Anticancer Drug Candidates Research Articles

STUDY IN SILICO OF THIOUREA-DERIVED COMPOUNDS AS TYROSINE KINASE RECEPTOR INHIBITORS

Cancer is a disease caused by protein mutations, which cause cells to proliferate uncontrollably. Inhibiting the action of protein kinases is one method of preventing the signal that initiates the process of uncontrolled cell proliferation. This research aimed to determine the affinity of thiourea-derived compound ligands with the protein tyrosine kinase enzyme (PDB ID: 5LMA). The binding energy between each ligand and the tyrosine kinase receptor ranged from -87,62 to -95,26 kcal/mol. The percentage of ligand interactions varies above 80%. On the active site of the amino acid residues Leu 456, Leu 495, Ala 496, Ala 497, Arg 498, and Val 500, the tyrosine kinase enzyme binds to the ligands of thiourea-derived compounds via hydrogen, pi alkyl, and alkyl bonds. Pharmacokinetic, toxicity, and Lipinski regulation of thiourea-derived compounds yielded significant results as anticancer drug candidates.

Molecular docking, ADMET profiling of gallic acid and its derivatives (N-alkyl gallamide) as an anti-breast cancer agent

Background In 2020, breast cancer has become the most common cancer in the world and in Indonesia. Searching for anticancer drugs using computational methods is considered more effective and selective than other methods. Gallic acid and its derivatives (esters and amides) are compounds that have biological activities such as anticancer effects. The purpose of this study was to analyse the molecular modelling and ADMET (Adsorption, Distribution, Metabolism, Excretion and Toxicity) profile of gallic acid derivative compounds (N-alkyl gallamides) as anticancer agents. Methods Target proteins were selected by analysis of protein-protein and drug-protein interactions. Molecular modelling was done by molecular docking. Predictive analysis of the ADMET profile of gallic acid and its derivatives (N-alkyl gallamide) was conducted using Marvin Sketch, Swissadme, protox II, and pkCSM pharmacokinetics. The selected target proteins were JUN, AKT1, CASP3, and CASP7. Results Compounds N-octyl gallamide, N-ters-butyl gallamide, and N-isoamil gallamide were the three best gallic acid derivatives based on molecular modelling analysis of target proteins associated with breast cancer. The ADMET profile of the N-alkyl gallamide compound is predictable and shows a good profile as a candidate for anticancer drugs. Conclusion N-octyl gallamide, N-ters-butyl gallamide, and N-isoamil gallamide have potential as anti-breast cancer agents.

Isoquercitrin Induces Endoplasmic Reticulum Stress and Immunogenic Cell Death in Gastric Cancer Cells.

Isoquercitrin is a natural flavonoid quercetin with anti-inflammatory, anti-anaphylactic, antiviral, and anticancer activities. Here, we investigated the effect of isoquercitrin on immunogenic cell death (ICD) of gastric cancer (GC). The effect of isoquercitrin on GC cell lines (AGS and HGC-27) was evaluated using cell counting kit-8 assays, colony formation assays, Annexin V/PI apoptosis detection kit, western blot analysis, JC-1 staining, immunofluorescence assays, and enzyme-linked immunosorbent assay. Isoquercitrin at doses greater than 20μM had significant inhibitory effects on the survival of GC cell lines, including HGC-27, AGS, MKN-45, and SNU-1. Isoquercitrin treatment decreased GC cell colony formation in a dose-dependent manner and induced apoptosis accompanied by downregulation of BCL-2 and upregulation of BAX, cleaved caspase-3, and caspase-12. In addition, isoquercitrin promoted the disruption of mitochondrial membrane potential in GC cells. The GC cell surface levels of calreticulin (CRT) and extracellular levels of CRT, ATP, and HMGB1 were enhanced by treatment with isoquercitrin. The protein levels of HMGB1, HSP70, and HSP90 were upregulated by isoquercitrin in a dose-dependent manner. Moreover, the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyrate reversed isoquercitrin-induced ICD in GC cells. Overall, our data suggested that isoquercitrin induces ER stress and ICD in GC cells. Isoquercitrin may be a candidate anticancer drug for the treatment of GC.

QSAR, molecular docking, ADMET properties in silico studies for a series of 7-propanamide benzoxaboroles as potent anti-cancer agents

The danger of ovarian cancer does not give any visible sign at the first stage of symptoms, for this reason, it is necessary to identify and discover effective drugs for this disease. In this work, we have performed 2D-QSAR and molecular docking studies for a series of 7-propanamide benzoxaboroles. The QSAR model was constructed using the seven descriptors, showed satisfactory internal and external validation parameters (R² train = 0.76, R² adjusted = 0.69, Q² cv = 0.62, R² test = 0.64) which passed the model acceptability criteria, the artificial neural network method showed a correlation coefficient of 0.88 with a 7-3-1. Molecular docking analysis was performed for the most active compound in the dataset, the resolved crystal structure of T. thermophilus LeuRS was obtained from the Protein Data Bank (PDB: 2V0G ), and the obtained docking results showed that the most important hydrogen interactions are ARG 719 and ASP 808, and two alkyl bonds (TYR 722, and ALA711), and a single Pi-anion bond GLU720 have a favorable effect on the biological activity. Finally, we made a study of ADMET properties on the ten selected most active compounds, the obtained results show that compounds number 1, 23, 26, 28, 32, and 37 have verified all the pharmacokinetic properties and toxicity, so we can select these different molecules as anti-cancer drug candidates.

Generation of multicellular tumor spheroids with micro-well array for anticancer drug combination screening based on a valuable biomarker of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. More than 30% of patients with diagnosed HCC have abnormally high expression of fibroblast growth factor receptor 4 (FGFR4). Currently, clinical trials for a variety of FGFR4-specific inhibitors have started. However, the effect of these inhibitors is not ideal, and it is necessary to find a drug combination to synergistically exert anti-tumor effects. We found strong correlations between FGFR4 and HCC clinicopathological characteristics in the present study. After grouping patients according to FGFR4 expression, the key gene signatures were inputted the drug-gene related databases, which predicted several potential drug candidates. More importantly, to achieve the reliable and high throughput drug cytotoxicity assessment, we developed an efficient and reproducible agarose hydrogel microwells to generate uniform-sized multicellular tumor spheroids, which provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates' effects. Using high content screening, we quickly evaluated the enhanced anti-tumor effects of these combinations. Finally, we demonstrated that Parthenolide is a potential drug that can significantly enhance the clinical efficacy of FGFR4 receptor inhibitors. In general, we offered a new therapeutic way for FGFR4 positive HCC patients.

In Silico Study of Compounds in Bawang Dayak (Eleutherine palmifolia (L) Merr.) Bulbs on Alpha Estrogen Receptors

Breast cancer is an uncontrolled malignancy of the breast that originates from glandular cells, gland ducts, and the supporting tissues of the breast. The development of herbal-based anticancer drugs is progressing, one of which is derived from the natural ingredients of Eleutherine palmifolia tubers. The aim of this study was to determine the activity of compounds derived from Eleutherine palmifolia tubers on the alpha-estrogen receptor (ERα) using an in silico study. The crystal structure of the enzyme used was 3ERT which was obtained from the Protein Data Bank (PDB). The applications used in this journal are Chem3D (initial preparation of ligands and receptors), AutoDock4 (redocking and calculation of root mean square deviation (RSMD)), and Biovia (visualization of redocking results). Tamoxifen was used as a reference ligand. Based on the results of the in silico study, the best compound that has the potential to be developed as a candidate for anticancer drug is Eleutherine because the results of the in silico test on Eleutherine have a value of G=-7.56 kkal/mol and the smallest KI=2.89 nM, so it can be concluded that eleutherine is one of potential drug candidate for anti cancer.Keywords: Breast cancer, eleutherine, estrogen receptor α.

Targeting tumor-intrinsic PD-L1 suppresses the progression and aggressiveness of head and neck cancer by inhibiting GSK3β-dependent Snail degradation.

PD-L1 is an immune checkpoint protein that allows cells to evade T-cell-mediated immune responses. Herein, we uncover a tumor-intrinsic mechanism of PD-L1 that is responsible for the progression and aggressiveness of HNC and reveal that the extracts of a brown alga can target the tumor-intrinsic signaling pathway of PD-L1. The biological functions of PD-L1 in the proliferation and aggressiveness of HNC cells in vitro were examined by metabolic activity, clonogenic, tumorigenicity, wound healing, migration, and invasion assays. The clinical importance of PD-L1 in the prognosis of patients with HNC was analyzed by immunohistochemistry. The relationship between PD-L1 and EMT was confirmed via western blotting, qPCR, and immunocytochemistry. Through our in silico approach, we found that PD-L1 was upregulated in HNC and was correlated with an unfavorable clinical outcome in patients with HNC. PD-L1 was crucial for promoting tumor growth, both in vitro and in vivo. High expression of PD-L1 was closely correlated with LN metastasis in OSCC. PD-L1 facilitated the cytoskeletal reorganization and aggressiveness of HNC cells. Moreover, PD-L1 enhanced the EMT of HNC cells by regulating the Snail/vimentin axis. Consistently, MEIO suppressed the PD-L1/Snail/vimentin axis, thereby inhibiting the aggressiveness of HNC cells. Inhibition of PD-L1 induced by PD-L1 silencing or MEIO treatment caused Snail degradation through a GSK3β-dependent mechanism. The tumor-intrinsic function of PD-L1 could be attributed to the regulation of the GSK3β/Snail/vimentin axis. The discovery of MEIO targeting the tumor-intrinsic function of PD-L1 may prove particularly valuable for the development of novel and effective anticancer drug candidates for HNCs overexpressing PD-L1.

Anti-Cancer Effects of a New Herbal Medicine PSY by Inhibiting the STAT3 Signaling Pathway in Colorectal Cancer Cells and Its Phytochemical Analysis.

Colorectal cancer (CRC) is an inflammation-associated common cancer worldwide. Paejang-san and Mori Cortex Radicis have been traditionally used for treating intestinal inflammatory diseases in Korea and China. In the present study, we developed a new herbal formula as an alternative to CRC treatments, which is composed of two main components of Paejangsan (Patriniae Radix (Paejang in Korean) and Coix Seed (Yiyiin in Korean)), and Mori Cortex Radicis (Sangbekpi in Korean) based on the addition and subtraction theory in traditional medicine, hence the name PSY, and explored the potential therapeutic effects of the new formula PSY in human CRC cells by analyzing viability, cell cycle and apoptosis. We found that PSY ethanol extract (EtOH-Ex), but not water extract, significantly suppressed the viability of human CRC cells, and synergistically decreased the cell proliferation compared to each treatment of Patriniae Radix and Coix Seed extract (PY) or Mori Cortex Radicis extract (S), suggesting the combination of PY and S in a 10-to-3 ratio for the formula PSY. PSY EtOH-Ex in the combination ratio reduced cell viability but induced cell cycle arrest at the G2/M and sub-G1 phases as well as apoptosis in CRC cells. In addition, the experimental results of Western blotting, immunofluorescence staining and reporter assays showed that PSY also inhibited STAT3 by reducing its phosphorylation and nuclear localization, which resulted in lowering STAT3-mediated transcriptional activation. In addition, PSY regulated upstream signaling molecules of STAT3 by inactivating JAK2 and Src and increasing SHP1. Moreover, the chemical profiles of PSY from UPLC-ESI-QTOF MS/MS analysis revealed 38 phytochemicals, including seven organic acids, eight iridoids, two lignans, twelve prenylflavonoids, eight fatty acids, and one carbohydrate. Furthermore, 21 potentially bioactive compounds were highly enriched in the PSY EtOH-Ex compared to the water extract. Together, these results indicate that PSY suppresses the proliferation of CRC cells by inhibiting the STAT3 signaling pathway, suggesting PSY as a potential therapeutic agent for treating CRC and 21 EtOH-Ex-enriched phytochemicals as anti-cancer drug candidates which may act by inhibiting STAT3.

Tat-hspb1 Suppresses Clear Cell Renal Cell Carcinoma (ccRCC) Growth via Lysosomal Membrane Permeabilization.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer, of which the incidence is increasing worldwide with a high mortality rate. Bioactive peptides are considered a significant class of natural medicines. We applied mass spectrometry-based peptidomic analysis to explore the peptide profile of human renal clear cell carcinoma and adjacent normal tissues. A total of 18,031 peptides were identified, of which 105 unique peptides were differentially expressed (44 were up-regulated and 61 were down-regulated in ccRCC tissues). Through bioinformatic analysis, we finally selected one peptide derived from the HSPB1 protein (amino acids 12-35 of the N-terminal region of HSPB1). Next, we fused this peptide to the HIV-Tat, generated a novel peptide named Tat-hspb1, and found that Tat-hspb1 inhibited ccRCC cells' viability while being less cytotoxic to normal epithelial cells. Furthermore, Tat-hspb1 induced apoptosis and inhibited the proliferation and migration of ccRCC cells. Furthermore, we demonstrated that Tat-hspb1 was predominantly localized in lysosomes after entering the ccRCC cell and induced lysosomal membrane permeabilization (LMP) and the release of cathepsin D from lysosomes. Taken together, Tat-hspb1 has the potential to serve as a new anticancer drug candidate.

Characterization of zinc(II) complex of 1,4,7,10-tetrazacyclododecane and deprotonated 5-fluorouracil (FU) in crystalline/solution states and evaluation of anticancer activity: Approach for improving the anticancer activity of FU

Structural and biological properties of 5-fluorouracil (FU) bound zinc(II)–cyclen complex (FU––ZnL2+, L = cyclen; 1,4,7,10-tetrazacyclododecane) were studied in to develop an anticancer drug candidate. The complex formation was analyzed by X-ray crystallography and pH-titration study, and the anticancer activity was investigated by cytotoxicity examination against HL-60 cells. The crystal structure revealed that FU– and ZnL+ form the complex with 1:1 stoichiometry. The pH titration study proved that FU– has a strong affinity to ZnL+ at the physiological pH range (6.5–9.0). The IC50 values of FU––ZnL2+ against HL-60 cells growth was 132 μM in a quantitating cellular ATP levels. These results provide the basis for designing novel anticancer drug complexes and controlling FU release.

Derivative Compounds of Chromanone As Candidates for Multiple Myeloma-Targeted Anticancer Drugs

Introduction: More than 70% of multiple myeloma (MM) cases occur in elderly patients over the age of 65 years, and the incidence of MM has remarkably increased in Korea over the past 20 years; thus, it is necessary to discover a new therapeutic agent that can be safely used in elderly patients. Lenalidomide-based therapeutics and proteasome inhibitors, which are currently used as the basis for the treatment of MM in clinical practice, have accompanying systemic side effects, such as pancytopenia, peripheral neuropathy, and severe skin lesions. Therefore, it is necessary to develop new therapeutic agents that can overcome the serious side effects, treatment tolerance, or resistance to these therapeutic agents. Methods: A chromanone-based (KBB-NX derivatives) low-molecular weight compound was synthesized by targeting prohibitin (PHB), which is our own companion diagnostic marker for hematologic cancers, such as MM. For the synthesized low-molecular weight synthetic substances, candidate synthetic compounds were identified through efficacy verification tests at the cell line level, blood stability tests, pharmacokinetic tests using laboratory animals, and single-dose toxicity tests. Further, after conducting an efficacy test using the mouse MM model that we built ourselves, we performed a study to discover a lead compound that can be used for non-clinical testing at the Good Laboratory Practices level. Results: In this study, 30 types of KBB-NX-based active substances that had an apoptotic effect on MM cells by blocking the PHB2 protein were obtained. When MM cells were treated with these active substances, the PHB2 function was inactivated to increase the intracellular reactive oxygen species (ROS) production, and then, proapoptotic and anti-proliferative effects were induced to kill MM cells. Among the discovered active substances, when a MM cell line was exposed to KBB-NX16, the amount of the target PHB2 protein was decreased by more than 90%, confirming the high molecular-target binding ability. Among the compounds synthesized by itself as a KBB-NX derivative, KBB-NX20 was found to have an IC50 of less than 1 μM. In the initial pharmacokinetic test for KBB-NX16 and KBB-NX20 compounds, which was conducted using rats, their half-lives were very short, less than 1 hour and 40 minutes; hence, there was a need for formulation studies. The need for early pharmacokinetic testing was increased. Conclusions: We identified effective substances from PHB-targeted chromanone compounds for the treatment of MM using an apoptosis mechanism through excessive production of intracellular ROS. These results suggested derivatives of PHB2 target chromanone compounds as candidates for MM-targeted anticancer drugs. Keywords: Multiple myeloma, PHB2, Targeted anticancer drugs, Chromanone compound Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Review on the Design, Synthesis, and Structure-activity Relationships of Benzothiazole Derivatives against Hypoxic Tumors.

There has been a growing body of studies on benzothiazoles and benzothiazole derivatives as strong and effective anti-tumor agents against lung, liver, pancreas, breast, and brain tumors. Due to the highly proliferative nature of the tumor cells, the oxygen levels get lower than that of normal tissues in the tumor microenvironment. This situation is called hypoxia and has been associated with increased ability for carcinogenesis. For the drug design and development strategies, the hypoxic nature of the tumor tissues has been exploited more aggressively. Hypoxia itself acts as a signal initiating system to activate the pathways that eventually lead to the spread of the tumor cells into the different tissues, increases the rate of DNA damage, and eventually ends up with more mutation levels that may increase the drug resistance. As one of the major mediators of hypoxic response, hypoxia-inducible factors (HIFs) have been shown to activate angiogenesis, metastasis, apoptosis resistance, and many other protumorigenic responses in cancer development. In the current review, we will be discussing the design, synthesis, and structureactivity relationships of benzothiazole derivatives against hypoxic tumors such as lung, liver, pancreas, breast, and brain as potential anti-cancer drug candidates. The focus points of the study will be the biology behind carcinogenesis and how hypoxia contributes to the process, recent studies on benzothiazole and its derivatives as anti-cancer agents against hypoxic cancers, conclusions, and future perspectives. We believe that this review will be useful for researchers in the field of drug design during their studies to generate novel benzothiazole-containing hybrids against hypoxic tumors with higher efficacies.

Apoptosis of Human Breast Cancer Cells (MCF-7) Induced by Psidium guajava Simplisia Extract

Cancer is one of the leading causes of death in the world. In 2014, the death rate caused by this cancer reached 585,720 cases. The most common cancers suffered by women include breast cancer (29%), lung cancer (13%), colon cancer (8%), uterine cancer (6%), and thyroid cancer (6%) (Siegel et al. 2014). Therefore, many studies have been conducted to find the best treatment for fighting this cancer. Breast cancer is caused by abnormal cells in the breast that occur continuously. Breast cancer can be affected by several mechanisms, such as angiogenesis (Schneider & Miller 2005), metastasis (Weigelt et al. 2005), and apoptosis (Yang et al. 2006). Apoptosis is a normal cell death process that occurs after several times of replication. This process of apoptosis has a critical role in normal cells and cancer cells. Cell death due to apoptosis is regulated by an interplay between pro-apoptotic and anti-apoptotic proteins. These proteins are the result of gene expression, for example, the Bax gene that expresses the Bax protein and the Bcl-2 gene that expresses the Bcl-2 protein (Martin & Dowsett 2013).Various kinds of treatments have been developed to inhibit the growth of cancer cells, such as radiation therapy, chemotherapy, hormone therapy, and surgery. However, this treatment only works in the early stages of cancer, and later, cells become resistant to these various treatments. In addition, multiple medications can also kill other normal cells. Therefore, research on the treatment of cancer has been developed using bioactive compounds found in natural ingredients, such as fruits (Abrahim et al. 2012). One of the plants that have been widely developed for cancer treatment is guava (Psidium guajava). This plant has been known to have many purposes, such as antibacterial, antidiarrheal, anti-acne, and anti-inflammatory (Ryu et al. 2012). This study aims to examine the effect of guava extract on the induction of apoptosis in MCF-7 breast cancer cells (ATCC HTB 22), which can later be used as candidates for anticancer drugs.

In vitro anticancer activity of Pd(II) complexes with pyridine scaffold: Their bioactivity, role in cell cycle arrest, and computational study

A series of Pd(II) based complexes [Pd(PEA)Cl2]; Pd1, [Pd(PEA)(H2O)2]2+; Pd2, [Pd(PEA)(DL-meth)]2+; Pd3, [Pd(PEA)(DL-pen)]+; Pd4, [Pd(PEA)(OX)]; Pd5 and [Pd(PEA)(CBDCA)]; Pd6 (where PEA = 2- pyridylethylamine, DL-meth = DL-methionine, DL-pen = DL-penicillamine, OX2− = oxalate and CBDCA2− = cyclobutanedicarboxylate) were investigated for their biological importance as anticancer drug candidates and bio-molecular interactions. Their interactions with CT-DNA were monitored with absorption and fluorescence spectrometric methods and viscometric titration. Their binding affinity with BSA and binding modes were elaborately investigated spectrophotometrically, including their thermodynamic parameters. Geometrical optimization and electronic transitions of the Pd(II) complexes are being performed by a DFT-based theoretical study. The molecular docking simulation with DNA and BSA was performed to find out a coherent relation with experimental observations. The antiproliferative property and selectivity of the complexes were screened against human breast carcinomas (MCF-7 and MDA-MB-231) and normal HEK293 cell lines. Most of the complexes generated significant ROS on the tumor cells following cell death. The cell cycle analysis with the complexes was studied on MCF-7 cells by flow-cytometric method to verify their vital role in cell apoptosis.

Novel chiral Schiff base Palladium(II), Nickel(II), Copper(II) and Iron(II) complexes: Synthesis, characterization, anticancer activity and molecular docking studies

In this study, two chiral Schiff base ligands (L1 and L2) were synthesized from the condensation reaction of (S)-2-amino-3-phenyl-1-propanol with 2-hydroxybenzaldehyde and 2-hydroxy-1-naphthaldehyde as metal precursors for the preparation of transition metal complexes with Pd(II), Fe(II), Ni(II) and Cu(II). The compounds were characterized by using X-ray (for L1-Pd(II)), NMR, FT-IR, UV–Vis, magnetic susceptibility, molar conductivity, and elemental analysis. The in vitro cytotoxic effects of ligands (L1 and L2) and their metal complexes on colon cancer cells (DLD-1), breast cancer cells (MDA-MB-231) and healthy lung human cell lines were investigated by using the 3-(4,5-dimethylthiazol-2-yl)-2,5‑diphenyl tetrazolium bromide (MTT) assay. Among the synthesized compounds, L1-Pd(II) was particularly found to be the most potent anticancer drug candidate in this series with IC50 values of 4.07, and 9.97 µM in DLD-1 and MDA-MB-231 cell lines, respectively. In addition, molecular docking results indicate that Glu122, Asn103, Ala104, Lys126, Phe114, Leu123, and Lys126 amino acids are the binding site of the colon cancer antigen protein, in which the most active complex, L1-Pd(II) can inhibit the current target.

Albumin fusion with human lactoferrin shows enhanced inhibition ofcancer cell migration.

The fusion of human serum albumin (HSA) with human lactoferrin (hLF) (designated as hLF-HSA) has improved the pharmacokinetic properties and anti-proliferative activities of hLF against cancer cells. In this study, we evaluated the anti-migratory activities of hLF and hLF-HSA against the human lung adenocarcinoma PC-14 cell line using wound healing and Boyden chamber assays. Despite the unexpected hLF-induced migration, hLF-HSA clearly demonstrated the complete inhibition of PC-14 cell migration. To examine the mechanism underlying the enhanced PC-14 cell migration by hLF alone but suppressed migration by hLF-HSA, we focused on the matrix metalloproteinase (MMP) family of endopeptidases because MMPs are often reported to play important roles in facilitating the migration and metastasis of cancer cells. Furthermore, hLF is a transactivator of MMP1 transcription. As expected, treatment of cells with hLF and hLF-HSA led to the upregulation and downregulation of MMP1, respectively. In contrast, MMP9 expression levels, which are often associated with cancer migration, were unchanged in the presence of either protein. An MMP inhibitor attenuated hLF-induced migration of PC-14 cells. Therefore, specific enhancement and suppression of MMP1 expression by hLF and hLF-HSA have been implicated as causes of a marked increase and decrease in PC-14 cell migration, respectively. In conclusion, the fusion of HSA with hLF (hLF-HSA) promoted its anti-migratory effects against cancer cells. Therefore, hLF-HSA is a promising anti-cancer drug candidate based on its improved anti-migratory activity towards cancer cells.

Discovery of Phenolic Matrix Metalloproteinase Inhibitors by Peptide Microarray for Osteosarcoma Treatment.

Because of the abnormal upregulation of matrix metalloproteinase (MMP) activities in tumors, MMP inhibitors (MMPIs) are validated anticancer drug candidates. We identified several MMPIs including mangiferin as an MMP-9 inhibitor with a half maximal inhibitory concentration (IC50) value of 250 nM, isosilybin as an MMP-13 inhibitor with an IC50 value of 250 nM, and isoliquiritigenin as a broad-spectrum MMPI (with IC50 values of 16 nM for MMP-1, 10 nM for MMP-2, 81 nM for MMP-3, 8 nM for MMP-7, 10 nM for MMP-9, and 14 nM for MMP-13) through studying the interactions of 6 MMPs secreted by U-2OS cells with 51 phenolic natural products on the peptide microarray platform. In addition, the inhibitory mechanisms of as-discovered MMPIs were evaluated by a molecular docking simulation. The antitumor efficiencies of MMPIs were demonstrated by both a cell scratch test and growth suppression of mouse-born OS tumors. The results of the cell scratch test suggested that isoliquiritigenin significantly inhibited the migration of U-2OS cells. In addition, administration of isoliquiritigenin significantly reduced the tumor size (by about 80%) and prolonged the survival time (by more than 70 days). This study suggests that the discovery of MMPIs from phenolic natural products is a meaningful way to screen anticancer agents.

Identification of novel mycocompounds as inhibitors of PI3K/AKT/mTOR pathway against RCC

PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from Astraeus hygrometricus against key cancer signaling proteins phosphoinositide 3‐kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.

Toxicity of Cisplatin and Herbal Medicine Complexed with Bovine Serum Albumin (BSA) and Folic Acid Nanoparticles as Anticancer Candidates

The prevalence of cancer in Indonesia has increased by 8.8 percent in the last two years (2018 and 2020) in terms of adding new cases and mortality. Because of therefor cancer treatment becomes important in reducing the high number of additional new cases and mortality due to cancer patients. Intensive cancer treatment is by surgery, chemotherapy, radiotherapy and immunotherapy. Chemotherapy drugs used for cancer treatment include herbal plant-based cancer drugs (Cancer Fit) and cisplatin its buy from online shop. This study aims to compare the toxicity of herbal drugs (Cancer fit) with cisplatin, a combination of BSA nanoparticles and folic acid as anticancer candidates. The research method is through the synthesis of nanoparticles with the desolvation method, then characterization is carried out using XRD and FT-IR tests. After that proceed to the toxicity test with the BSLT method. The results obtained from XRD analysis on BSA and folic acid nanoparticles from cisplatin (As-NP-BSA-CP) showed a peak of 34.45 while BSA and folic acid nanoparticles from herbal medicine (As-NP-BSA-Oh) obtained a peak of 22.77. The purpose of XRD analysis was to determine the crystalline characteristics of the synthesized nanoparticles and to analyze the crystalline index. FT-IR analysis on (As-NP-BSA-CP) showed that there are functional groups O-H alcohol, C-H, C-C, NO2 that play a role in the synthesis of nanoparticles. Meanwhile, (As-NP-BSA-Oh) showed that the functional groups were C-H alkene, C-O alcohol, and C-N amine/amide. The toxicity level of As-NP-BSA-CP LC50 is 69.14 ppm while the toxicity level of As-NP-BSA-Oh LC50 is 44.14 ppm. Nanoparticles consisting of a combination of bovine serum albumin (BSA), folic acid and cisplatin drugs or herbal drugs can be used as candidates for anticancer drugs.

Toxicity of Cisplatin and Herbal Medicine Complexed with Bovine Serum Albumin (BSA) and Folic Acid Nanoparticles as Anticancer Candidates

The prevalence of cancer in Indonesia has increased by 8.8 percent in the last two years (2018 and 2020) in terms of adding new cases and mortality. Because of therefor cancer treatment becomes important in reducing the high number of additional new cases and mortality due to cancer patients. Intensive cancer treatment is by surgery, chemotherapy, radiotherapy and immunotherapy. Chemotherapy drugs used for cancer treatment include herbal plant-based cancer drugs (Cancer Fit) and cisplatin its buy from online shop. This study aims to compare the toxicity of herbal drugs (Cancer fit) with cisplatin, a combination of BSA nanoparticles and folic acid as anticancer candidates. The research method is through the synthesis of nanoparticles with the desolvation method, then characterization is carried out using XRD and FT-IR tests. After that proceed to the toxicity test with the BSLT method. The results obtained from XRD analysis on BSA and folic acid nanoparticles from cisplatin (As-NP-BSA-CP) showed a peak of 34.45 while BSA and folic acid nanoparticles from herbal medicine (As-NP-BSA-Oh) obtained a peak of 22.77. The purpose of XRD analysis was to determine the crystalline characteristics of the synthesized nanoparticles and to analyze the crystalline index. FT-IR analysis on (As-NP-BSA-CP) showed that there are functional groups O-H alcohol, C-H, C-C, NO2 that play a role in the synthesis of nanoparticles. Meanwhile, (As-NP-BSA-Oh) showed that the functional groups were C-H alkene, C-O alcohol, and C-N amine/amide. The toxicity level of As-NP-BSA-CP LC50 is 69.14 ppm while the toxicity level of As-NP-BSA-Oh LC50 is 44.14 ppm. Nanoparticles consisting of a combination of bovine serum albumin (BSA), folic acid and cisplatin drugs or herbal drugs can be used as candidates for anticancer drugs.