Selective Anticancer Activity Research Articles

Exploring the Binding of Natural Compounds to Cancer-Related G-Quadruplex Structures: From 9,10-Dihydrophenanthrenes to Their Dimeric and Glucoside Derivatives.

In-depth studies on the interaction of natural compounds with cancer-related G-quadruplex structures have been undertaken only recently, despite their high potential as anticancer agents, especially due to their well-known and various bioactivities. In this frame, aiming at expanding the repertoire of natural compounds able to selectively recognize G-quadruplexes, and particularly focusing on phenanthrenoids, a mini-library including dimeric (1-3) and glucoside (4-5) analogues of 9,10-dihydrophenanthrenes, a related tetrahydropyrene glucoside (6) along with 9,10-dihydrophenanthrene 7 were investigated here by several biophysical techniques and molecular docking. Compounds 3 and 6 emerged as the most selective G-quadruplex ligands within the investigated series. These compounds proved to mainly target the grooves/flanking residues of the hybrid telomeric and parallel oncogenic G-quadruplex models exploiting hydrophobic, hydrogen bond and π-π interactions, without perturbing the main folds of the G-quadruplex structures. Notably, a binding preference was found for both ligands towards the hybrid telomeric G-quadruplex. Moreover, compounds 3 and 6 proved to be active on different human cancer cells in the low micromolar range. Overall, these compounds emerged as useful ligands able to target G-quadruplex structures, which are of interest as promising starting scaffolds for the design of analogues endowed with high and selective anticancer activity.

Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and -Resistant to Cisplatin.

Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10-20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd3Spd2 and Pt3Spd2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes' ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd3Spd2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC50 values 4.65-8.99 µM and 9.24-13.34 µM, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB-231/R cells. Altogether, the data presently gathered reveal Pd3Spd2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms.

Ru/Pt@BSA nanoparticles for efficient photo-catalytic oxidation of NAD(P)H and targeted cancer treatment under hypoxic conditions

Photo-catalytic oxidation of intracellular nicotinamide adenine dinucleotide (2′-phosphate) (NAD(P)H) has attracted much attention for cancer therapy. However, the general oxygen-dependent mechanism heavily depresses the efficacy in hypoxic tumors. To solve this problem, herein platinum nanoparticles (Pt NPs) with catalase-like (CAT-like) and catalytic H2 evolution activities were introduced as a powerful assistant to enhance the photo-catalytic NAD(P)H oxidation of Ru1 ([Ru(phen)2(PIP-OCH3)]2+, phen = 1,10-phenanthroline, PIP-OCH3 = 2-(4‑methoxy phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) under hypoxic and even oxygen-free conditions. Firstly, Pt NPs can transform the original and in situ formed H2O2 once again into O2 by the CAT-like activity, thus relieving tumor hypoxia and realizing cyclic utilization (at least in part) of the precious oxygen in hypoxia. Secondly, Pt NPs can also be served as H2 evolution catalysts while using Ru1 as the photosensitizer and NAD(P)H as the electron and proton donor. In this process, NAD(P)H is oxidized without the participation of oxygen, which can provide an effective way even under oxygen-free conditions. Via co-encapsulation of Ru1 and Pt NPs in bovine serum albumin (BSA) with tumor targeting ability, the resultant Ru/Pt@BSA could photo-catalyze intracellular NAD(P)H oxidation under hypoxic conditions (3% O2), and exhibited an efficient and selective anticancer activity both in vitro and in vivo. Our results may provide new sights for efficient and targeted cancer treatment under hypoxic conditions.

Artificial Diets with Selective Restriction of Amino Acids and Very Low Levels of Lipids Induce Anticancer Activity in Mice with Metastatic Triple-Negative Breast Cancer.

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show for the first time that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were also tested in this model. AA manipulation led to modest improvements in mice survival when the levels of lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Some mice fed the artificial diets as monotherapy lived much longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers.

Selective Targeting of Cancer-Related G-Quadruplex Structures by the Natural Compound Dicentrine.

Aiming to identify highly effective and selective G-quadruplex ligands as anticancer candidates, five natural compounds were investigated here, i.e., the alkaloids Canadine, D-Glaucine and Dicentrine, as well as the flavonoids Deguelin and Millettone, selected as analogs of compounds previously identified as promising G-quadruplex-targeting ligands. A preliminary screening with the G-quadruplex on the Controlled Pore Glass assay proved that, among the investigated compounds, Dicentrine is the most effective ligand of telomeric and oncogenic G-quadruplexes, also showing good G-quadruplex vs. duplex selectivity. In-depth studies in solution demonstrated the ability of Dicentrine to thermally stabilize telomeric and oncogenic G-quadruplexes without affecting the control duplex. Interestingly, it showed higher affinity for the investigated G-quadruplex structures over the control duplex (Kb~106 vs. 105 M-1), with some preference for the telomeric over the oncogenic G-quadruplex model. Molecular dynamics simulations indicated that Dicentrine preferentially binds the G-quadruplex groove or the outer G-tetrad for the telomeric and oncogenic G-quadruplexes, respectively. Finally, biological assays proved that Dicentrine is highly effective in promoting potent and selective anticancer activity by inducing cell cycle arrest through apoptosis, preferentially targeting G-quadruplex structures localized at telomeres. Taken together, these data validate Dicentrine as a putative anticancer candidate drug selectively targeting cancer-related G-quadruplex structures.

Comparative Study of Molecular Interaction of Quercetin and B4S With Kinensin-5 Protein In-Silico for the selective anticancer activity of Quercetin

Aim: To study the comparative molecular interactions of Quercetin and 3’-fluoro-4’-(trifluoromethyl)biphenyl-4-sulfonamide (B4S) with the active sites of Kinesin-5 protein using molecular docking analysis for the selective anticancer activity. Materials and Methods: The protein structures are collected from the protein data bank (PDB) website and the ligand structures were collected from the PUBCHEM website.The samples were regarded as (N=10) for Kinensin-5 protein with quercetin and (N=10) for Kinensin-5 protein with B4S according to the sample size calculations performed from clinicalc.com with pretest G power 80%. The total sample size was 20. The binding energy (kcal/mol) was calculated using Autodock vina software. The non-covalent protein ligand interactions were detected using protein–ligand interaction profiler (PLIP) webserver. Results: The mean binding affinity of Quercetin (-9.5 kcal/mol) was significantly (p=<0.001, p<0.05, 2-tailed t-test) higher than B4S (-7.21 kcal/mol) towards the active site aminoacid resiues of Kinensin-5 protein. Conclusion: The results indicate that Quercetine has better binding affinity compared the standard Kinensin-5 inhibitor B4S. Hence it may more selectively bind to the cancerous cells to inhibit their proliferation and can acts as a novel anti-cancer agent.

Mitochondria-targeting sonosensitizer-loaded extracellular vesicles for chemo-sonodynamic therapy.

Sonodynamic therapy (SDT) has emerged as an effective therapeutic modality as it employs ultrasound (US) to eradicate deep-seated tumors noninvasively. However, the therapeutic efficacy of SDT in clinical settings remains limited owing to the low aqueous stability and poor pharmacokinetic properties of sonosensitizers. In this study, extracellular vesicles (EVs), which have low systemic toxicity, were used as clinically available nanocarriers to effectively transfer a sonosensitizer to cancer cells. Chlorin e6 (Ce6), a sonosensitizer, was conjugated to a mitochondria-targeting triphenylphosphonium (TPP) moiety and loaded into EVs to enhance the efficacy of SDT, because mitochondria are critical subcellular organelles that regulate cell survival and death. Additionally, piperlongumine (PL), a pro-oxidant and cancer-specific chemotherapeutic agent, was co-encapsulated into EVs to achieve efficient and selective anticancer activity. The EVs substantially amplified the cellular internalization of TPP-conjugated Ce6 (TPP-Ce6), resulting in the enhanced generation of intracellular reactive oxygen species (ROS) in MCF-7 human breast cancer cells upon US exposure. Importantly, EVs encapsulating TPP-Ce6 effectively destroyed the mitochondria under irradiation with US, leading to efficient anticancer activity. The co-encapsulation of pro-oxidant PL into EVs significantly enhanced the SDT efficacy in MCF-7 cells through the excessive generation of ROS. Moreover, the EV co-encapsulating TPP-Ce6 and PL [EV(TPP-Ce6/PL)] exhibited cancer-specific cell death owing to the cancer-selective apoptosis triggered by PL. In vivo study using MCF-7 tumor-xenograft mice revealed that EV(TPP-Ce6/PL) effectively accumulated in tumors after intravenous injection. Notably, treatment with EV(TPP-Ce6/PL) and US inhibited tumor growth significantly without causing systemic toxicity. This study demonstrated the feasibility of using EV(TPP-Ce6/PL) for biocompatible and cancer-specific chemo-SDT.

Polyethyleneglycol-Betulinic Acid (PEG-BA) Polymer-Drug Conjugate Induces Apoptosis and Antioxidation in a Biological Model of Pancreatic Cancer.

Pancreatic cancer (PC) is one of the most aggressive solid malignancies with poor treatment response and low survival rates. Herbal medicines such as betulinic acid (BA) have shown potential in treating various solid tumours, but with limitations that can be circumvented by polymer-drug conjugation. Polyethylene glycol-BA (PEG-BA) polymer-drug conjugate has previously shown selective anticancer activity against PC cells. Here, we elucidate the mechanism of cell death and the cell death pathway, anti-inflammatory and antioxidant activities of PEG-BA. PEG-BA induced apoptotic cell death by arresting MIA-PaCa-2 cells in the Sub-G1 phase of the cell cycle compared with BA and untreated cells (39.50 ± 5.32% > 19.63 ± 4.49% > 4.57 ± 0.82%). NFκB/p65 protein expression was moderately increased by PEG-BA (2.70 vs. 3.09 ± 0.42 ng/mL; p = 0.1521). However, significant (p < 0.05) overexpression of the proapoptotic genes TNF (23.72 ± 1.03) and CASPASE 3 (12,059.98 ± 1.74) compared with untreated cells was notable. The antioxidant potential of PEG-BA was greater (IC50 = 15.59 ± 0.64 µM) compared with ascorbic acid (25.58 ± 0.44 µM) and BA-only (>100 µM) and further confirmed with the improved reduction of hydroperoxide levels compared with BA-only (518.80 ± 25.53 µM vs. 542.43 ± 9.70 µM). In conclusion, PEG-BA activated both the intrinsic and extrinsic pathways of apoptosis and improved antioxidant activities in PC cells, suggesting enhanced anticancer activity upon conjugation.

Niclosamide is a potential candidate for the treatment of chemo-resistant osteosarcoma

Chemotherapy is the main treatment option for advanced osteosarcoma, which is the most common type of primary bone malignancy. However, patients develop resistance rapidly and many succumb to the disease. Niclosamide, an anthelmintic drug, has been recently identified to display potent and selective anti-cancer activity. In this work, we show that niclosamide at sub-micromolar concentrations inhibits proliferation and migration, and induces apoptosis in both parental and chemo-resistant osteosarcoma cells, with much less toxicity in normal osteoblastic cells. Interestingly, chemo-resistant osteosarcoma cells are more sensitive to niclosamide compared to parental cells. We further identify that inhibition of β-catenin is the underlying mechanism of niclosamide's action in osteosarcoma cells. In addition, we reveal that chemo-resistant osteosarcoma cells display increased β-catenin activity compared to parental cells, which might explain the hypersensitivity of chemo-resistant cells to niclosamide. Our work provides pre-clinical evidence that niclosamide can be repurposed for treating osteosarcoma. Our findings also suggest the therapeutic value of β-catenin to overcome osteosarcoma chemo-resistance.

Green synthesis of fluorescent carbon nanodots from sage leaves for selective anticancer activity on 2D liver cancer cells and 3D multicellular tumor spheroids.

Carbon nanodots, a family of carbon-based nanomaterials, have been synthesized through different methods from various resources, affecting the properties of the resulting product and their application. Herein, carbon nanodots (CNDs) were synthesized with a green and simple hydrothermal method from sage leaves at 200 °C for 6 hours. The obtained CNDs are well dispersed in water with a negative surface charge (ζ-potential = -11 mV) and an average particle size of 3.6 nm. The synthesized CNDs showed concentration-dependent anticancer activity toward liver cancer (Hep3B) cell lines and decreased the viability of the cancer cells to 23% at the highest used concentration (250 μg ml-1 of CNDs). More interestingly, the cytotoxicity of the CNDs was tested in normal liver cell lines (LX2) revealed that the CNDs at all tested concentrations didn't affect their viability including at the highest concentration showing a viability of 86.7%. The cellular uptake mechanisms of CNDs were investigated and they are thought to be through energy-dependent endocytosis and also through passive diffusion. The main mechanisms of endocytosis were lipid and caveolae-mediated endocytosis. In addition, the CNDs have hindered the formation of 3D spheroids from the Hep3B hepatocellular carcinoma cell line. Hence, it would be concluded that the synthesized CNDs from sage are more highly selective to liver cancer cells than normal ones. The CNDs' cancer-killing ability would be referred to as the production of reactive oxygen species.

A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity

The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road toward desirable success rates of cancer treatments is still long and paved with uncertainty. This work aims to select natural products that act via endoplasmic reticulum (ER) stress, a known vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Among an in-house chemical library, nontoxic molecules towards noncancer cells were assessed for toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. Active molecules towards at least one of these cell lines were studied in a battery of ensuing assays to clarify the involvement of ER stress and unfolded protein response (UPR) in the cytotoxic effect. Several natural products are selectively cytotoxic against malignant cells, and the effect often relies on ER stress induction. Berberine was the most promising molecule, being active against both cell models by disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation. Our results indicate that berberine and emodin are potential leads for the development of more potent ER stressors to be used as selective anticancer agents.

Manipulation of Amino Acid Levels with Artificial Diets Induces a Marked Anticancer Activity in Mice with Renal Cell Carcinoma.

Targeted therapies with antiangiogenic drugs (e.g., sunitinib) and immune checkpoint inhibitors (e.g., anti-PD-1 antibodies) are the standard of care for patients with metastatic renal cell carcinoma. Although these treatments improve patient survival, they are rarely curative. We previously hypothesized that advanced cancers might be treated without drugs by using artificial diets in which the levels of specific amino acids (AAs) are manipulated. In this work, after showing that AA manipulation induces selective anticancer activity in renal cell carcinoma cells in vitro, we screened 18 artificial diets for anticancer activity in a challenging animal model of renal cell carcinoma. The model was established by injecting murine renal cell carcinoma (Renca) cells into the peritoneum of immunocompetent BALB/cAnNRj mice. Mice survival was markedly improved when their normal diet was replaced with our artificial diets. Mice fed a diet lacking six AAs (diet T2) lived longer than mice treated with sunitinib or anti-PD-1 immunotherapy; several animals lived very long or were cured. Controlling the levels of several AAs (e.g., cysteine, methionine, and leucine) and lipids was important for the anticancer activity of the diets. Additional studies are needed to further evaluate the therapeutic potential and mechanism of action of this simple and inexpensive anticancer strategy.

In silico mapping of the dynamic interactions and structure-activity relationship of flavonoid compounds against the immune checkpoint programmed-cell death 1 pathway

Flavonoids are a class of natural products widely available in medicinal and dietary plants. Their pharmacological use has shown the potential to reduce the risk of different types of cancer, among other prevalent diseases. Their molecular scaffold inhibits the PD-1/PD-L1 axis, an important pathway related to the adaptive immune resistance of cancer cells already targeted for developing new cancer immunotherapy. However, despite the availability of kinetic and thermodynamic experimental data on the flavonoid–PD-1/PD-L1 interaction, there is still a lack of reliable information about their binding mode at the atomic level. Thus, we aimed to computationally predict the binding mode of flavonoid molecules with PD-1 and/or PD-L1 proteins using unbiased computational methodologies such as blind docking and supervised molecular dynamics simulation. The molecular interactions and dynamics of these predicted poses of protein-flavonoid complexes were further analyzed through multiple molecular dynamics simulations. This information, corroborated with the IC50 and KD values from available literature, was used to perform molecular matched-pair analysis to comprehensively describe the main interactions governing the inhibition of the complex PD-1/PD-L1 by the flavonoid scaffold. By analyzing the effect of substitutions in such a scaffold, we observed a clear correspondence with literature binding assays. Thus, we propose, for dimeric PD-L1, that the 7-O-glucoside forces the molecule displacement in the dimer interface. Furthermore, the 3-OH plays an essential role in stabilizing the buried binding mode by water-bridged hydrogen bonds with Asp122 and Gln66 in both extremities of the pocket. In PD-1, we suggest that flavonoids could bind through the BC loop by inducing a flip of Phe56 after a conformational change of the Asn58 glycosylation. Hence, our results introduced unprecedented information on flavonoid interaction and dynamics when complexed with PD-1 checkpoint pathway proteins and can pave the road for developing new flavonoid derivatives with selective anticancer activity.

Fucosterol exhibits selective antitumor anticancer activity against HeLa human cervical cell line by inducing mitochondrial mediated apoptosis, cell cycle migration inhibition and downregulation of m-TOR/PI3K/Akt signalling pathway.

[This retracts the article DOI: 10.3892/ol.2018.7769.].

Surface chemistry dependent toxicity of inorganic nanostructure glycoconjugates on bacterial cells and cancer cell lines

Surface functionalized nanostructures have outstanding potential in biological applications owing to their target-specific design. In this study, we utilized laboratory synthesized carbohydrate-derivatives (i.e., galactose, mannose, lactose, and cellobiose derivatives) for aqueous one-pot synthesis of gold (Au) and silver (Ag) nanostructure glycoconjugates (NSs), and iron metal-organic framework glycoconjugates (FeMOFs). This work aims to test whether differences in the surface chemistry of the inorganic nanostructures play roles in revealing their toxicities towards bacterial cells and cancerous cell lines. As of the first step, biological activity of AuNSs, AgNSs, and FeMOFs were tested against a variety of gram (−) and gram (+) bacterial strains, where AgNSs possessed moderate to high antibacterial activities against all the tested bacterial strains, while AuNSs and FeMOFs showed their bacterial toxicity mostly depending on the strain. Minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) determination studies were performed for the nanostructure glycoconjugates, for which μg/mL MBC values were obtained such as (Cellobiose p-aminobenzoic acid_AgNS) CBpAB_AgNS gave 50 μg/mL MBC value for P.aeruginosa and S.kentucy. The activity of selected sugar ligands and corresponding glycoconjugates were further tested on MDA-MB-231 breast cancer and A549 lung cancer cell lines, where selective anticancer activity was observed depending on the surface chemistry as well. Besides, d-penicillamine was introduced to galectin specific sugar ligand coated AuNS glycoconjugates, which showed very strong anticancer activities even at low doses. Overall, the importance of this work is that the surface chemistry of the inorganic nanostructures can be critical to reveal their toxicity towards bacterial cells and cancerous cell lines.

The C30-Modulation of Betulinic Acid Using 1,2,4-Triazole: A Promising Strategy for Increasing Its Antimelanoma Cytotoxic Potential.

Cancer, in all its types and manifestations, remains one of the most frequent causes of death worldwide; an important number of anticancer drugs have been developed from plants, fungi and animals, starting with natural compounds that were later derivatized in order to achieve an optimized pharmacokinetic/pharmacological profile. Betulinic acid is a pentacyclic triterpenic compound that was identified as an anticancer agent whose main advantage consists in its selective activity, which ensures the almost total lack of cytotoxic side effects. Conjugates of betulinic acid with substituted triazoles, scaffolds with significant pharmacological properties, were synthesized and tested as anticancer agents in order to achieve new therapeutic alternatives. The current paper aims to obtain a C30-1,2,4-triazole derivative of betulinic acid simultaneously acetylated at C3 whose biological activity was tested against RPMI melanoma cells. The compound revealed significant cytotoxic effects at the tested concentrations (2, 10 and 50 μΜ) by significantly decreasing the cell viability to 88.3%, 54.7% and 24.5%, respectively, as compared to the control. The compound's testing in normal HaCaT cells showed a lack of toxicity, which indicates its selective dose-dependent anticancer activity. The investigation of its underlying molecular mechanism revealed an apoptotic effect induced at the mitochondrial level, which was validated through high-resolution respirometry studies.

Cisplatin conjugation with an exopolysaccharide extracted from Lactobacillus gasseri potentiates its efficacy and attenuates its toxicity

The development of newer cisplatin analogs is constantly being investigated owing to its low solubility, poor pharmacokinetics, and dose-related toxicity. In order to address the limitations of current cisplatin therapy, the present study was undertaken. Cisplatin conjugation with an exopolysaccharide extracted from Lactobacillus gasseri (LG-EPS) showed remarkably enhanced and selective anticancer activity by targeting tumor cells overexpressing glucose transporter 1 (GLUT1). The EPS-cisplatin complex exhibited a 600-fold increase in aqueous solubility with a better pharmacokinetic profile (longer half-life) in comparison to cisplatin. Cell viability assay and western blotting demonstrated a strong correlation between the cytotoxicity profile and GLUT1 expressions in different cell lines. The concentration of DNA-bound platinum was also found to be significantly higher in EPS-cisplatin-treated cells. Quercetin, a competitive inhibitor of GLUTs, was shown to prevent this selective uptake of EPS-cisplatin complex. Surprisingly, EPS-cisplatin complex showed an exceptionally safer profile (4 times the maximum tolerated dose of cisplatin) in the acute toxicity study and was also more efficacious against the xenograft mice model. The study suggests that this green glycoconjugation can be an effective and safer strategy to broaden the therapeutic potential of anti-cancer drugs in general and cisplatin in particular.

Downregulation of PRMT5 by AMI-1 enhances therapeutic efficacy of compound kushen injection in lung carcinoma in vitro and in vivo.

Protein arginine methyltransferase 5 (PRMT5) is overexpressed in lung carcinoma, which promotes tumor cell proliferation, survival, migration and invasion. Compound Kushen injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling, which are mainly used to stop in cancer pain and bleeding. Here we found that cell viability and colony formation were inhibited after the incubation of AMI-1. Meanwhile, AMI-1 suppressed cell migration, enhanced apoptosis, induced cell cycle arrest, inhibited PRMT5 expression and histone H3R8 and H4R3 symmetric di-methylation (H3R8me2s and H4R3me2s) accumulation, down-regulated the expression of eukaryotic translation initiation factor 4E (eIF4E) in lung carcinoma cells. Moreover, AMI-1 suppressed tumor growth, decreased H3R8me2s and H4R3me2s accumulation, down-regulated eIF4E expression and increased p53 expression in lung carcinoma xenografts of BALB/c nude mice. Of note, combined and CKI markedly enhanced the anticancer efficacy CKI in lung carcinoma. The above findings demonstrated that AMI-1 has established antineoplastic activity and this role may be associated with affecting the function of eIF4E via inhibiting PRMT5 activity or protein levels in lung carcinoma. This study highlights evidence of novel selective anticancer activity of AMI-1 in combination with CKI in lung carcinoma.

Azole-Pyrimidine Hybrid Anticancer Agents: A Review of Molecular Structure, Structure Activity Relationship, and Molecular Docking.

Cancer has emerged as one of the leading causes of death globally, partly due to the steady rise in anticancer drug resistance. Pyrimidine and pyrimidine-fused heterocycles are some of the privileged scaffolds in medicine, as they possess diverse biological properties. Pyrimidines containing azole nucleus possess inestimable anticancer potency and can potentially regulate cellular pathways for selective anticancer activity. The present review outlines the molecular structure of pyrimidine-fused azoles with significant anticancer activity. The structure activity relationship and molecular docking studies have also been discussed. The current review is the first complete compilation of significant literature on the proposed topic from 2016 to 2020. The information contained in this review offers a useful insight to chemists in the design of new and potent anticancer azole-pyrimidine analogues.

Lactoferrin perturbs intracellular trafficking, disrupts cholesterol-rich lipid rafts and inhibits glycolysis of highly metastatic cancer cells harbouring plasmalemmal V-ATPase

The milk-derived bovine lactoferrin (bLf) is an iron-binding glycoprotein with remarkable selective anticancer activity towards highly metastatic cancer cells displaying the proton pump V-ATPase at the plasma membrane. As studies aiming to dissect the bLf mechanisms of action are critical to improve its efficacy and boost its targeted clinical use, herein we sought to further uncover the molecular basis of bLf anticancer activity. We showed that bLf co-localizes with V-ATPase and cholesterol-rich lipid rafts at the plasma membrane of highly metastatic cancer cells. Our data also revealed that bLf perturbs cellular trafficking, induces intracellular accumulation of cholesterol and lipid rafts disruption, downregulates PI3K, and AKT or p-AKT and inhibits glycolysis of cancer cells harbouring V-ATPase at the plasma membrane lipid rafts. Altogether, our results can lay the foundation for future bLf-based targeted anticancer strategies as they unravel a novel cascade of molecular events that explains and further reinforces bLf selectivity for cancer cells displaying plasmalemmal V-ATPase.