Potent Anticancer Activity Research Articles

Engineering Superaffinity Antibody Dependent Cellular Cytotoxcity Receptors into iPSC-Derived NK Cells As Next-Generation Immunotherapies for Cancer

Engineered immune cells have provided an important new approach to treating cancer. Most of the progress so far has focused on autologous CAR-T cell therapy, although this approach has been met with several limitations including high-cost and complexity of manufacturing, donor-to-donor variability, and severe toxicities in some patients. Allogenic natural killer (NK) cell therapies have also been shown to mount potent responses against hematologic malignancies but are less likely to cause high-grade toxicities and can be mass produced for off-the-shelf usage. We have developed an induced pluripotent stem cell (iPSC) derived NK (iNK) platform amenable to engineering multiple features in immune cells to improve efficacy against both solid and liquid tumors. Our previous studies showed that knocking out the CISH gene, which encodes a key regulator of activation, in iNK cells significantly improves their anti-cancer activity, in vivo persistence, metabolic fitness, polyfunctional cytokine production, and resistance to cell exhaustion. In these CISH Knockout (KO) iNK cells, we have screened a library of CAR constructs containing domains from diverse immune cell signaling receptors including NK cell activating receptors, cytokine receptors, and integrins. Our screen identified SLNK12, a CAR signaling domains that performed better than both T cell CARs and previously reported NK cell CARs in the context of CISH KO iNK cells. In this study, we describe the development of iNK cells with enhanced antibody dependent cellular cytotoxicity (ADCC) activity. NK cells normally bind antibodies via their CD16A receptor, which has medium-to-low affinity for the antibody Fc domain and is also typically expressed at a low level in unmodified iNKs. We have constructed a recombinant Fc-receptor that combines a high-affinity Fc-binding domain (to improve antibody binding) with our NK cell optimized SLNK12 CAR signaling domain to enhance ADCC-mediated killing. When co-cultured with multiple NC cell resistant tumor lines such as BT-474 (breast cancer) or FaDu (squamous cell carcinoma), these SuperAffinity ADCC receptor CISH KO iNK cells possess potent anti-cancer activity in combination with several different therapeutic monoclonal antibodies, including anti-EGFR (Cetuximab) and anti-HER2 (Trastuzumab) amongst others (Figure 1). We have assessed efficacy in a variety of different 2D and 3D spheroid cytotoxicity assays, as well as cytokine release and CAR activation assays. In addition, we demonstrate that our SuperAffinity receptor mediates tumor cell killing at lower antibody concentrations than do CD16A variants. Furthermore, introduction of serum IgG inhibits, but does not stop ADCC killing for both our SuperAffinity ADCC receptor and the CD16A receptor. Taken together, our results show that engineering CISH KO iNK cells with NK-optimized CARs for enhanced ADCC improves anti-tumor activity against a variety of solid tumor target lines. Future work will focus on advancing the new cellular therapies into clinical development.

Targeting the Oncofetal Transcription Factor Protein SALL4 in Cancer By a Non-IMiD Degrader

Sal-like protein 4 (SALL4) is a C2H2 zinc finger transcription factor (TF) with two naturally occurring isoforms; SALL4A and SALL4B. It is typically detected in fetal tissues and silenced in most normal adult tissues. It is therefore intriguing that SALL4 is aberrantly re-expressed in about one-third of almost all primary human malignancies, presumably by demethylation dependent mechanisms. Direct evidence of the causative role of SALL4 in cancer has been demonstrated in SALL4 transgenic mice, which developed myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and/or liver tumors. Loss-of-function studies by SALL4 knock-down using shRNA showed cell growth inhibition and death in leukemias and solid tumors in culture and in in vivo xenotransplants. TF's, such as SALL4, which are critical for cancer development and survival, have historically been viewed as “undruggable”. However, rather than blocking activity, an alternative approach to target TFs is to induce protein degradation. Immunomodulatory imide drugs (IMiDs), including thalidomide, lenalidomide and pomalidomide, are used in treating patients with multiple myeloma (MM), MDS with 5q deletion, mantle cell lymphoma (MCL), and other hematological malignancies. Recently, several groups have reported that IMiDs can degrade SALL4 in a proteasome-dependent manner. To that end, we sought to investigate whether IMiDS could be utilized to treat SALL4-positive/expressing cancers. Initially, our studies observed that IMiDs had no effect on SALL4-positive cancer cells. Additional investigations thereafter demonstrated that IMiDs could only degrade SALL4A. These findings suggested that SALL4B may not be affected by IMiDs, and may be essential for SALL4-mediated cancer cell survival. Further investigation revealed that SALL4B knockdown led to an increase in apoptosis and inhibition of cancer cell growth. Moreover, through high-throughput screening, we identified a new non-IMiD SALL4 degrader that targets SALL4B via proteasomal degradation and which exhibited potent anti-cancer activity, inhibiting cancer cell proliferation in culture and in vivotumor growth by 70%. Our observation therefore suggest that protein degraders could possess isoform specific effects. Additionally, our results exemplify the importance of delineating drug action and oncogenesis at the isoform level to develop more effective cancer therapeutics.

Design, synthesis, and characterization of 3-(2-(pyrimidin-5-yl)thiazol-4-yl)-1,2,4-oxadiazole derivatives: Anticancer and molecular docking investigations

Herein, we present a new library of 3-(2-(pyrimidin-5-yl)thiazol-4-yl)-1,2,4-oxadiazole (14a–j) as an anticancer agent designed based on in silico fragment-based drug design (FBDD). The derivatives were synthesized and characterized by 1HNMR,13CNMR, HRMS, and FT-IR. The library was named “pyrimidine-thiazole-1,2,4-oxadiazoles.” In addition, the MTT assay was used to test the compounds (14a–j) for their potential anticancer activity in a panel of four human cancer cell lines, such as PC3 & DU-145 (prostate cancer), A549 (lung cancer), MCF-7 (breast cancer), and the normal Vero cell lines, using the widely used anticancer drug etoposide acting as a reference drug and positive control. The value obtained was presented as IC50 (µM). The IC50 values of the reference standard ranged from 1.97 ± 0.45 µM to 3.08 ± 0.135 µM, while the library of tested compounds showed IC50 values ranging from 0.02 ± 0.0031 µM to 10.3 ± 6.25 µM. Among the tested compounds, six of them showed promising anticancer activity: 14a, 14b, 14c, 14d, 14e and 14j. Especially, one compound, 14a, showed excellent anticancer activity in all the tested cell lines. All compounds showed selective cytotoxicity against cancer cells but not against normal Vero cells (IC50 = >19 µM), justifying the designing approach to develop a selective anticancer agent. These compounds were also subjected to docking experiments to investigate potential binding site interactions, and the results were consistent with the in vitro results.

Harnessing small extracellular vesicles for pro-oxidant delivery: novel approach for drug-sensitive and resistant cancer therapy

Multidrug resistance (MDR) is an inevitable clinical problem in chemotherapy due to the activation of abundant P-glycoprotein (P-gp) that can efflux drugs. Limitations of current cancer therapy highlight the need for the development of a comprehensive cancer treatment strategy, including drug-resistant cancers. Small extracellular vesicles (sEVs) possess significant potential in surmounting drug resistance as they can effectively evade the efflux mechanism and transport small molecules directly to MDR cancer cells. One mechanism mediating MDR in cancer cells is sustaining increased levels of reactive oxygen species (ROS) and maintenance of the redox balance with antioxidants, including glutathione (GSH). Herein, we developed GSH-depleting benzoyloxy dibenzyl carbonate (B2C)-encapsulated sEVs (BsEVs), which overcome the efflux system to exert highly potent anticancer activity against human MDR ovarian cancer cells (OVCAR-8/MDR) by depleting GSH to induce oxidative stress and, in turn, apoptotic cell death in both OVCAR-8/MDR and OVCAR-8 cancer cells. BsEVs restore drug responsiveness by inhibiting ATP production through the oxidation of nicotinamide adenine dinucleotide with hydrogen (NADH) and inducing mitochondrial dysfunction, leading to the dysfunction of efflux pumps responsible for drug resistance. In vivo studies showed that BsEV treatment significantly inhibited the growth of OVCAR-8/MDR and OVCAR-8 tumors. Additionally, OVCAR-8/MDR tumors showed a trend towards a greater sensitivity to BsEVs compared to OVCAR tumors. In summary, this study demonstrates that BsEVs hold tremendous potential for cancer treatment, especially against MDR cancer cells.

Effects of Usnic Acid on Cytotoxicity, Colony Formation and Migration in SK-UT-1 Human Uterine Leiomyosarcoma Cells

Usnic acid (UA) is a common lichenic secondary metabolite with therapeutic potential. Anticancer, antimicrobial, and antioxidant effects have been demonstrated and UA-enriched extracts are often used to treat various diseases in traditional medicine. First, we performed a viability assay of UA in human uterine leiomyosarcoma (SK-UT-1) since no in vitro cytotoxicity data have been reported so far. For this purpose, the cytotoxicity of UA on SK-UT-1 and embryonic kidney (HEK293) cells was studied at 24 and 48 hours. The toxicity of UA was investigated by the MTT test. In addition, we assessed UA colony formation and migration properties against SK-UT-1 cells in 6-well plates. Our results showed a significant cytotoxic effect of UA at the 5.34 µM; UA was also effective against colony formation ability and wound healing assay. In conclusion, our study suggests that UA exerts anti-proliferative effects on SK-UT-1 cells by inducing cell death. Moreover, our results suggest that the potential anticancer activities of UA should be further studied by additional molecular biological approaches.

Synthesis, structure–activity relationship studies using density functional theory and in silico molecular docking on substituted benzohydrazide derivatives

The present study demonstrates the utility of benzohydrazide derivatives based on an approach to identify potential targets for a series of synthesized compounds that show potent anticancer activities against four cancer cell lines compared to other structurally related molecules. Benzohydrazide compounds have been synthesized effectively by the condensation of aldehyde and hydrazide at a 1:1 molar ratio. The complete series of compounds 1a-j were characterized by FT-IR, NMR, and one of them by single-crystal X-ray diffraction. The crystal structure of compound 1a shows a trans configuration around the CN bond and crystallized in a monoclinic system with C 2/c space group. All compounds exhibited good anticancer activity against four cancer cell lines such as A375 (human malignant melanoma), A549 (human lung adenocarcinoma), HT-29 (human epithelial intestinal) and MDA-MB-232(human metastatic breast). Among them, compound 1e shows the highest cytotoxic effect against the HT29 (IC50 = 0.47 µM) and A375 (IC50 = 0.80 µM) cell lines. Other compounds also exhibited promising anticancer activity. In addition, the nontoxic action was verified using the cytocompatibility assay on the L929 normal cell line and the hemolysis assay on human red blood cells. Parameters such as HOMO-LUMO energies, Hirshfeld surface analysis, and Molecular Electrostatic Potential (MEP) surface have been calculated using DFT and compared to experimental values of compounds 1a-c. In silico molecular docking studies revealed that the compound 1 h interacted very strongly with the 1T46 protein, with a docking score of −9.7 kcal/mol and very good binding via π–π, π-alkyl and π–σ interactions as compared to the standard drug. As a result of their potent cytotoxicity activities and computational analysis, these can be considered promising anticancer agents.

Deciphering the molecular mechanistic paths describing the chemotherapeutic potential and epigenetic regulation of curcumin in lung cancer: a mini review.

In an uncontrolled inflammatory environment, the complex process of lung carcinogenesis occurs. Lung cancer remains the leading cause of cancer-related mortality worldwide. The average 5-year survival rate is still low despite significant advancements in our knowledge of lung carcinogenesis and the development of innovative therapies in recent decades. Research on adjuvant treatment, lung carcinogenesis pathways, and possible prognostic indicators has to be refocused using an innovative approach. The majority of lung cancers are discovered at an advanced stage when there is little chance of recovery. It has grown in popularity in recent years to supplement already available chemotherapeutic therapies with adjuvant herbal medications, which may lessen toxicity and adverse effects without sacrificing therapeutic efficiency. One such prospective contender is curcumin. In-depth research has been done on curcumin as a multi-target anti-tumor and anti-inflammatory molecule. A pharmacologically active polyphenol produced from turmeric is called curcumin. Over the past few decades, curcumin's therapeutic potential has been thoroughly studied, and data indicate that curcumin may play a part in a variety of biological processes, most notably its potent anticancer activity. Being a pleiotropic chemical, curcumin regulates a variety of molecules that are key players in many cell signaling pathways. It has been shown to stifle transformation, restrain proliferation, and trigger apoptosis. Curcumin can reduce the development of non-small cell LC by downregulating Circular RNA hsa_circ_0007580, which in turn controls the expression of integrin subunit beta 1 by adsorbing miR-384. Nevertheless, despite all these advantages, curcumin's effectiveness is still restricted because of its weak bioavailability, poor absorption within the systemic circulation, and quick removal from the body. In an effort to overcome these constraints, scientists from all around the world are working to develop a synthetic and improved curcuminoid by appropriately altering the parent skeleton structurally. These curcuminoids will simultaneously improve the physicochemical properties and efficacy. This review presents evidence from the most recent clinical trials coupled with the molecular mechanisms of curcumin in LC.

Divergent and Stereoselective Synthesis of Ustusal A, (-)-Albrassitriol, and Elegansin D.

The first synthesis of ustusal A as well as expeditious access to (-)-albrassitriol is described as featuring a singlet oxygen [4 + 2] cycloaddition, achieving the desired stereoselectivity for the 1,4-cis-hydroxyl groups. Transformation of (+)-sclareolide to III followed by a key Horner-Wadsworth-Emmons (HWE) reaction and stereospecific allylic oxidation facilitated the first synthesis of elegansin D. The biological evaluation of these natural products together with seven elegansin D analogues was performed, among which several elegansin D analogues exhibited potential anticancer activity against liver cancer HepG2 cells (IC50 = 11.99-25.58 μM) with low cytotoxicity on normal liver HL7702 cells (IC50 > 100 μM).

Design, Synthesis, Anticancer Evaluation, and Molecular Docking Studies of Oxazole-Incorporated Naphthyridine Derivatives.

A novel series of oxazole incorporated naphthyridine (21 a-j) derivatives were designed and, synthesized followed by screening of their anticancer activity profiles against human breast cancer (MCF-7), human lung cancer (A549) and human prostate (PC3 & DU-145) cancer cell lines by employing MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay using etoposide as the positive control. Of these compounds, N-(6-chloro-3-(4-(3,4,5-trimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine with 3,4,5-trimethoxy substituent on the aryl moiety attached to oxazole ring showed potent anticancer activity against PC3, A549, MCF-7, and DU-145 cell lines with IC50 values of 0.13±0.095 μM; 0.10±0.084 μM; 0.18±0.087 μM and 0.15±0.076 μM respectively. Apart from this, compounds N-(6-chloro-3-(4-(3,5-dimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, N-(6-chloro-3-(4-(4-methoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, and N-(6-chloro-3-(4-(3,5-dimethylphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine also showed better anticancer activities against four cancer cell lines screened for. These activities were also validated through the molecular docking simulations, which further indicated demonstration of better interaction energy and profile by these compounds.

Chalcone-based imidazo[2,1-b]thiazole derivatives: synthesis, crystal structure, potent anticancer activity, and computational studies

In this work, two novel chalcone-based imidazothiazole derivatives ITC-1 and ITC-2 were synthesized and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry with electrospray ionization, and chemical structure of ITC-1 was confirmed by single-crystal X-ray diffraction. Also, the anticancer activity of ITC-1 and ITC-2 was evaluated. First, antiproliferative activity tests were performed against cancer cells namely, human-derived breast adenocarcinoma (MCF-7), lung carcinoma (A-549), and colorectal adenocarcinoma (HT-29) cell lines, and mouse fibroblast healthy cell line (3T3-L1) by XTT assay. Afterward, mitochondrial membrane disruption (MMP), caspase activity, and apoptosis tests were performed on MCF-7 cells to elucidate the anticancer mechanism of action of the test compounds by flow cytometry analysis. XTT results revealed that both compounds exhibited a very high degree of antiproliferative effects on each tested cancer cell line with very low IC50 values while showing much lower antiproliferation on 3T3-L1 normal cells with much higher IC50 values. Besides, ITC-2 was determined to have a striking cytotoxic power competing with the chemotherapeutic drug carboplatin. Flow cytometry results demonstrated the mitochondrial-mediated apoptotic effects of both compounds through membrane disruption and multi-caspase activation in MCF-7 cells. Finally, molecular docking studies were performed to determine the structural understanding of the test compounds by their interactions on caspase-3 and DNA dodecamer enzymes, respectively. The interactions between the compound and the crystal structure were determined according to parameters such as free binding energies (ΔGBind), Glide score values, and determination of the active binding site. The obtained data suggest that ITC-1 and ITC-2 may be considered remarkable anticancer drug candidates. In addition to molecular docking via in silico approaches, the pharmacokinetic properties of compounds ITC-1 and ITC-2 were calculated using the Schrödinger 2021-2 Qikprop wizard. Communicated by Ramaswamy H. Sarma

Targeted delivery of essential oils of Salvia officinalis L to AGS cancer cells using PLA-spermine-PEG-FA

The MTT test was used in this study to evaluate anticancer potential of Salvia officinalis L's essential oil on AGS cells. The results showed that the Salvia officinalis L's essential oil has high potential anticancer activity against AGS cells. To improve the solubility of the essential oil and its targeted administration to AGS cells, poly lactic acid-spermine-poly ethylene glycol-folic acid (PLA-Spermine-PEG-FA) (FPSP) was utilized. For this purpose, Salvia officinalis L's essential oil and silver nanoparticles were encapsulated into the PLA-Spermine-PEG-FA (FPSP) using the solvent diffusion technique. Then, using transmission electron microscope (TEM) and dynamic light scattering (DLS), respectively, morphology, zeta potential, as well as average particle size characteristics of the nanoparticles were evaluated. The FPSP/essential oil nanoparticles (FPSP/EO) were spherical in shape and had an average particle size of 200–300 nm. The mean particle dimensions for both PSP/silver/EO and FPSP/silver/EO nanoparticles assemblies are measured at 236.52 ± 22.64 nm and 248.95 ± 28.17 nm, respectively. The results showed that the zeta potential values for PSP/silver/EO and FPSP/silver/EO were −18.3 ± 0.7 mV and −20.6 ± 1.3 mV, respectively. The results of this test showed that FPSP/Silver/EO significantly reduced the percentage of AGS cell viability better than EO and PSP/Silver/EO. The best treatment in this experiment was FPSP/Silver/EO at a concentration of 50 μL/mL and time 72 h. The minimum value of IC50 in FPSP/Silver/EO was observed as 21.11 μL/mL in 72 h.

Design, synthesis and biological evaluation of newly triazolo-quinoxaline based potential immunomodulatory anticancer molecules

It is evident that cancer is a serious disease with a growing incidence and high mortality rate. Based on the CRBN binding properties of glutarimide moiety of thalidomide molecule, and triazolo-quinoxaline cytotoxic activity, we decided to innovate new triazolo-quinoxaline based molecules hybridized with glutarimide moiety for potential immunomodulatory anticancer activity. The biological data revealed that 4-oxotriazoloquinoxaline based candidate (15) was of particular antiproliferative significance compared to doxorubicin. It showed IC50 of 9.81 ± 0.7, 15.49 ± 1.2, and 10.09 ± 0.9 μM against hepatocellular (HepG2), prostate cancer (PC3), and breast cancer (MCF-7), respectively. Meanwhile, doxorubicin revealed IC50 of 14.61 ± 1.1, 16.32 ± 1.1, and 12.41 ± 0.74 μM, respectively. Moreover, compound 15 was comparable to thalidomide in elevating the levels of caspase-8 by about 8 folds in HepG-2 cells. Similarly, it showed almost the same effect as thalidomide in reducing VEGF levels in HepG-2 cells. Whereas it was superior to thalidomide in decreasing the levels of NF-κB P65 in HepG-2 cells from 278.1 pg/mL to 82.4 pg/mL compared to 110.5 pg/mL reported for thalidomide. At the same time, 15 and thalidomide were comparable in their significant reduction of TNF-α levels in HepG-2 cells by about one third. Furthermore, molecular docking studies demonstrated the binding properties of the new candidates to CRBN. Accordingly, this work suggests the significance of the triazolo-quinoxaline derivatives carrying glutarimide moiety, in particular compound 15, that showed considerable data for further consideration in order to develop new effective anticancer drugs.

Synthesis and discovery of novel 1,2,3-triazole based cabotegravir derivatives with potent anticancer activity

A series of 28 novel cabotegravir derivatives, incorporating the 1,2,3-triazole moiety, were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against four different human cancer cell lines: HuH-7 (hepatocellular), MCF-7 (breast), SKOV3 (ovarian), and HCT-116 (colon). Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds KJ9 and KJ23 demonstrated the most pronounced effects, with IC50 values of 6.59 and 7.83μM in HuH-7 cells, 27.24 and 8.59μM in MCF-7 cells, 4.46 and 6.30μM in SKOV3 cells, 23.90 and 17.00μM in HCT-116 cells, respectively. Further investigations demonstrated that compound KJ9 and KJ23 induced cell apoptosis, elevated reactive oxygen species (ROS) levels, and ultimately led to cell death. Additionally, western blot analysis revealed altered expressions of proteins involved in autophagy and DNA damage following treatment with compound KJ9 and KJ23. Molecular structure analysis found that the novel compounds tend towards a planar conformation which contained multiple rigid planar structures. This planar structure makes it possible for the compounds to intercalate into DNA and causing DNA damage. These findings suggested that cabotegravir-1,2,3-triazole derivatives possess potential antitumor abilities and warrant further investigations for the development of novel anticancer drugs.

Multi-step Synthesis of Novel Pyrazole Derivatives as Anticancer Agents

The attractiveness of pyrazole and its derivatives is increasing because of their numerous potential pharmacological applications. A novel series of pyrazole hybrid compounds (6A–6L) has been synthesized, and all the intermediates and the final products were characterized by 1H NMR, IR, and mass spectrometry. Pyrazole derivatives were screened for their anticancer activity against the NCI-60 cell lines, and grouped into nine different subpanels. In-vitro anticancer studies of the targeted compounds showed that the compounds 6C, 6D, 6F, 6I, and 6J showed potent anticancer activity against renal cancer, ovarian cancer, melanoma, and leukemia cancer.

Development of a Cu/ZnO@ZIF-8 nanocomposite as a pH-responsive drug delivery vehicle for the sustained release of doxorubicin in human lung cancer cell lines

Nowadays the targeted drug release from a stable and non-toxic drug delivery vehicle is an onerous task. In this work, we developed a ZIF-8 based nanocomposite by the incorporation of copper doped zinc oxide nanoparticles onto the ZIF-8 frameworks. The formation of the composite was confirmed with the help of various spectral analyses such as FTIR, UV–visible, PXRD, XPS, TEM, SEM-EDS, TG/DTG, BET, and photoluminescent spectroscopy. The feasibility of the material as a drug delivery vehicle was analyzed by loading doxorubicin (DOX) and monitoring its release in human lung cancer cell line A549 under different pH conditions such as 1.2, 5.5, and 7.4. The release kinetics is in good agreement with the Higuchi model with a regression coefficient of 0.9999. The composite possesses a better drug loading capacity of 43.2 % and follows a sustained release kinetics at pH 5.5. The biocompatibility of the material is also noticed by monitoring the in vitro cytotoxicity and anticancer activity through MTT assay. The composite material shows a cytotoxicity of 71.99 % against human lung cancer cell line A549 and cell viability of 37 % towards the normal fibroblast cell line L929 at 100 μg/mL. The anticancer activity of the composite loaded with DOX was compared with the pure DOX. The results showed that the composite loaded with DOX shows better anticancer activity than that of pure DOX with an IC50 of 69.89 μg/mL, lower than that of pure DOX (85.52 μg/mL). The combined effect such as better drug loading, sustained and pH-responsive release and potential anticancer activity leads to the conclusion that the ZIF-8 based nanocomposite can be used as a better therapeutic agent against human lung cancer cell line A549.

Complexation of histone deacetylase inhibitor belinostat to Cu(II) prevents premature metabolic inactivation in vitro and demonstrates potent anti-cancer activity in vitro and ex vivo in colon cancer.

The histone deacetylase inhibitor (HDACi), belinostat, has had limited therapeutic impact in solid tumors, such as colon cancer, due to its poor metabolic stability. Here we evaluated a novel belinostat prodrug, copper-bis-belinostat (Cubisbel), in vitro and ex vivo, designed to overcome the pharmacokinetic challenges of belinostat. The in vitro metabolism of each HDACi was evaluated in human liver microsomes (HLMs) using mass spectrometry. Next, the effect of belinostat and Cubisbel on cell growth, HDAC activity, apoptosis and cell cycle was assessed in three colon cancer cell lines. Gene expression alterations induced by both HDACis were determined using RNA-Seq, followed by in silico analysis to identify master regulators (MRs) of differentially expressed genes (DEGs). The effect of both HDACis on the viability of colon cancer patient-derived tumor organoids (PDTOs) was also examined. Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro half-life of Cubisbel was significantly longer than belinostat. Belinostat and its Cu derivative commonly dysregulated numerous signalling and metabolic pathways while genes downregulated by Cubisbel were potentially controlled by VEGFA, ERBB2 and DUSP2 MRs. Treatment of colon cancer PDTOs with the HDACis resulted in a significant reduction in cell viability and downregulation of stem cell and proliferation markers. Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly enhances its metabolic stability in vitro and targets anti-cancer pathways by perturbing key MRs in colon cancer. Complexation of HDACis to a metal ion might improve the efficacy of clinically used HDACis in patients with colon cancer.

New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study.

A new series of thiazolyl-pyrazoline derivatives (4a-d, 5a-d 6a, b, 7a-d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a-b). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC50 = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC50 = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC50 = 0.024, and 0.005 µM, respectively, whereas their IC50 = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC50 = 0.007 and 0.018 µM). Both compounds 6a and 10a induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates 6a and 10a showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study.

Novel approaches targeting ferroptosis in treatment of glioma.

Glioma is a malignant brain tumor with a high mortality rate; hence novel treatment approaches are being explored to improve patient outcomes. Ferroptosis, a newly described form of regulated cell death, is emerging as a potential therapeutic target in glioma. Ferroptosis is characterized by the accumulation of lipid peroxides due to a loss of intracellular antioxidant systems represented by the depletion of glutathione and decreased activity of glutathione peroxidase 4 (GPX4). Since glioma cells have a high demand for iron and lipid metabolism, modulation of ferroptosis may represent a promising therapeutic approach for this malignancy. Recent studies indicate that ferroptosis inducers like erastin and RSL3 display potent anticancer activity in a glioma model. In addition, therapeutic strategies, including GPX4 targeting, lipid metabolism modulation, inhibition of amino acid transporters, and ferroptosis targeting natural compounds, have shown positive results in preclinical studies. This review will provide an overview of the functions of ferroptosis in glioma and its potential as a suitable target for glioma therapy.

Design, synthesis, and molecular docking studies of N-substituted sulfonamides as potential anticancer therapeutics

ObjectivesThe goal of this study was to design and enable development of anticancer sulfonamides by coupling amines and dansyl chloride with strategically selected substituents. The synthesized structures were characterized by NMR and mass spectrometry. In addition, molecular docking analysis was used to determine the binding ability of sulfonamides toward 1AZM, a possible drug target, as compared with that of the well-known drug acetazolamide. MethodsSulfonamides were synthesized by coupling amines and dansyl chloride under highly favorable conditions. The designed sulfonamides incorporated strategically positioned substituents to impart diverse biological properties. The synthesized structures were validated with NMR and mass spectra. Molecular docking analysis was performed to evaluate the binding affinities of the synthesized sulfonamides with the potential drug target 1AZM. ResultsThe synthesis of sulfonamides through the coupling of amines and dansyl chloride was successfully achieved. The validation of the synthesized structures with NMR and mass spectra confirmed their chemical identities. Molecular docking analysis revealed that the synthesized sulfonamides displayed binding affinities ranging from −6.8 to −8.2 kcal/mol toward the potential drug target 1AZM. Importantly, all derivatives exhibited superior binding affinities to acetazolamide (−5.25 kcal/mol). ConclusionsThe coupling of amines and dansyl chloride enabled efficient, straightforward sulfonamide synthesis. The strategic design of sulfonamides with specific substituents endows diverse biological properties, including potential anti-cancer activity. The elucidation of the synthesized compounds with NMR and mass spectra confirmed their structures. Molecular docking analysis demonstrated that the synthesized sulfonamides exhibited favorable binding affinities toward the potential drug target 1AZM. Notably, all derivatives displayed higher binding affinities, ranging from −6.8 to −8.2 kcal/mol, than the recommended drug acetazolamide (−5.25 kcal/mol), thus suggesting their potential as highly effective analogues for further validation in cancer therapy.

A Systematic Review of Curtisia dentata Endemic to South Africa: Phytochemistry, Pharmacology, and Toxicology.

The use of traditional medicine in treating a variety of both human and animal infections is ancient and still relevant. This is due to the resistance exhibited by most pathogenic microbial stains to currently-used antibiotics. The current work reports the phytochemistry, ethno-medicinal uses, toxicology, and most important pharmacological activities that validate the use of the plant species in African traditional medicine. Curtisia dendata is used in the treatment of many human and animal infections, including diarrhea, skin and related conditions, sexually transmitted infections, cancer, and a variety of ethno-veterinary infections. Pharmacologically, the plant species exhibited potent antimicrobial activity against a variety of pathogens. Further, both extracts and compounds isolated from the plant species exhibited potent antioxidant, anticancer, anti-parasitic, anti-inflammatory, and other important biological activities. Phytochemically, the plant species possess a variety of compounds, particularly triterpenes, that may well explain the various pharmacological activities of the plant species. The toxicological parameters, antimicrobial activities against microorganisms related to sexually transmitted infections, anti-diabetic effects, and inflammatory properties of the plant species are not well studied and still need to be explored. The biological activities observed validate the use of the plant species in African traditional medicine, particularly in the treatment of pulmonary infections associated with Mycobacterium species, and may well be due to the presence of triterpenes prevalent in the leaves.