability of DDPF-20. Mechanism studies proved that DDPF-20 inhibited the PI3K/Akt/VEGF signaling pathway. In an in vivo study, DDPF-20 inhibited tumor growth of an A549 xenograft. Analysis of the molecular mechanism underlying this effect revealed that the PI3K/Akt/VEGF pathway was involved in DDPF-20-induced cell death and inhibited angiogenesis in vivo. Conclusion: This study suggested that the novel PARP inhibitor DDPF-20 may have therapeutic potential in treating lung cancer.

Background: The demand for millet-based diets has increased significantly in recent years due to their beneficial effects on human health. Foxtail Millet (Setaria italica (L.) P. Beauv, previously known as Panicum italicum L., referred as FTM in this manuscript) seeds have been not only used as astringent and diuretic agents, but they are also used to treat dyspepsia and rheumatism. Recent studies have shown that solvent extracts from FTM seeds exhibited antioxidant and antiinflammatory activities. However, the nature and antiproliferative potential of phytochemical constituents of solvent extracts are not much explored. Objectives: Major objectives of this study are to generate and characterize the phytochemical-rich fractions from Foxtail millet seeds, test the antioxidant activity, and antiproliferative potential against cell lines representing carcinomas of the breast, and determine the mechanisms of cell growth inhibition. Method: Phytochemical-rich fractions were generated by extracting the seeds using 70% ethanol (FTM-FP) and 10% alkali (FTM-BP). Antioxidant potential was determined by ferric reducing antioxidant power (FRAP) assay and DPPH radical scavenging activity assays. The antiproliferative potential was determined using sulforhodamine-B assay. The impact on cell cycle and DNA fragmentation was analyzed by staining the cells with DAPI followed by analyzing the stained cells using NC-3000. Results: Analysis of the results showed the presence of phenolics and flavonoids in the FTM-FP and FTM-BP fractions. Both fractions exhibited antiproliferative potential against breast cancer cell lines. Mechanistically, both fractions induced G2/M cell cycle arrest and increased the fragmentation of DNA, which lead to the accumulation of cells in the Sub-G1 phase. Conclusion: In summary, results of this study demonstrated the potential of foxtail millet phytochemical fractions for retarding the proliferative potential of breast cancer cells.

Background: Aberrant expression of cell adhesion molecules and matrix metalloproteinase (MMPs) plays a pivotal role in tumor biological processes, including progression and metastasis of cancer cells. Targeting these processes and acquiring a detailed understanding of their underlying molecular mechanism are an essential step in cancer treatment. Dexamethasone (Dex) is a type of synthetic corticosteroid hormone used as adjuvant therapy in combination with current cancer treatments such as chemotherapy in order to alleviate its side effects like acute nausea and vomiting. Recent evidences suggest that Dex may have antitumor characteristics. Objective: Dex affects the migration and adhesion of T47D breast cancer cells as well as cell adhesion molecules, e.g. cadherin and integrin, and MMPs by regulating the expression levels of associated genes. Methods: In this study, we evaluated the cytotoxicity of Dex on the T47D breast cancer cell line through MTT assay. Cell adhesion assay and wound healing assay were performed to determine the impact of Dex on cell adhesion and cell migration, respectively. Moreover, real-time PCR was used to measure the levels of α and β integrin, E-cadherin, N-cadherin, MMP-2, and MMP-9. Results: Dex decreased the viability of T47D cells in a time and dose-dependent manner. Cell adhesion and migration of T47D cells were reduced upon Dex treatment. The expressions of α and β integrin, E-cadherin, Ncadherin, MMP-2, and MMP-9 were altered in response to the Dex treatment. Conclusion: Our findings demonstrated that Dex may play a role in the prevention of metastasis in this cell line.