Development Of Anticancer Drugs Research Articles

Eltrombopag directly activates BAK and induces apoptosis

Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its function as a BAX inhibitor, Eltro directly binds BAK but induces its activation in vitro. Moreover, Eltro induces or sensitizes BAK-dependent cell death in mouse embryonic fibroblasts (MEFs) and Jurkat cells. Chemical shift perturbation analysis by NMR indicates that Eltro binds to the BAK α4/α6/α7 groove to initiate BAK activation. Further molecular docking by HADDOCK suggests that several BAK residues, including R156, F157, and H164, play an important role in the interaction with Eltro. The introduction of an R156E mutation in the BAK α4/α6/α7 groove not only decreases Eltro binding and Eltro-induced BAK activation in vitro but also diminishes Eltro-induced apoptosis. Thus, our data suggest that Eltro directly induces BAK activation and BAK-dependent apoptosis, providing a starting point for the future development of more potent and selective direct BAK activators.

Design, Synthesis and Biological Evaluation of Histone Deacetylase Inhibitors Based on Pyrrolo[2,3-d]pyrimidine and Pyrrolo[2,3-b]pyridine Scaffolds.

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDAC inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds. Compound B3 {(E)-3-(4-(((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide} exhibits potent inhibitory activity against HDACs 1, 2, 3, 6, and 8 with IC50 values of 5.2, 6.0, 8.8, 4.4, and 173.0 nM, respectively. It exhibited potent antiproliferative effects against three tumour cell lines (IC50 values of 0.13, 0.37, and 1.11 μM, against MV-4-11, K562, and WSU-DLCL-2 cells, respectively) with two- to sixfold improvement relative to suberoylanilide hydroxamic acid (SAHA). Mechanistic studies on WSU-DLCL-2 cells revealed that B3 exhibits anticancer effects through the induction of G0 /G1 -phase arrest and promotion of apoptosis. The results of this study warrant further investigation of this compound series for the treatment of hematological malignancy.

In Situ Activation of the Receptor Aggregation for Cell Apoptosis by an AI-Au Intelligent Nanomachine via Tumor Extracellular Acidity.

Polyvalent ligand-induced cell receptor aggregation is closely related to cell behavior regulation. At present, most of the means to induce receptor aggregation rely on external stimuli such as light, heat, and magnetic fields, which may cause side effects to normal cells. How to achieve receptor aggregation on the cancer cell surface to achieve cell apoptosis selectively is still a challenge. Therefore, by taking advantage of the unique property of cancer cells' slightly acidic microenvironment, an easy-to-use apoptosis-inducing mode for the in situ activation of cell surface nucleolin clustering has been developed, which not only opened a new channel for nucleolin receptor aggregation to regulate cell function and further development but also avoided damage to normal cells, providing a new strategy for tumor treatment. Dual functional ssDNA (AS1411 aptamer and pH-responsive I-strand sequence) was modified on the surface of gold nanoparticles (AuNPs) to fabricate AI-Au intelligent nanomachines. Then, the specific binding on cancer cells and aggregation of the nucleolin receptors can be achieved via the formation of an i-Motif structure among adjacent AuNPs under the acidic microenvironment. The result showed that AI-Au nanomachines mediated nucleolin cross-linking on the cell surface, resulting in a cytotoxic effect of approximately 60%. Experiments such as calcein-AM/PI staining, nuclear dye staining, and flow cytometry demonstrated that cell apoptosis became more evident with the increase of acidity under the cell surface microenvironment. Immunofluorescence imaging further confirmed the Cyt-c/caspase-3 apoptosis pathway induced by AI-Au nanomachines. The proposed strategy used for specific cancer cell apoptosis by the in situ activation of tumor cell membrane receptor aggregation is inexpensive and simple to use, which not only provides a new means of nucleolin receptor aggregation for regulating cell function but also offers a new strategy for tumor treatment with reduced side effect to normal cells. This work is significant for comprehending the ligand-induced receptor aggregation process and can lead to the development of a promising anticancer drug.

The development of an anti-cancer peptide M1-21 targeting transcription factor FOXM1

BackgroundTranscription factor FOXM1 is a potential target for anti-cancer drug development. An interfering peptide M1-21, targeting FOXM1 and FOXM1-interacting proteins, is developed and its anti-cancer efficacy is evaluated.MethodsFOXM1 C-terminus-binding peptides are screened by in silico protocols from the peptide library of FOXM1 (1-138aa) and confirmed by cellular experiments. The selected peptide is synthesized into its D-retro-inverso (DRI) form by fusing a TAT cell-penetrating sequence. Anti-cancer activities are evaluated in vitro and in vivo with tumor-grafted nude mice, spontaneous breast cancer mice, and wild-type metastasis-tracing mice. Anti-cancer mechanisms are analyzed. Distribution and safety profiles in mice are evaluated.ResultsWith improved stability and cell inhibitory activity compared to the parent peptide, M1-21 binds to multiple regions of FOXM1 and interferes with protein-protein interactions between FOXM1 and its various known partner proteins, including PLK1, LIN9 and B-MYB of the MuvB complex, and β-catenin. Consequently, M1-21 inhibits FOXM1-related transcriptional activities and FOXM1-mediated nuclear importation of β-catenin and β-catenin transcriptional activities. M1-21 inhibits multiple types of cancer (20 µM in vitro or 30 mg/kg in vivo) by preventing proliferation, migration, and WNT signaling. Distribution and safety profiles of M1-21 are favorable (broad distribution and > 15 h stability in mice) and the tested non-severely toxic dose reaches 200 mg/kg in mice. M1-21 also has low hemolytic toxicity and immunogenicity in mice.ConclusionsM1-21 is a promising interfering peptide targeting FOXM1 for the development of anti-cancer drugs.

Assessment of antibacterial, antioxidant, and anticancer effects of biosynthesized silver nanoparticles using Teucrium polium extract

One of the key areas of nanotechnology is the synthesis of nanoparticles using environmentally friendly methods without using harmful and toxic chemicals. In this study, silver nanoparticles (AgNPs) were synthesized using a medicinal plant of Teucrium polium. X-ray diffraction analysis confirmed the presence of AgNP crystal planes at (111), (200), (220), and (311). Dynamic light scattering, zeta potential analysis, and transmission electron microscopy showed that the nanoparticles are spherical with various size distributions from 8 to 28 nm and high stability in the reaction mixture. The results of energy-dispersive X-ray spectroscopy analysis showed the elemental composition of AgNPs with a sharp peak at 3.0 kV, which indicates the synthesis and high purity of AgNPs. According to Fourier transform infrared spectroscopy (FTIR), most of the peaks of AgNPs coincided with the FTIR spectrum of this plant and confirmed the presence of plant extract biomolecules as a reducing and stabilizing agent on the surface of nanoparticles. The total antioxidant capacity and 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) assay results showed that AgNPs have higher antioxidant activity than the plant extract. Also, the AgNPs indicated strong antibacterial activity against six pathogenic bacterial strains. AgNPs showed 60% cytotoxicity against breast cancer cell lines (MCF-7), while these nanoparticles showed much less cytotoxicity against normal breast cell lines (MCF-10A). The results of this study represent the strong therapeutic value of synthesized green AgNPs and the field of further development of antibacterial and anticancer drugs.

STUB1-mediated ubiquitination regulates the stability of GLUD1 in lung adenocarcinoma

The dysregulation of glutamine metabolism provides survival advantages for tumors by supplementing tricarboxylic acid cycle. Glutamate dehydrogenase 1 (GLUD1) is one of the key enzymes in glutamine catabolism. Here, we found that enhanced protein stability was the key factor for the upregulation of GLUD1 in lung adenocarcinoma. We discovered that GLUD1 showed a high protein expression in lung adenocarcinoma cells or tissues. We elucidated that STIP1 homology and U-box-containing protein 1 (STUB1) was the key E3 ligase responsible for ubiquitin-mediated proteasomal degradation of GLUD1. We further showed that lysine 503 (K503) was the main ubiquitination site of GLUD1, inhibiting the ubiquitination at this site promoted the proliferation and tumor growth of lung adenocarcinoma cells. Taken together, this study clarifies the molecular mechanism of GLUD1 in maintaining protein homeostasis in lung adenocarcinoma, which provides a theoretical basis for the development of anti-cancer drugs targeting GLUD1.

Orellanine: From Fungal Origin to a Potential Future Cancer Treatment.

Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin orellanine, found in mushrooms including Cortinarius orellanus (Fools webcap). Emphasis will be placed on its historical significance, structural features, and associated toxicomechanics. Chromatographic methods for analysis of the compound and its metabolites, its synthesis, and chemotherapeutic potential are also discussed. Although orellanine's exceptional selectivity for proximal tubular cells is well documented, the mechanics of its toxicity in kidney tissue remains disputed. Here, the most commonly proposed hypotheses are detailed in the context of the molecule's structure, the symptoms seen following ingestion, and its characteristic prolonged latency period. Chromatographic analysis of orellanine and its related substances remains challenging, while biological evaluation of the compound is complicated by uncertainty regarding the role of active metabolites. This has limited efforts to structurally refine the molecule; despite numerous established methods for its synthesis, there is minimal published material on how orellanine's structure might be optimized for therapeutic use. Despite these obstacles, orellanine has generated promising data in preclinical studies of metastatic clear cell renal cell carcinoma, leading to the early 2022 announcement of phase I/II trials in humans.

Synthesis and biological evaluation of anthracene-9,10 dione derivatives as CK2 inhibitors

Human protein kinase CK2 is an important target for the development of anticancer drugs. Many inhibitors were developed in the last few decades, among them emodin, a natural inhibitor with anthracene-9,10-dione backbone. In this work the inhibitory activity of another natural compound endocrocin having similar chemical structure to emodin was evaluated and turned out to be a moderate inhibitor with IC50 value of 6 µM. Additionally, a series of anthracene-9,10-dione derivatives was synthesized and their inhibitory activity toward the target enzyme was evaluated and compared to the activity of emodin. Only one compound namely 1-amino-6-methylanthracene-9,10-dione (4i) resulted be a potent inhibitor with an IC50 value of 1.45 µM. The rest of derivatives showed moderate or no inhibitory activities when were tested at 10 µM concentration. Additionally, the effect of emodin, endocrocin and compound 4i was evaluated on breast cancer cells (MCF7). Using IncuCyte TM life cell monitoring, cell growth of MCF7 cells was blocked almost completely after addition of 30 µM of emodin, whereas endocrocin was able to reduce cell growth by around 45%. Endocrocin with a concentration of 30 µM was able to reduce the viability of MCF7 cells to around 70% after 48 h of incubation. While only 20% of MCF7 cells were still able to synthesize DNA upon incubation with 100 μM endocrocin for 24 h. On the other hand, compound 4i showed weak effect on MCF7 cell line.

Genomic screening methodology not requiring barcoding: Single nucleotide polymorphism-based, mixed-cell screening (SMICS)

Although high-throughput, cancer cell-line screening is a time-honored, important tool for anti-cancer drug development, this process involves the testing of each, individual drug in each, individual cell-line. Despite the availability of robotic liquid handling systems, this process remains a time-consuming and costly investment. The Broad Institute developed a new method called Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) to screen a mixture of barcoded, tumor cell-lines. Although this methodology significantly improved the efficiency of screening large numbers of cell-lines, the barcoding process itself was tedious that requires gene transfection and subsequent selection of stable cell-lines. In this study, we developed a new, genomic approach for screening multiple cancer cell-lines using endogenous “tags” that did not require prior barcoding: single nucleotide polymorphism-based, mixed-cell screening (SMICS). The code for SMICS is available at https://github.com/MarkeyBBSRF/SMICS.

Cyanobacterial metabolites as novel potential suppressors of breast cancer: A comparative in silico pharmacological assessment

The potent estrogen estradiol (E2) is a factor responsible for stimulating breast cancer. In some genetic and phenotypic cases, it also plays a significant role in disease onset and progression. Today, synthetic cancer drugs are expensive and have side effects when taken for a long time to cure such diseases. Therefore, scientists are trying to find alternative drugs to replace the drugs that pose a serious health burden to humans. Since natural sources have low toxicity and no negative consequences, some unexplored cyanobacterial metabolites were chosen for this study. To identify safe and effective drugs, the current study examined anti-breast cancer drugs using Schrödinger's tools. Finally, usneoidone Z showed remarkable docking scores of −13.421, followed by lyngbyabellin E1 (−12.765), malyngamide R (−12.501) and malyngamide T (−11.372). The notable MM-GBSA values of these metabolites were −76.366, −64.691, −69.482, and −67.289, respectively. These four cyanobacterial metabolites showed remarkable hydrogen bonding, docking scores, and MM-GBSA values better than the phytochemicals identified as potent candidates for breast cancer and the drugs prescribed for breast cancer. In fact, ADMET assessment revealed that these molecules have better water solubility, gut absorption, skin permeability, BBB permeability, CNS permeability, total clearance, etc. In particular, Usneoidone Z was found to have better pharmacological properties for manufacturing as a drug. This is the first report on the drug potential of usneoidone Z, lyngbyabellin E1, malyngamide R and malyngamide T for breast cancer. According to the results, the present study assumes that the therapeutic effects of these metabolites will be stronger than those of phytochemicals and drugs against breast cancer in the clinical phase. Furthermore, the present research could be very useful to accelerate the development of novel anticancer drugs from cyanobacteria. In addition, we hope that this research will be a good source to develop a novel drug with no side effects and at a reasonable cost.

The Myc Family and the Metastasis Suppressor NDRG1: Targeting Key Molecular Interactions with Innovative Therapeutics.

Cancer is a leading cause of death worldwide, resulting in ∼10 million deaths in 2020. Major oncogenic effectors are the Myc proto-oncogene family, which consists of three members including c-Myc, N-Myc, and L-Myc. As a pertinent example of the role of the Myc family in tumorigenesis, amplification of MYCN in childhood neuroblastoma strongly correlates with poor patient prognosis. Complexes between Myc oncoproteins and their partners such as hypoxia-inducible factor-1α and Myc-associated protein X (MAX) result in proliferation arrest and pro-proliferative effects, respectively. Interactions with other proteins are also important for N-Myc activity. For instance, the enhancer of zest homolog 2 (EZH2) binds directly to N-Myc to stabilize it by acting as a competitor against the ubiquitin ligase, SCFFBXW7, which prevents proteasomal degradation. Heat shock protein 90 may also be involved in N-Myc stabilization since it binds to EZH2 and prevents its degradation. N-Myc downstream-regulated gene 1 (NDRG1) is downregulated by N-Myc and participates in the regulation of cellular proliferation via associating with other proteins, such as glycogen synthase kinase-3β and low-density lipoprotein receptor-related protein 6. These molecular interactions provide a better understanding of the biologic roles of N-Myc and NDRG1, which can be potentially used as therapeutic targets. In addition to directly targeting these proteins, disrupting their key interactions may also be a promising strategy for anti-cancer drug development. This review examines the interactions between the Myc proteins and other molecules, with a special focus on the relationship between N-Myc and NDRG1 and possible therapeutic interventions. SIGNIFICANCE STATEMENT: Neuroblastoma is one of the most common childhood solid tumors, with a dismal five-year survival rate. This problem makes it imperative to discover new and more effective therapeutics. The molecular interactions between major oncogenic drivers of the Myc family and other key proteins; for example, the metastasis suppressor, NDRG1, may potentially be used as targets for anti-neuroblastoma drug development. In addition to directly targeting these proteins, disrupting their key molecular interactions may also be promising for drug discovery.

QSAR Study on the Antitumor Activity of Novel 1,2, 3-Triazole Compounds based on Topomer Comfa Method

Background: The high mortality rate of cancer is endangering human health, and the research and development of new anticancer drugs have the attention of scientists worldwide. Sulfonamides have become the focus of anticancer drug research. 1,2,3-triazole compounds can inhibit the formation of a variety of tumor cells. Based on the excellent antitumor activity exhibited by the 1,2,3-triazole compound skeleton, the sulfonamide moiety in the sulfonamide structure can be introduced into the triazole compound skeleton to obtain highly active anticancer drugs. Methods: The Topomer CoMFA method was used to study the three-dimensional quantitative structureactivity relationship of 58 new 1,2,3-triazole compounds with sulfa groups, and a 3D-QSAR model was obtained. Results: The cross-validation coefficient q2 is 0.545, the non-cross-correlation coefficient r2 is 0. 754, r_pred2 is 0.930, the optimal number of principal components N is 4, and the standard estimation error SEE is 0.319. These results show that the model has good internal and external forecasting capabilities. By searching for the R group in the Topomer search module and combining with the more active groups in the existing molecules, 6 new compounds with theoretically higher anti-HL-60 (leukemia cell line) activity are obtained. Conclusion: The prediction result of the Topomer CoMFA model is good, and the statistical verification is effective. The prediction results of ADMET show that the 6 new compounds meet the drug requirements and are expected to become potential anti-HL-60 inhibitors, providing guidance for the synthesis of anti-tumor drugs.

Application of Zebrafish as a Model for Anti-Cancer Activity Evaluation and Toxicity Testing of Natural Products.

Developing natural product-based anti-cancer drugs/agents is a promising way to overcome the serious side effects and toxicity of traditional chemotherapeutics for cancer treatment. However, rapid assessment of the in vivo anti-cancer activities of natural products is a challenge. Alternatively, zebrafish are useful model organisms and perform well in addressing this challenging issue. Nowadays, a growing number of studies have utilized zebrafish models to evaluate the in vivo activities of natural compounds. Herein, we reviewed the application of zebrafish models for evaluating the anti-cancer activity and toxicity of natural products over the past years, summarized its process and benefits, and provided future outlooks for the development of natural product-based anti-cancer drugs.

Natural therapeutics for cancer treatment: success, challenges, and prospect

Cancer is a terrifying disease that has become one of the world’s most challenging health concerns, necessitating a proactive approach to its treatment. Nature is a rich source of new chemical entities and a promising avenue for cancer research. Because of their different modes of action on target events in many ways, nature-derived chemicals are considered good possibilities for anticancer drug development. The current review article highlights recent breakthroughs in cancer therapeutics, including natural therapeutic molecules and their mechanisms of action against cancer treatment, as well as their limits, challenges, and prospect. For the review, article data have been collected from previously studied and published research reports, clinical evaluations, case studies, and clinical statistical data generated by scientific research organizations of repute. The chemical structures have been drawn using computational software (chemsketch). The development of promising candidates that can prevent or reduce the proliferation of cancer cells without causing adverse effects from these therapeutics is now underway. Further, nature-derived products are a game-changer because they are simple, safer, environmentally friendly, low-cost, quick, and less toxic than traditional treatment techniques. However, many bioactive chemicals and their analogs have been discovered as possible anticancer treatment options. In the review, the potent therapeutics phytochemicals derived from nature with their tremendous anticancer effects with limitations and prospects have been studied and analyzed based on previously published articles and reports.

MicroRNAs and Long Non-coding RNAs as Novel Targets in Anti-cancer Drug Development.

Non-coding RNAs comprise the majority of RNAs that have been transcribed from the human genome, and these non-coding RNAs have essential regulatory roles in the cellular processes. They have been discovered to influence the expression of the genes, including tumorsuppressive and oncogenes, that establish the non-coding RNAs as novel targets for anti-cancer drug development. Among non-coding RNAs, microRNAs have been extensively studied in terms of cancer biology, and some microRNA-based therapeutics have been reached in clinical studies. Even though most of the research regarding targeting non-coding RNAs for anti-cancer drug development focused on microRNAs, long non-coding RNAs have also started to gain importance as potential therapeutic targets for cancer therapy. In this chapter, the strategies and importance of targeting microRNAs and long non-coding RNAs will be described, along with the clinical studies that involve microRNA-based cancer therapeutics and preclinical studies that involve long noncoding RNA-based therapeutics. Finally, the delivery strategies that have great importance in the effective delivery of the non-coding RNA-based cancer therapeutics, hence the therapy's effectiveness, will be described.

Exopolysaccharide from Lactiplantibacillus plantarum YT013 and Its Apoptotic Activity on Gastric Cancer AGS Cells

Cancer is a significant health burden in the world. Natural product drugs have received widespread attention because of their safety and effectiveness, stable effects and fewer side effects. Some studies have demonstrated that exopolysaccharide (EPS) from lactic acid bacteria (LAB) can inhibit the growth of many types of cancer cells. In this work, the effects of the EPS from Lactiplantibacillus plantarum YT013 on gastric cancer cells were investigated. Its cytotoxicity was evaluated by MTT assay; at the concentration of 1000 μg/mL, the most significant inhibitory effect occurred in AGS cells, followed by SGC-7901, PANC-1 and HCT116, and less inhibited in HepG2 cells. Cell cycle results showed that EPS prevented AGS cells from transitioning from the S phase to the G2/M phase. In addition, the results of flow cytometry showed that EPS promoted apoptosis in a concentration-dependent manner. Western blotting also indicated that EPS might lead to apoptosis via the endogenous mitochondrial apoptotic pathway. The safety of lyophilized powder, cell-free culture supernatant and EPS from Lactiplantibacillus plantarum YT013 were evaluated by observing tissue organs through H&E staining, and the results showed that the components were safe and effective and could provide a basis for the development of natural anticancer active drugs.

Diorganotin(IV) N-methyl-N-phenethyldithiocarbamate Compounds Induce Cytotoxicity via Apoptosis in K562 Human Erythroleukaemia Cells

Imatinib mesylate (IM), a leading treatment for chronic myeloid leukaemia (CML), has sparked worries about the possibility of CML patients developing a resistance to it. As a result, researchers are becoming more interested in organotin(IV) compounds due to their strong potential to be developed as anticancer agents and employed as an option to address the issues regarding IM-resistance therapy. Generally, this study is to determine the cytotoxicity induced by diorganotin(IV) dithiocarbamate compounds in K562 human erythroleukaemia cells. The two novel diorganotin(IV) compounds namely diphenyltin(IV) N-methyl-N-phenethyldithiocarbamate (C1) and dibutyltin(IV) N-methyl-N-phenethyldithiocarbamate (C2) were assessed their cytotoxicity via MTT [3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and mode of cell death via Annexin V-FITC/PI assay with the duration treatment of 24 h. Both compounds displayed strong cytotoxicity in K562 cells. At concentration of 4.2 µM for C1 and 1.6 µM for C2, both compounds were able to induce 49.70% and 46.83% apoptotic events, respectively. The changes in cells' morphological can also be seen 24 h after being exposed to the compounds at their respective IC50 doses. The findings demonstrated that the morphology of the cells was similar to apoptotic features, including cell shrinkage and the production of apoptotic bodies, meanwhile, the low levels of necrotic cells (<1%) also can be seen via cell lysis. In conclusion, both compounds possess the potential as antileukaemia drugs nevertheless, further studies on their action mechanism are required to ratify their qualities and suitability in the research of anticancer drugs development.

Targeting Pancreatic Cancer with Novel Plumbagin Derivatives: Design, Synthesis, Molecular Mechanism, In Vitro and In Vivo Evaluation.

Pancreatic tumors grow in an "austerity" tumor microenvironment characterized by nutrient deprivation and hypoxia. This leads to the activation of adaptive pathways in pancreatic cancer cells, promoting tolerance to nutrition starvation and aggressive malignancy. Conventional anticancer drugs are often ineffective against tumors that grow in such austerity condition. Plumbagin, a plant-derived naphthoquinone, has shown potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions. Therefore, we synthesized a series of plumbagin derivatives and found that 2-(cyclohexylmethyl)-plumbagin (3f) was the most promising compound with a PC50 value of 0.11 μM. Mechanistically, 3f was found to inhibit the PI3K/Akt/mTOR signaling pathways, leading to cancer cell death under nutrient-deprived conditions. In vivo studies using pancreatic cancer xenograft mouse models confirmed the efficacy of 3f, demonstrating significant inhibition of tumor growth in a dose-dependent manner. Compound 3f represents a highly promising lead for anticancer drug development based on an antiausterity strategy.

Natural Cyclophilin A Inhibitors Suppress the Growth of Cancer Stem Cells in Non-Small Cell Lung Cancer by Disrupting Crosstalk between CypA/CD147 and EGFR.

Non-small cell lung cancer (NSCLC) is a fatal malignant tumor with a high mortality rate. Cancer stem cells (CSCs) play pivotal roles in tumor initiation and progression, treatment resistance, and NSCLC recurrence. Therefore, the development of novel therapeutic targets and anticancer drugs that effectively block CSC growth may improve treatment outcomes in patients with NSCLC. In this study, we evaluated, for the first time, the effects of natural cyclophilin A (CypA) inhibitors, including 23-demethyl 8,13-deoxynargenicin (C9) and cyclosporin A (CsA), on the growth of NSCLC CSCs. C9 and CsA more sensitively inhibited the proliferation of epidermal growth factor receptor (EGFR)-mutant NSCLC CSCs than EGFR wild-type NSCLC CSCs. Both compounds suppressed the self-renewal ability of NSCLC CSCs and NSCLC-CSC-derived tumor growth in vivo. Furthermore, C9 and CsA inhibited NSCLC CSC growth by activating the intrinsic apoptotic pathway. Notably, C9 and CsA reduced the expression levels of major CSC markers, including integrin α6, CD133, CD44, ALDH1A1, Nanog, Oct4, and Sox2, through dual downregulation of the CypA/CD147 axis and EGFR activity in NSCLC CSCs. Our results also show that the EGFR tyrosine kinase inhibitor afatinib inactivated EGFR and decreased the expression levels of CypA and CD147 in NSCLC CSCs, suggesting close crosstalk between the CypA/CD147 and EGFR pathways in regulating NSCLC CSC growth. In addition, combined treatment with afatinib and C9 or CsA more potently inhibited the growth of EGFR-mutant NSCLC CSCs than single-compound treatments. These findings suggest that the natural CypA inhibitors C9 and CsA are potential anticancer agents that suppress the growth of EGFR-mutant NSCLC CSCs, either as monotherapy or in combination with afatinib, by interfering with the crosstalk between CypA/CD147 and EGFR.

Synthesis, Characterization and in vitro Anticancer Evaluation of 5-Sulfinyl(sulfonyl)-4-arylsulfonyl-Substituted 1,3-Oxazoles.

A novel series of 5-sulfinyl(sulfonyl)-4-arylsulfonyl-substituted 1,3-oxazoles has been synthesized, characterized and subjected to NCI in vitro assessment. Cancer cell lines of all subpanels were most sensitive to 2-{[4-[(4-fluorophenyl)sulfonyl]-2-(2-furyl)-1,3-oxazol-5-yl]sulfinyl}acetamide (3 l). Its antiproliferative and cytotoxic activity averaged over each subpanel was manifested in a very narrow range of concentrations (GI50 : 1.64-1.86 μM, TGI: 3.16-3.81 μM and LC50 : 5.53-7.27 μM), i. e. practically did not depend on the origin of the cancer cell line. The COMPARE matrix using TGI vector showed a high positive correlation of 3 l (r=0.88) with the intercalating agent aclarubicin, which inhibits topoisomerases. The absence in the database of standard agents that have a high correlation with the cytotoxicity of this compound suggests that it may have a unique mechanism of action. According to the results of the docking analysis, the most promising anticancer target for compound 3 l is DNA topoisomerase IIβ. The obtained results indicate the anticancer activity of 5-sulfinyl(sulfonyl)-4-arylsulfonyl-substituted 1,3-oxazoles, which may be useful for the development of new anticancer drugs. 2-{[4-[(4-Fluorophenyl)sulfonyl]-2-(2-furyl)-1,3-oxazol-5-yl]sulfinyl}acetamide (3 l), as the most active, can be recommended for further in-depth studies.