Potential Cancer Drug Research Articles

The Inhibitory Effects of the Natural Stilbene Piceatannol on Lactate Transport In Vitro Mediated by Monocarboxylate Transporters.

Lactate, a signaling molecule and energy source, crosses membranes through monocarboxylate transporters (MCTs). MCT1 and MCT4 are potential cancer drug targets due to their role in metabolic reprogramming of cancer cells. Stilbenes, plant secondary metabolites found in several food sources, have anticancer effects, though their mechanisms of action are not well understood. This study links the anticancer activity of natural stilbenes to tumor cell lactate metabolism. The impact of resveratrol, pinostilbene, pterostilbene, rhapontigenin, and piceatannol on lactate transport is studied using a fluorescence resonance energy transfer (FRET)-based lactate sensor. The viability and migration of cells expressing MCT1 or MCT4 are also evaluated. Piceatannol inhibits MCT1 effectively at low micromolar concentrations, with less effect on MCT4. All stilbenes significantly reduce cell viability and migration. These findings indicate that both MCTs are stilbene targets, with piceatannol highlighted as a cost-effective, low-toxicity compound for studying MCTs in cancer, providing a new mechanism of action of the therapeutic and nutraceutical effects of natural polyphenols. This enriches the understanding of dietary polyphenols in cancer prevention and therapy.

Epidermal growth factor receptor mutant T790M-L858R-V948R inhibitor from Calophyllum inophyllum L. leaf as potential non-small cell lung cancer drugs

Epidermal growth factor receptor mutant T790M-L858R-V948R inhibitor from Calophyllum inophyllum L. leaf as potential non-small cell lung cancer drugs

Host-specific endophytes of Momordica charantia: A promising source for affordable lung cancer therapeutics

Endophyte-host interactions lead to the production of various bioactive compounds. Thus, endophytes from a medicinal plant such as Momordica charantia, can be promising candidates for producing pharmacological compounds. Our study therefore aims to evaluate these endophytes as sustainable sources of potential low-cost lung cancer drugs. We determined the endophytes associated with M. charantia (fruit and leaf) and assessed anti-inflammatory, antioxidant and antiproliferative potential against NCI-H23 lung cancer cells. LC-Q-TOF-MS of the endophyte extracts was conducted to determine the metabolite profile.Leaf endophyte F. circinatum showed anti-inflammatory (114.29 %), antioxidant (IC50=27.39 µg/ml) and antiproliferative activity (IC50=98.62 µl/ml) with decreased Beclin1 expression (autophagy regulator) in NCI-H23 cells. It produced five anticancer compounds namely linamarin, xestoaminol C, phytosphingosine, cucurbitacin E and margarolic acid. Fruit endophyte E. fergusonii also showed significant antiproliferative potential (IC50=170.8 µl/ml) with upregulated apoptosis regulator Bcl2 expression. It produced compounds such as eplerenone, kuguacin C and H. With the production of triterpenoids momordicine I, cucurbitacin E and kuguaglycoside A, leaf endophyte A. faecalis showed antioxidant potential (IC50=29.65 µg/ml) but limited antiproliferative activity. This is the first report of endophytes-mediated biosynthesis of host-specific compounds in M. charantia including momordicine I, cucurbitacin E and kuguacins, which are known to have anti-cancer properties. Thus, these medicinal plant endophytes can be low-cost sustainable candidates with anti-cancerous potential, especially against lung cancer.

Synergistic Effect of Layered Double Hydroxides Nanodosage Form to Induce Apoptosis and Ferroptosis in Breast Cancer.

Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy. In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer. The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe2+ in cells through the release of Fe3+, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis. In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.

5-Methylcoumarin-4β-glucoside mitigated colon tumor progression in mice with AOM/DSS-induced colon carcinogenesis

ContextThe in vitro cytotoxicity profile of 5-Methylcoumarin-4β-glucoside (5-MC4βG) has been demonstrated to inhibit the proliferation of HT-29 adenocarcinoma cells. Aim: The need for newer and affordable chemotherapeutic agents is critical. Main methodsWe investigated the effect of 5-MC4βG on an azoxymethane /dextran sodium sulfate-induced colon carcinogenesis model in six groups of laboratory BALB/c mice for six weeks. While the first and second groups of mice served as vehicle and disease controls respectively, the third, fourth, and fifth groups were administered oral graded doses (25, 50, and 100 mg/kg) of 5-MC4βG. The sixth group was treated with 5-Flourouracil (15 mg/kg). Key findingsThe 100 mg/kg dose of 5-MC4βG upregulated APC mRNA expression by two-fold and downregulated β-catenin mRNA expression by two-fold compared to their respective disease controls. Furthermore, tumorigenic gene transcripts (MDM2, BCL2, CDK1, and cyclin D1) were downregulated by one-fold (except cyclin D1 which was downregulated by two-fold), whereas pro-apoptotic genes (p53, Bax, and Casp3) were upregulated by two-fold following treatment with 100 mg/kg dose of 5-MC4βG. At the metabolic level, the bioactive compound lowered the expression of classical tumor markers; tissue polypeptide antigen, tumor-associated glycoprotein 72, and carcinoembryonic antigen by at least half. Histologically, 5-MC4βG intervention revealed a reduction in neoplastic cells associated with cellular necrosis. Significance5-MC4βG reduced colon carcinogenesis in mice. Thus, this compound may be a promising candidate for colorectal cancer chemotherapy. Further development of 5-MC4βG will hopefully lead to the development of a potential anti-colon cancer drug candidate.

In-silico design of novel potential HDAC inhibitors from indazole derivatives targeting breast cancer through QSAR, molecular docking and pharmacokinetics studies

Latest studies confirmed that abnormal function of histone deacetylase (HDAC) plays a pivotal role in formation of tumors and is a potential therapeutic target for treating breast cancer. In this research, in-silico drug discovery approaches via quantitative structure activity relationship (QSAR) and molecular docking simulations were adapted to 43 compounds of indazole derivatives with HDAC inhibition for anticancer activity against breast cancer. The QSAR models were built from multiple linear regression (MLR), and models predictability was cross-validated by leave-one-out (LOO) method. Based on these results, compounds C32, C26 and C31 from model 3 showed superior inhibitory activity with pIC50 of 9.30103, 9.1549 and 9.1549. We designed 10 novel compounds with molecular docking scores ranging from −7.9 to −9.3 kcal/mol. The molecular docking simulation results reveal that amino acid residues ILE1122 and PRO1123 play a significant role in bonding with 6CE6 protein. Furthermore, newly designed compounds P5, P2 and P7 with high docking scores of −9.3 kcal/mol, −8.9 kcal/mol and −8.8 kcal/mol than FDA-approved drug Raloxifene (-8.5 kcal/mol) and aid in establishment of potential drug candidate for HDAC inhibitors. The in-silico ADME functionality is used in the final phase to evaluate newly designed inhibitors as potential drug candidates. The results suggest that newly designed compounds P5, P2 and P7 can be used as a potential anti-breast cancer drug candidate.

Microfluidic nanoprecipitation of PEGylated PLGA nanoparticles with rapamycin and performance evaluation

Rapamycin (RAP) is currently being developed as potential antibreast cancer drug. However, its poor solubility completely limits its use. The aim of this study was to develop polyethylene glycol-poly(lactide-co-glycolide) (PEG-PLGA)-based nanoparticles (NPs) to load RAP via microfluidics with an appropriate polyethylene glycol (PEG) content to enhance the bioavailability of RAP. Polydimethylsiloxane (PDMS) chips with a Y-shaped channel were designed to obtain RAP-loaded PEG-PLGA NPs (RAP-PEG-PLGA). The entrapment efficiency (EE) and drug loading (DL) as well as release profile of RAP-PEG-PLGA were evaluated, and their resistance to plasma albumin adsorption of NPs with different PEG contents was evaluated and compared. RAW264.7 and 4T1 cells were used to assess the antiphagocytic and anticancer cells effect of NPs, respectively. RAP-PEG-PLGA of around 124 nm in size were successfully prepared with the EE of 82.0% and DL of 12.3%, and sustained release for around 40 d. A PEG relative content of 10% within the PEG-PLGA molecule was shown superior in resisting protein adsorption. RAP-PEG-PLGA inhibited the growth of breast cancer cells when the concentration was over 10 μg/mL, and the inhibition efficiency was significantly higher than free RAP. Hence, the current RAP-PEG-PLGA could be a potential therapeutic system for breast cancer treatment.

In silico exploration of potential breast cancer drugs

In silico exploration of potential breast cancer drugs

Quantum DFT analysis and molecular docking investigation of various potential breast cancer drugs

Breast cancer is the most often diagnosed and deadliest type of cancer in the world. These days, the world is facing the threat of breast cancer. It is essential to...

Application of pyroptosis score in the treatment and prognosis evaluation of gastric cancer.

Pyroptosis is a kind of proinflammatory programmed cell death mediated by inflammasome. It affects the occurrence and development of gastric cancer through different ways, showing dual effects. On the one hand, inflammasome-mediated inflammatory response is highly likely to participate in the formation and development of early tumors; on the other hand, drugs can inhibit the deterioration process of tumor proliferation, invasion and metastasis through activating the pathways of inflammasome and pyroptosis. Recently, many agents based on pyroptosis have been found to inhibit gastric cancer by promoting the secondary pyroptosis pathway, regulating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and inhibiting caspase-1. The establishment of cell pyrodeath models can predict the prognosis of gastric cancer patients. Most of the models show that gastric cancer patients with high pyroptosis level have better prognosis and longer overall survival. Pyroptosis scores can also be used to predict the response of gastric cancer patients to immunotherapy and to screen potential anti-gastric cancer drugs. Therefore, in-depth understanding of the potential mechanism of pyroptosis affecting the progression of gastric cancer and the role of pyroptosis score in the treatment and prognosis assessment of gastric cancer will be helpful to find a new and effective method for the treatment of gastric cancer.

Identification of potential oral cancer drugs as Bcl-2 inhibitors from known anti-neoplastic agents through docking studies

Identification of potential oral cancer drugs as Bcl-2 inhibitors from known anti-neoplastic agents through docking studies

Structure-based design, synthesis and biological evaluation of N-substituted 6H-thiochromeno[2,3–c]quinolin-12(12H)-one as potential breast cancer drugs

Tetraheterocyclic compounds, derived from natural sources and contemporary pharmaceuticals, have shown promise as multitarget therapeutic agents. However, their mechanisms of action remain partially understood. In this study, we synthesized a series of 6H-thiochromeno[2,3-c]quinolin-12(12H)-one derivative, totaling 26 compounds, and assessed their potential for therapeutic application. We evaluated their effects on cell proliferation and conducted NCI-60 cell panel assays. MTT assays revealed that select compounds exhibited notable antiproliferative activity against two breast cancer cell lines (MCF-7 and MDA-MB-468). Notably, compounds 17 and 18 displayed the highest cytotoxicity against these cell lines. Furthermore, one-dose assays of the NCI-60 human tumor cell line screening program identified compounds 6, 7, 16, 18, 20, 24, 25, and 30 for further investigation.Subsequent five-dose cytotoxicity studies focused on compounds 18 and 20, which met the threshold inhibition criteria across a panel of cell lines. Our study highlights the effectiveness of compounds 18 and 20 in targeting breast cancer cell lines. Molecular docking simulations revealed that these compounds bind to the active sites of topoisomerase I (TOPO I). Our findings suggest that these novel compounds are promising anticancer agents, particularly against breast cancer, and are worthy of consideration as lead pharmacological candidates.

Alpha Satellite DNA in Targeted Drug Therapy for Prostate Cancer.

Prostate cancer is the most common solid cancer in men and, despite the development of many new therapies, metastatic castration-resistant prostate cancer still remains a deadly disease. Therefore, novel concepts for the treatment of metastatic prostate cancer are needed. In our opinion, the role of the non-coding part of the genome, satellite DNA in particular, has been underestimated in relation to diseases such as cancer. Here, we hypothesise that this part of the genome should be considered as a potential target for the development of new drugs. Specifically, we propose a novel concept directed at the possible treatment of metastatic prostate cancer that is mostly based on epigenetics. Namely, metastatic prostate cancer is characterized by the strongly induced transcription of alpha satellite DNA located in pericentromeric heterochromatin and, according to our hypothesis, the stable controlled transcription of satellite DNA might be important in terms of the control of disease development. This can be primarily achieved through the epigenetic regulation of pericentromeric heterochromatin by using specific enzymes as well as their activators/inhibitors that could act as potential anti-prostate cancer drugs. We believe that our concept is innovative and should be considered in the potential treatment of prostate cancer in combination with other more conventional therapies.

MAGCN: A Multiple Attention Graph Convolution Networks for Predicting Synthetic Lethality.

Synthetic lethality (SL) is a potential cancer therapeutic strategy and drug discovery. Computational approaches to identify synthetic lethality genes have become an effective complement to wet experiments which are time consuming and costly. Graph convolutional networks (GCN) has been utilized to such prediction task as be good at capturing the neighborhood dependency in a graph. However, it is still a lack of the mechanism of aggregating the complementary neighboring information from various heterogeneous graphs. Here, we propose the Multiple Attention Graph Convolution Networks for predicting synthetic lethality (MAGCN). First, we obtain the functional similarity features and topological structure features of genes from different data sources respectively, such as Gene Ontology data and Protein-Protein Interaction. Then, graph convolutional network is utilized to accumulate the knowledge from neighbor nodes according to synthetic lethal associations. Meanwhile, we propose a multiple graphs attention model and construct a multiple graphs attention network to learn the contribution factors of different graphs to generate embedded representation by aggregating these graphs. Finally, the generated feature matrix is decoded to predict potential synthetic lethal interaction. Experimental results show that MAGCN is superior to other baseline methods. Case study demonstrates the ability of MAGCN to predict human SL gene pairs.

Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 μM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.

Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation.

BRD4 (bromodomain-containing protein 4) is an epigenetic reader that realizes histone proteins and promotes the transcription of genes linked to cancer progression and non-cancer diseases such as acute heart failure and severe inflammation. The highly conserved N-terminal bromodomain (BD1) recognizes acylated lysine residues to organize the expression of genes. As such, BD1 is essential for disrupting BRD4 interactions and is a promising target for cancer treatment. To identify new BD1 inhibitors, a SuperDRUG2 database that contains more than 4600 pharmaceutical compounds was screened using in silico techniques. The efficiency of the AutoDock Vina1.1.2 software to anticipate inhibitor-BRD4-BD1 binding poses was first evaluated based on the co-crystallized R6S ligand in complex with BRD4-BD1. From database screening, the most promising BRD4-BD1 inhibitors were subsequently submitted to molecular dynamics (MD) simulations integrated with an MM-GBSA approach. MM-GBSA computations indicated promising BD1 binding with a benzonaphthyridine derivative, pyronaridine (SD003509), with an energy prediction (ΔGbinding) of -42.7 kcal/mol in comparison with -41.5 kcal/mol for a positive control inhibitor (R6S). Pharmacokinetic properties predicted oral bioavailability for both ligands, while post-dynamic analyses of the BRD4-BD1 binding pocket demonstrated greater stability for pyronaridine. These results confirm that in silico studies can provide insight into novel protein-ligand regulators, specifically that pyronaridine is a potential cancer drug candidate.

Spatiotemporal quantitative microRNA-155 imaging reports immune-mediated changes in a triple-negative breast cancer model.

MicroRNAs are small non-coding RNAs and represent key players in physiology and disease. Aberrant microRNA expression is central to the development and progression of cancer, with various microRNAs proposed as potential cancer biomarkers and drug targets. There is a need to better understand dynamic microRNA expression changes as cancers progress and their tumor microenvironments evolve. Therefore, spatiotemporal and non-invasive in vivo microRNA quantification in tumor models would be highly beneficial. We developed an in vivo microRNA detector platform in which the obtained signals are positively correlated to microRNA presence, and which permitted stable expression in cancer cells as needed for long-term experimentation in tumor biology. It exploits a radionuclide-fluorescence dual-reporter for quantitative in vivo imaging of a microRNA of choice by radionuclide tomography and fluorescence-based downstream ex vivo tissue analyses. We generated and characterized breast cancer cells stably expressing various microRNA detectors and validated them in vitro. We found the microRNA detector platform to report on microRNA presence in cells specifically and accurately, which was independently confirmed by real-time PCR and through microRNA modulation. Moreover, we established various breast tumor models in animals with different levels of residual immune systems and observed microRNA detector read-outs by imaging. Applying the detector platform to the progression of a triple-negative breast cancer model, we found that miR-155 upregulation in corresponding tumors was dependent on macrophage presence in tumors, revealing immune-mediated phenotypic changes in these tumors as they progressed. While applied to immunooncology in this work, this multimodal in vivo microRNA detector platform will be useful whenever non-invasive quantification of spatiotemporal microRNA changes in living animals is of interest.

Comparison of experimental and theoretical spectral groups, electronic properties, topological, and molecular docking investigations of 1-N-Cbz-piperidine-4-carboxylic acid- Potential Cancer drug

In this present work, the theoretical and experimental spectroscopic (FT-IR, FT-Raman) investigations were performed for 1-N-Cbz-piperidine-4-carboxylic acid (1NCPA). The theoretical approaches were computed using Density Functional Theory (DFT)/ B3LYP/6–311++G(d,p) as a basis set. Using the aforementioned basis set, the optimized molecular geometrical parameters and computed wavenumbers were determined. The theoretical (TD-SCF) UV–Vis's spectra for the solvent phases and recorded wavelength were compared to one another. Frontier molecular orbitals (energy parameters), hole-electron distribution for the excited states, and ESP analyses were reported. The QTAIM theory was used to accomplish the topological analysis of electron density. Further, ELF, LOL, and RDG analyses were reported. The title compound (as a ligand) and ALK inhibitors (as protein) with their bonding interactions were studied using molecular docking analysis. It was compared with the standard drug and the least binding energy was calculated.

Synthesis of Lactosyl Conjugated 6A,6D-Bifunctionalized β -Cyclodextrin Derivatives as Potential Liver Cancer Drug Carriers

Abstract: Transformations of the difunctionalizated cyclodextrin derivatives is a daunting task due to the challenging purification and unambiguous characterization of the final compounds. Lactose has the ability to recognize the liver cells, and the folate receptor (alpha subunit) is overexpressed in multiple tumors, including liver cancer. Therefore, cyclodextrin conjugated with lactose and folic acid should have the liver cell targeting capability, and its inclusion complex with liver cancer drug such as Sorafenib, not only can increase drug ‘s water solubility but also increase the drug’s targeting ability. Fondaparinux as a synthetic heparin may improve the survival of cancer patients, so lactose and Fondaparinux conjugated cyclodextrin derivative can increase drug’s solubility and drug’s anti-tumor efficacy. Accordingly, Fondaparinux, folic acid and lactose conjugated 6A,6D-bifunctionlized β-cyclodextrin derivatives are designed and synthesized as potential liver cancer drug carriers in order to increase cancer drug’s targeting ability, solubility and stability.

Virtual Screening on Molecules Targeting the Interaction Between Estrogen Receptor Beta and Murine Double Minute 2

Estrogen receptor beta (ERβ) is an isoform of estrogen receptor that plays a role in breast cancer. An E3 ubiquitin ligase, murine double minute 2 (MDM2), can bind to ERβ and degrade it. Virtual screening and protein-protein docking studies are one of the approaches that can be performed to discover FDA-approved drugs targeting the interaction of the ERβ-MDM2 complex. This study aimed to conduct virtual screening of 1615 compounds targeting the interaction between ERβ-MDM2 as an initial study to discover potential breast cancer drugs. Biovia Discovery Studio 2021, ClusPro 2.0, PyRx 8.0, and PyMOL software were utilized in this study. ERβ (PDB ID: 3OLS) and MDM2 (PDB ID: 1T4E) receptors were docked to obtain the ERβ-MDM2 protein complex. The ligands used in the virtual screening were FDA-approved drugs downloaded from the ZINC database. PIC and PLIP web tools were also utilized to analyze the amino acid residues involved in the interaction. The virtual screening results showed that ergotamine was the drug with the lowest energy score (-12.0 kcal/mol) among 1057 drugs and was able to establish the strongest interaction between ERβ-MDM2. In conclusion, based on this computational study, ergotamine strengthens the interaction between ERβ-MDM2 and thus could be used as a candidate for breast cancer drug. Thorough validation of in vitro, biochemical, and in vivo studies are needed to confirm this finding.Keywords: Estrogen receptor beta, breast cancer, protein-protein interaction, MDM2.