Leukemia Cancer Cell Lines Research Articles

Development of Novel 1,3,4‐Trisubstituted Pyrazole Derivatives Bearing Sulfonamide Moiety as Anticancer Agents Targeting JNK Kinases

AbstractIn the present work, a new set of N‐(2‐((4‐(1,3‐diphenyl‐1H‐pyrazol‐4‐yl)pyridine sulfonamide derivatives was synthesized. Final target compounds were tested against JNK1 and JNK2 isoforms. Compounds 8f and 8d showed the highest activity over both JNK isoforms. They showed submicromolar activity over JNK1 (IC50 0.90 µM and 0.96 µM, respectively). They also showed excellent activity over JNK2 (IC50 0.62 µM and 1.07 µM, respectively). Moreover, the final target compounds were tested over HL‐60 and K‐562 cell lines for assessing the in vitro anticancer activity using sorafenib as a positive control. Compound 8f showed the highest potency at IC50 values of 6.21 and 7.43 µM, respectively. Furthermore, compounds 8e and 8g exhibited strong effects on both acute leukemia cancer cell lines with IC50 values of 13.83 and 10.02 µM, respectively, as well as chronic leukemia cancer cell line with IC50 of 12.65 and 9.51 µM, respectively. Compound 8f was also tested to examine its effect on the cell cycle. Finally, a molecular docking study was conducted to understand the plausible binding modes of the most active compounds 8d and 8f within the JNK1 and JNK2 binding sites.

Paulownin elicits anti-tumor effects by enhancing NK cell cytotoxicity through JNK pathway activation.

Paulownin, a natural compound derived from Paulownia tomentosa wood, exhibits various physiological functions, including anti-bacterial and anti-fungal effects. However, the impact of paulownin on natural killer (NK) cell immune activity remains largely unknown. In this study, we investigated the effect of paulownin on NK cell activity both in vitro and in vivo, and explored its potential mechanisms. NK-92 cells were used for in vitro experiments and a BALB/c mouse model with B16F10 cells injected subcutaneously were used for in vivo anti-tumor analysis. We found that paulownin enhanced the cytolytic activity of NK-92 cells against leukemia, human colon, and human lung cancer cell lines. Paulownin treatment increased the expression of the degranulation marker protein CD107a and cytolytic granules, including granzyme B and perforin in NK-92 cells. Moreover, these enhancements of cytotoxicity and the expression of cytolytic granules induced by paulownin were also observed in human primary NK cells. Signaling studies showed that paulownin promoted the phosphorylation of JNK. The increased perforin expression and elevated cytotoxic activity induced by paulownin were effectively inhibited by pre-treatment with a JNK inhibitor. In vivo studies demonstrated that the administration of paulownin suppressed the growth of B16F10 melanoma cells allografted into mice. Paulownin administration promoted the activation of NK cells in the spleen of mice, resulting in enhanced cytotoxicity against YAC-1 cells. Moreover, the anti-tumor effects of paulownin were reduced upon the depletion of NK cells. Therefore, these results suggest that paulownin enhances NK cell cytotoxicity by activating the JNK signaling pathway and provide significant implications for developing new strategies for cancer immunotherapy.

1,3-Disubstituted thiourea derivatives: Promising candidates for medicinal applications with enhanced cytotoxic effects on cancer cells

The distinct chemical structure of thiourea derivatives provides them with an advantage in selectively targeting cancer cells. In our previous study, we selected the most potent compounds, 2 and 8, with 3,4-dichloro- and 3-trifluoromethylphenyl substituents, respectively, across colorectal (SW480 and SW620), prostate (PC3), and leukemia (K-562) cancer cell lines, as well as non-tumor HaCaT cells. Our research has demonstrated their anticancer potential by targeting key molecular pathways involved in cancer progression, including caspase 3/7 activation, NF-κB (Nuclear Factor Kappa-light-chain-enhancer of activated B cells) activation decrease, VEGF (Vascular Endothelial Growth Factor) secretion, ROS (Reactive Oxygen Species) production, and metabolite profile alterations. Notably, these processes exhibited no significant alterations in HaCaT cells. The effectiveness of the studied compounds was also tested on spheroids (3D culture). Both derivatives 2 and 8 increased caspase activity, decreased ROS production and NF-κB activation, and suppressed the release of VEGF in cancer cells. Metabolomic analysis revealed intriguing shifts in cancer cell metabolic profiles, particularly in lipids and pyrimidines metabolism. Assessment of cell viability in 3D spheroids showed that SW620 cells exhibited better sensitivity to compound 2 than 8. In summary, structural modifications of the thiourea terminal components, particularly dihalogenophenyl derivative 2 and para-substituted analog 8, demonstrate their potential as anticancer agents while preserving safety for normal cells.

Synthesis of Novel Benazepril-Derived Trizole Compounds Assisted by Ultrasound: In Vitro and In Silico Analysis for Potential Anticancer Properties.

Benazepril-based novel trizole derivatives are being explored as potential anticancer agents, designed with an N-substituted 1,2,3-triazole moiety linked to Benazepril's N-1 position via a methylene bridge. An ultrasound irradiated CuAAC method was used to prepare all these compounds and evaluated their anti-proliferative activities against cancer and drug-resistant cell lines. While some of these compounds demonstrated anti-proliferative activity towards leukemic cancer cell line K562, two of them displayed complete inhibitory activity. Interestingly, the compounds 5n and 5o showed potent activity against imatinib-resistant cell lines suggesting their promise to overcome cancer drug resistance. Furthermore, molecular docking analysis revealed that compounds 5n and 5o have higher predicted sensitivity towards ACE protein when compared to benazepril and lisinopril indicating their value as potential drug lead molecules. This research introduces a distinctive approach by employing ultrasound to facilitate CuAAC reactions in medicinal chemistry.

Prospects for Prostate Cancer Chemotherapy: Cytotoxic Evaluation and Mechanistic Insights of Quinolinequinones with ADME/PK Profile.

The evaluation of in vitro biological activity of several previously reported quinolinequinones (AQQ1-5) against 60 human cancer cell lines (NCI-60) used by the National Cancer Institute's Developmental Therapeutics Program (DTP) contributed to our earlier research on possible anticancer and/or antibacterial agents. Of interest, NCI-60 screening revealed that two quinolinequinones (AQQ1 and AQQ2) significantly reduced the proliferation of several cancer genotypes. Following the administration of a single dose and five additional doses, all quinolinequinones demonstrated a significant inhibitory effect on the growth of leukemia and other cancer cell lines. Hence, a series of subsequent in vitro biological assessments were performed to further understand the mechanistic impact of the compounds. In MTT assays, it was found that AQQ1 and AQQ2 exhibited higher efficacy against DU-145 cells (IC50 4.18 µM and 4.17 µM, respectively) compared to MDA-MB-231 (IC50 8.27 and 13.33 µM, respectively) and HCT-116 cells (IC50 5.83 and 9.18 µM, respectively). Additionally, AQQ1 demonstrated greater activity in this context. Further investigations revealed that AQQ1 inhibited DU-145 cell growth and migration dose-dependently. Remarkably, arrest of the DU-145 cell cycle at G0/G1 phase and ROS elevation were observed. Pharmacokinetic (PK) studies revealed that AQQ1 has better PK parameters than AQQ2 with %F of 9.83 in rat. Considering the data obtained with human liver microsomal stability studies, AQQ1 should have a better PK profile in human subjects. In silico studies (molecular dynamics) with three kinases (CDK2, CDK4, and MAPK) leading to cell cycle arrest at G0/G1 identified MAPK as a probable target for AQQ1. Taken together, our results showed that AQQ1 could be a potential chemotherapeutic lead molecule for prostate cancer.

Facile Synthesis of a Crystalline Zinc Sulfide/Chitosan Biopolymer Nanocomposite: Characterization and Application for Photocatalytic Degradation of Textile Dyes and Anticancer Activity.

In the present study, we have synthesized a zinc sulfide/chitosan (ZS/CS) nanocomposite by utilizing simple, economical, and environmentally friendly methods. The synthesized nanomaterials were characterized by different analytical techniques such as XRD, FE-SEM, EDS, and FTIR to determine the phase structure, morphology, and elemental composition. FTIR spectroscopy was used to confirm the functional groups of the synthesized zinc sulfide (ZS) nanoparticles and ZS/CS composite. Besides, the optical properties of the as-synthesized nanocomposite was analyzed by a UV-visible spectrophotometer, and the estimated band gap energy is ∼3.03 eV. The photocatalytic efficiency of the synthesized ZS/CS nanocomposite was investigated against two textile dyes, Crystal Violet (CV) and Acid Red-I (AR-I), under UV-visible light irradiation. The nanocomposite showed excellent photocatalytic activity against the dyes, and photodegradation was estimated to be about 93.44 and 90.67% for CV and AR-I, respectively. The nanocomposite was reused for three consecutive cycles. The results revealed that the photocatalyst displayed good reusability during the photocatalytic decomposition and thus is considered a cost-effective and promising photocatalyst in degrading dye pollutants. The kinetic study proved that the pseudo-first-order reaction kinetics was followed by the degradation process. We also examined the anticancer activity of ZS and ZS/CS against human breast and myelogenous leukemia cancer cell lines, namely, MCF-7 and K-562, and the half minimal inhibitory concentrations were found to be less than 50 μg/mL.

Harnessing molecular hybridization approach to discover novel quinoline EGFR-TK inhibitors for cancer treatment.

Aim: Using molecular hybridization approach, novel 18 quinoline derivatives (6a-11) were designed and synthesized as EGFR-TK inhibitors. Materials & methods: The antiproliferative activity was assessed against breast (MCF-7), leukemia (HL-60) and lung (A549) cancer cell lines. Moreover, the most active quinoline derivatives (6d and 8b) were further investigated for their potential as EGFR-TK inhibitors. In addition, cell cycle analysis and apoptosis induction activity were conducted. Results: A considerable cytotoxic activity was attained with IC50 values spanning from 0.06 to 1.12μM. Besides, the quinoline derivatives 6d and 8b displayed potent inhibitory activity against EFGR with IC50 values of 0.18 and 0.08μM, respectively. Conclusion: Accordingly, the afforded quinoline derivatives can be used as promising lead anticancer candidates for future optimization.

Production of highly cytotoxic and low immunogenic L-asparaginase from Stenotrophomonas maltophilia EMCC2297

L-asparaginase is an important therapeutic enzyme that is frequently utilized in the chemotherapy regimens of adults as well as pediatric patients with acute lymphoblastic leukemia. However, a high rate of hypersensitivity with prolonged use has limited its utilization. Stenotrophomonas maltophilia (S. maltophilia) EMCC2297 isolate was reported as a novel and promising source for L- asparaginase. The present study aimed at the production, purification, and characterization of L- asparaginase from S. maltophilia EMCC2297 isolate. The microbial production of L-asparaginase by the test isolate could be increased by pre-exposure to chloramphenicol at 200 µg/ml concentration. S. maltophilia EMCC2297 L-asparaginase could be purified to homogeneity by ammonium sulphate precipitation and the purified form obtained by gel exclusion chromatography showed total activity of 96.4375 IU/ml and specific activity of 36.251 IU/mg protein. SDS-PAGE analysis revealed that the purified form of the enzyme is separated at an apparent molecular weight of 17 KDa. Michaelis-Menten constant analysis showed a Km value of 4.16 × 10− 2 M with L-asparagine as substrate and Vmax of 10.67 IU/ml. The antitumor activity of the purified enzyme was evaluated on different cell lines and revealed low IC50 of 2.2 IU/ml and 2.83 IU/ml for Hepatocellular cancer cell line (HepG-2), human leukemia cancer cell line (K-562), respectively whereas no cytotoxic effect could be detected on normal human lung fibroblast cells (MRC-5). However, mice treated with native L-asparaginase showed lower IgG titre compared to commercial L-asparaginase. This study highlights the promising characteristics of this enzyme making it a valuable candidate for further research and development to be an adduct in cancer chemotherapy.

Development of cancer-targeted nano gold functionalized ruthenium(III)-doxorubicin complex: Synthesis, characterization and evaluation of DNA cleavage, anticancer and bioimaging activity

Metal-based drugs have attracted greater attention for cancer diseases because of biological relevance. However, some drawbacks are present in the metal complexes such as low stability and low bioavailability. Nanomaterials functionalized metal complexes can protect the stability and enhanced the bioavailability. In the present study, Nano gold functionalized ruthenium(III) complex from doxorubicin have been synthesized from ruthenium(III) complex and characterized using various spectrochemical techniques such as IR, UV, and NMR. In the metal complex, Doxorubicin (DOX) acts as a monobasic bidentate ligand and is coordinated through the carbonyl oxygen and phenolate oxygen of the anthracene ring. Based on spectral evidences, the complex [Ru(DOX)(PPh3)2Cl2] has an octahedral geometry. The Nano Au-Ru(III) DOX is analysed for their size, and morphology using XRD, SEM and HRTEM. X-ray diffraction pattern revealed that the complex has nanocrystalline in nature. The Nano Au-Ru(III) DOX is spherical shape and particle size is less than 15 nm. The DNA cleavage activity of [Ru(DOX)(PPh3)2Cl2] and Nano Au-Ru(III) DOX has been evaluated using pUC18 plasmid DNA and the results showed significant cleavage. The [Ru(DOX)(PPh3)2Cl2] and Nano Au-Ru(III) DOX have been tested against human breast cancer (MCF-7) and leukemia cancer cell lines (K-562) in vitro for its antitumor effects. The tumour activity of the Nano Au-Ru(III) DOX showed more promising activity than the [Ru(DOX)(PPh3)2Cl2]. The cell imaging of the Nano Au-Ru(III) DOX was examined against epithelial human breast cancer cell line (MDA-MB-231) using fluorescent microscopy. The fluorescence images showed high scattering light in tumour tissue at 100 µg/mL Hence, Nano Au-Ru(III) DOX can serve as a promising drug for cancer therapy and cellular imaging.

Halimane Derivatives from Plectranthus ornatus Codd. as Novel Anti-cancer Agents

The Plectranthus genus is often cited for its medicinal properties. Plectranthus ornatus Codd. is traditionally used in Africa for the treatment of gastric and liver diseases and their leaves are used for their antibiotic action. The main constituent of P. ornatus is the halimane compound, 11 R∗−acetoxyhalima−5,13E−dien−15−oic acid (Hal), described for its antimicrobial and anticancer properties. The objective of this work was to improve the activity of the halimane lead molecule. Further physiochemical characterisation was performed on Hal. To the best of our knowledge, this work constitutes the first published data of the absolute configurations by SCXRD and thermal stability of Hal. Using Hal, reactions with different amines were carried out to afford novel semi-synthetic derivatives and their structural elucidation was completed. The cytotoxicity of the derivatives was assessed against three leukaemia cancer cell lines (CCRF-CEM, K562 and HL-60). The antioxidant activity was investigated using H2O2-induced HGF-1 cells and their anti-inflammatory activity was studied using RT-PCR and ELISA. Our data showed that amide derivatives of Hal presented moderate cytotoxicity and more potent activity when compared to the parent molecule, giving insight into the SAR of Hal. The derivatives also displayed protection against oxidative damage to DNA. Finally, the derivatives possessed anti-inflammatory properties at the level of gene and protein expression for the cytokines IL-1β, TNF-α and IL-6, induced by LPS in normal HGF-1 cells. Overall, our study provides useful insight into the enhanced biological activities of semi-synthetic Hal derivatives, as a starting point for novel drug formulations in cancer therapy.

Thiazole Derivatives as RORγt Inhibitors: Synthesis, Biological Evaluation, and Docking Analysis

Background: Cancer is a serious concern in developing countries. Due to various worldwide impacts, it has surpassed coronary disorders becoming the leading cause of mortality. In cancer progression, the involvement of RORs (retinoic acid receptor-related orphan receptors) has gained attention in the search for versatile agents. Thiazole has the potential to be used as a scaffold in the development of anticancer drugs. Objective: This work’s major goal was to design and synthesize promising anticancer candidates. Methods: Docking investigations concerning the RORγt receptor were utilized in the design of the compounds. A series of novel thiazole derivatives was synthesized employing Hantsch synthesis. Melting points, TLC development, and spectral analyses were considered for the synthesized compounds' characterization. Corresponding spectra were analyzed and determined to be consistent with the assigned structure. On 60 human cancer cell lines, selected compounds were investigated in vitro by NCI (National Cancer Institute), USA, for anticancer action. Results: Varying ratios of anticancer potential were presented by the compounds in in vitro studies. Compound 3c was determined to be the most active compound in the series, with a -15.03 mean growth percent. In silico study revealed that the synthesized compounds could have anticancer possibilities. In the targeted pdb id (6q7a) binding site, compound 3c demonstrated excellent docking scores in molecular docking analyses, supporting its ability to be utilized as a lead compound in rational drug design. Conclusion: Compounds with satisfactory docking scores within the binding pocket of chosen pdb id (6q7a) validated their suitability for usage as lead compounds in rational drug design. Outcomes of in silico investigations were in agreement with the findings of the cytotoxicity experiments. Leukemia, renal, breast, and lung cancer cell lines were most sensitive to the substance-treated tumor cells. Electronwithdrawing groups were essential for antiproliferative action, according to the findings.

Abstract 4519: Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving complete tumor regression

Abstract STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic targets for cancer and other human diseases. We have previously reported the discovery of SD-36 and SD-91 as potent, selective and highly efficacious STAT3 degraders. In the present study, we report the discovery and extensive evaluation of highly potent, selective and efficacious new STAT3 degraders designed using novel cereblon ligands and novel STAT3 ligands. Our most potent STAT3 degraders are >10-times more potent than SD-36 in inducing STAT3 degradation in cells and demonstrates >100-fold degradation selectivity over other STAT members. They achieve nanomolar IC50 values in leukemia and lymphoma cancer cell lines with activated STAT3. A single intravenous dose of these STAT3 degraders reduces the STAT3 protein for >48 hrs in xenograft tumor and native tissues, without reducing another other STAT members. Weekly administration of these STAT3 degraders is capable of achieving complete tumor regression in xenograft tumor models without any signs of toxicity. Taken together, these STAT3 degraders are promising lead compounds for extensive evaluation for the treatment of the treatment of human cancers and other human diseases in which STAT3 plays a key role. Citation Format: Haibin Zhou, Dimin Wu, Longchuan Bai, Ranjan K. Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving complete tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4519.

Abstract 3881: Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression

Abstract STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic targets for cancer and other human diseases. We have previously reported the discovery of SD-36 and SD-91 as potent, selective and highly efficacious STAT3 degraders. In the present study, we report the discovery and extensive evaluation of new, highly potent, selective and efficacious new STAT3 degraders. In direct comparison, these compounds are >50-times more potent than SD-36 in inducing STAT3 degradation in cells and demonstrates >500-fold degradation selectivity over other STAT members. Proteomic analysis showed that our best lead compound (UM-STAT3-1218) only reduces the levels of STAT3 protein in cells over other >6,700 proteins. (UM-STAT3-1218) achieves low nanomolar IC50 values in leukemia and lymphoma cancer cell lines with activated STAT3. A single intravenous dose of (UM-STAT3-1218) at 3 mg/kg reduces the STAT3 protein for >4 days in xenograft tumor and native tissues, without reducing another other STAT members. Impressively, a single dose of (UM-STAT3-1218) at 3 mg/kg achieves complete and long-lasting tumor regression in multiple xenograft tumor models without any signs of toxicity. Taken together, (UM-STAT3-1218) is a highly promising STAT3 degrader for the treatment of the treatment of human cancers and other human diseases in which STAT3 plays a key role. Citation Format: Haibin Zhou, Dimin Wu, Longchuan Bai, Ranjan K. Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of highly potent, selective and efficacious STAT3 PROTAC degraders capable of achieving long-lasting tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3881.

New monoquaternary salts of N-heterocycles: synthesis and antitumor assessment

This manuscript presents the synthesis, structural characterization, and antitumor evaluation of new monoquaternary salts derived from various N-heterocycles. For quinoline and quinoxaline, respectively, unexpected H-bonded mixtures of the reactants have been obtained. To assess their potential antitumor activity, the comprehensive panel of NCI's 60 human cancer cell lines was employed. Remarkably, mixtures 3g and 3h displayed significant inhibitory activity against leukemia, melanoma, and colon cancer cell lines. Furthermore, mixtures 3g and 3h displayed good cytotoxicity on MCF7 breast cancer cells, but not on normal fibroblasts, at 2.5x10-5 M, showing promise for therapeutic applications.

Assessment of iridoids and their similar structures as antineoplastic drugs by in silico approach

Iridoids commonly found in plants as secondary metabolites have been reported to possess significant biological activities such as anticancer, antioxidant, hypoglycemic, antimicrobial etc. The strong interactions of iridoids with cyclic-dependent kinase 8 (CDK8) protein could show inhibitory effects that could modulate tumour growth. From the molecular docking calculations, some iridoids interacted effectively with the target CDK8 protein (PDB ID: 5ICP) with better binding affinities of −9.1, −9.0, −9.0, −8.9 kcal/mol, than that observed for the native ligand with −8.7 kcal/mol and for the reference compound gemcitabine with −6.9 kcal/mol. The GI50 values (<5 μM) obtained from graph-based signatures showed activity in breast, colon, leukaemia, and renal cancer cell lines. The IC50 predictions as CDK2 inhibitors were greater than 10 µM with type I non-allosteric binding mode. The stability analysis of protein-ligand complex from 125 ns long molecular dynamics simulations showed moderately smooth trajectories and RSMD value around 5 Å for the docked ligands. The binding free energy changes up to −47.65 ± 5.97 kcal/mol from MMGBSA method and −30.33 ± 5.40 kcal/mol from MMPBSA method hinted at the spontaneous nature of the complex formation. Furthermore, geometrical evaluators like RMSF, Rg, SASA, and hydrogen bond count also corroborated with the structural stability of the complexes and the capacity of hit molecules to inhibit the target, indicating its therapeutic potential against cancer. The toxicity and drug-likeness from ADMET predictions suggested experimental verification and that the proposed candidates could be employed for further trials in the development of safer and more effective anticancer drugs. Communicated by Ramaswamy H. Sarma

Levofloxacin reposition-based design: synthesis, biological evaluation of new levofloxacin derivatives targeting topoisomerase II beta polymerase as promising anticancer agents, molecular docking, and physicochemical characterization.

Repositioning of already approved medications through repurposing or re-profiling for new medical uses after certain structural modifications is a novel approach in drug discovery. Fluoroquinolone antibiotics are one of the cardinal agents investigated for potential anticancer activities. In this work, levofloxacin was repositioned for anticancer activities. A series of levofloxacin-based compounds were designed and synthesized through the derivatization of levofloxacin's carboxylic acid functionality. The newly synthesized compounds were screened for cytotoxic activities against breast, liver, and leukemia cancer cell lines. Their effect on normal cells was also investigated. The target compounds were evaluated for their proliferative inhibitory activity toward topoisomerase II beta polymerization. Compound 5 showed higher inhibitory activity against a breast cancer cell line (MCF-7) with IC50 = 1.4 μM and lesser side effects on a normal breast cell line (MCF-10a) with IC50 = 30.40 μM than reference drugs. The best activity against a liver cancer cell line (Hep3B) was exhibited by compounds 3c, 4b, 5, 7, 8, 13a and 13c with IC50 values ranging from 0.43 to 8.79 μM. Regarding the effect of compounds 5 and 13a on a leukemia cancer cell line (L-SR), their IC50 values were 0.96 and 3.12 μM, respectively. Compounds 3c and 5 showed Topo2β inhibitory effects on Hep3B cells (81.33% and 83.73%, respectively), which was better than levofloxacin and etoposide as reference drugs. Cytometry cell cycle analysis revealed that compounds 3c and 5 arrested the cell cycle at the S phase (37.56% and 39.09%, respectively). Compounds 3c and 5 exhibited an elevation in active caspase-3 levels by 4.9 and 4.5 folds, respectively. Molecular modeling simulation of compounds 3c and 5 demonstrated energy scores (-29.77 and -20.46 kcal mol-1, respectively) more than those of the reference drugs as they interact with the most essential amino acids required for good affinity towards human topoisomerase II beta enzyme (PDB ID: 3QX3). Physicochemical characteristics of the most promising cytotoxic compounds 3c and 5 were investigated and compared to etoposide and levofloxacin as reference drugs. However, they showed high gastrointestinal absorption and could not penetrate the blood-brain barrier.

NK3.3-Derived Extracellular Vesicles Penetrate and Selectively Kill Treatment-Resistant Tumor Cells.

Cancer treatments often become ineffective due to the development of tumor resistance, leading to metastasis and relapse. Treatments may also fail because of their inability to access cells deep within the tumor tissue. When this occurs, new therapeutic agents are needed. We previously reported that NK3.3EVs, extracellular vesicles (EVs) derived from the normal human natural killer (NK) cell line, NK3.3, have strong cytotoxic activity against leukemia and breast cancer cell lines, without harming normal cells. Here, we used a three-dimensional (3D) MCF7 breast cancer mammosphere model to reproduce a more physiological environment that NK3.3EVs would encounter in vivo. NK3.3EVs penetrated MCF7 mammospheres, inducing death by apoptosis. We generated an imatinib-resistant K562 chronic myeloid leukemia (CML) cell line to investigate whether NK3.3EVs were able to kill tumor cells resistant to front-line chemotherapy. NK3.3EVs were even more cytotoxic to imatinib-resistant cells than parental cells, inducing apoptosis via caspase-3/-7 activation. The small population of cancer stem cells (CSCs) within tumors also contributes to therapeutic resistance. NK3.3EVs reduced the CSC-like CD34+/CD38- subpopulation in imatinib-resistant and parental K562 cultures and decreased CSC-associated expression of tumor-promoting genes. Our results provide strong evidence that NK3.3EVs may be a potential new immunotherapeutic agent for difficult-to-treat cancers.

Thiophene derivative inflicts cytotoxicity via an intrinsic apoptotic pathway on human acute lymphoblastic leukemia cells.

In an effort to identify novel anti-cancer agents, we employed a well-established High Throughput Screening (HTS) assay to assess the cytotoxic effect of compounds within the ChemBridge DIVERSet Library on a lymphoma cell line. This screen revealed a novel thiophene, F8 (methyl 5-[(dimethylamino)carbonyl]-4-methyl-2-[(3-phenyl-2-propynoyl) amino]-3-thiophenecarboxylate), that displays anti-cancer activity on lymphoma, leukemia, and other cancer cell lines. Thiophenes and thiophene derivatives have emerged as an important class of heterocyclic compounds that have displayed favorable drug characteristics. They have been previously reported to exhibit a broad spectrum of properties and varied uses in the field of medicine. In addition, they have proven to be effective drugs in various disease scenarios. They contain anti-inflammatory, anti-anxiety, anti-psychotic, anti-microbial, anti-fungal, estrogen receptor modulating, anti-mitotic, kinase inhibiting and anti-cancer activities, rendering compounds with a thiophene a subject of significant interest in the scientific community. Compound F8 consistently induced cell death at a low micromolar range on a small panel of cancer cell lines after a 48 h period. Further investigation revealed that F8 induced phosphatidylserine externalization, reactive oxygen species generation, mitochondrial depolarization, kinase inhibition, and induces apoptosis. These findings demonstrate that F8 has promising anti-cancer activity.

Three snake venoms from Bothrops genus induced apoptosis and cell cycle arrest in K562 human leukemic cell line

Cancer is indisputably one of the leading causes of death worldwide. Snake venoms are a potential source of bioactive compounds, complex mixtures constituted mainly of proteins and peptides with several pharmacological possibilities, including the potential to inhibit tumoral cell growth. In the present study, it was evaluated the antitumor effect of crude venom of Bothrops erythromelas (BeV), Bothrops jararaca (from Southern and Southeastern- BjsV and BjsdV, respectively) and Bothrops alternatus (BaV) in in vitro Chronic myeloid leukemia (CML) cancer cell line model. After 24 h of cell exposure to 10 and 50 μg/mL, BjsV, BjsdV, and BaV exerted a decrease in cell viability in both concentrations. BeV was not cytotoxic and, therefore wasn’t chosen for further mechanism of action investigation. Furthermore, morphological alterations show modification typical of apoptosis. Also, was observes a significant cell cycle arrest in the S phase by BjsdV and BaV treatment. Flow cytometry evidenced the involvement of changes in the cell membrane permeability and the mitochondrial function by BjsV and BjsdV, corroborating with the triggering of the apoptotic pathway by the venom administration. BjsV, BjsdV, and BaV also led to extensive DNA damage and were shown to modulate the gene expression of transcripts related to the cell cycle progression and suppress the expression of the BCR-ABL1 oncogene. Altogether, these findings suggest that the venoms trigger the apoptosis pathway due to mitochondrial damage and cell cycle arrest, with modulation of intracellular pathways important for CML progression. Thus, indicating the pharmacological potential of these venoms in the development of new antitumoral compounds.

Antitumor and antioxidant activities of polysaccharides from the seaweed Durvillaea antarctica.

The present study was carried out to determine the antitumor and antioxidant activities of the seaweed Durvillaea antarctica. Extraction and purification of polysaccharides from D. antarctica were performed. They were characterized by FT-IR and GC-MS, identifying isomers of arabinose, fucose, mannose, and galactose. The antioxidant capacity of polysaccharides was analyzed using the ABTS method (14.3 ± 0.5 μmol TE g-1 PS) and the DPPH method (21.82 ± 0.32 μmol TE g-1 PS). The antitumor capacity of polysaccharides was studied by MTT colorimetric assays in human leukemia, colon, breast, and lung cancer cell lines, obtaining the lowest IC50 in colon cancer (19.99 μg mL-1 ). In the line of healthy human gingival fibroblasts (HGF-1), an IC50 of 444.39 μg mL-1 was obtained. Flow cytometry in the HL60 cell line showed that polysaccharides at concentrations higher than IC50 inhibited cell proliferation, demonstrating a possible antitumor capacity invitro. In the proteomic analysis with HGF-1, nine proteins involved in different biological processes were identified. In conclusion, polysaccharides from D. antarctica could be considered powerful nutraceuticals, mainly against colon cancer.