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Background: Chalcones have been described in the literature as promising antineoplastic compounds., Objectives: Therefore, the objective of this study was to analyze the cytotoxic effect of 23 synthetic chalcones on human acute leukemia (AL) cell lines (Jurkat and K562)., Methods: Cytotoxicity assessment was performed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cell death was evaluated using fluorescence microscopy, the DNA fragmentation technique, and the assessment of proteins involved in apoptosis by flow cytometry., Results: The most cytotoxic chalcone (R32) showed no cytotoxicity towards peripheral blood mononuclear cells (PBMC). It exhibited no hemolytic activity, did not alter platelet aggregation after adenosine diphosphate (ADP) and epinephrine stimulation, and did not affect blood coagulation as measured by prothrombin time (PT) and activated partial thromboplastin time (APTT). R32 demonstrated cytotoxic activity by inducing both intrinsic and extrinsic apoptosis, leading to caspase-3 activation and DNA fragmentation. In Jurkat and K562 cells, intrinsic apoptosis was associated with changes in mitochondrial membrane potential (MMP). There was a decreased expression of Bcl-2, increased expression of Bax, decreased expression of survivin, and increased expression of apoptosis-inducing factor (AIF). Extrinsic apoptosis involvement was also observed in both cell lines, characterized by increased expression of the Fas receptor. Additionally, Jurkat cells exhibited decreased expression of the KI-67 cell proliferation marker., Conclusion: These findings suggest R32 as a potential compound for the development of novel drugs for the treatment of AL., (© 2025 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Four new transition metal complexes, [M(PPh 3 )(L)] . CH 3 OH (M = Ni(II) (1), Pd(II) (2)) [Pt (PPh 3 ) 2 (HL)]Cl (3) and [Ru(CO)(PPh 3 ) 2 (L)] (4) (H 2 L = 2,4-dihydroxybenzaldehyde-S-methyldithiocarbazate, PPh 3  = triphenylphosphine) have been synthesized and characterized by elemental analyses (C, H, N), FTIR, NMR ( 1 H, 31 P), ESI-MS and UV-visible spectroscopy. The molecular structure of (1) and (2) complexes was confirmed by single-crystal X-ray crystallography. It showed a distorted square planar geometry for both complexes around the metal center, and the H 2 L adopt a bi-negative tridentate chelating mode. The interaction with biomolecules viz., calf thymus DNA (ct DNA), yeast RNA (tRNA), and BSA (bovine serum albumin) was examined by both UV-visible and fluorescence spectroscopies. The antioxidant activity of all compounds is discussed on basis of DPPH • (2,2-diphenyl-1-picrylhydrazyl) scavenging activity and showed better antioxidant activity for complexes compared to the ligand. The in vitro cytotoxicity of the compounds was tested on human (breast cancer (MCF7), colon cancer (HCT116), liver cancer (HepG2), and normal lung fibroblast (WI38)) cell lines, showing that complex (1) the most potent against MCF7 and complex (4) against HCT116 cell lines based on IC 50 and selective indices (SI) values. So, both complexes were chosen for further studies such as DNA fragmentation, cell apoptosis, and cell cycle analyses. Complex (1) induced MCF7 cell death by cellular apoptosis and arrest cells at S phase. Complex (4) induced HCT116 cell death predominantly by cellular necrosis and arrested cell division at G2/M phase due to DNA damage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acute myeloid leukemia is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Despite recent advances in the treatment of this disease, the prognosis and overall long-term survival for patients remain poor, which drives the search for new chemotherapeutics and treatment strategies. Piceatannol, a polyphenolic compound present in grapes and wine, appears to be a promising chemotherapeutic agent in the treatment of leukemia. The aim of the present study was to examine whether piceatannol induces autophagy and/or apoptosis in HL-60 human acute myeloid leukemia cells and whether HL-60 cells are able to acquire resistance to piceatannol toxicity. We found that piceatannol at the IC 90 concentration of 14 µM did not induce autophagy in HL-60 cells. However, it induced caspase-dependent apoptosis characterized by phosphatidylserine externalization, disruption of the mitochondrial membrane potential, caspase-3 activation, internucleosomal DNA fragmentation, PARP1 cleavage, chromatin condensation, and fragmentation of cell nuclei. Our findings also imply that HL-60 cells are able to acquire resistance to piceatannol toxicity via mechanisms related to MRP1 activity. Our results suggest that the use of piceatannol as a potential chemotherapeutic agent may be associated with the risk of multidrug resistance, warranting its use in combination with other chemotherapeutic agents.

Pancreatic cancer is the fourth most lethal cancer type worldwide. Due to multiple levan applications including anticancer activities, studies related to levansucrase production are of interest. To our knowledge, levan effect on pancreatic cancer cells has not been tested previously. In this work, among eighteen bacterial honey isolates, Bacillus subtilis MT453867 showed the highest levan yield (33 g/L) and levansucrase production (8.31 U/mL). One-factor-at-a-time technique increased levansucrase activity by 60% when MgSO 4 was eliminated. The addition of 60 g/L banana peels enhanced the enzyme activity (192 U/mL). Placket Burman design determined the media composition for maximum levan yield (54.8 g/L) and levansucrase production (505 U/mL). The identification of levan was confirmed by thin-layer chromatography, Fourier-Transform Infrared spectrometric analysis, 13 C-nuclear-magnetic resonance, and 1 H-nuclear-magnetic resonance. Both crude and dialyzed levan completely inhibited the pancreatic cancer cell line at 100 ppm with no cytotoxicity on the normal retinal cell line. The LD 50 of crude levan was 4833 mg/kg body weight. Levan had strong antioxidant activity and significantly reduced the expression of CXCR4 and MCM7 genes in pancreatic cancer cells with significant DNA fragmentation. In conclusion, Bacillus subtilis MT453867 levan is a promising adjunct to pancreatic-anticancer agents with both anti-cancer and chemoprotective effects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Quinones are plant-derived secondary metabolites that present diverse pharmacological properties, including antibacterial, antifungal, antiviral, anti-inflammatory, antipyretic and anticancer activities. In the present study, we evaluated the cytotoxic effect of a new naphthoquinone 6b,7-dihydro-5H-cyclopenta [b]naphtho [2,1-d]furan-5,6 (9aH)-dione) (CNFD) in different tumor cell lines. CNFD displayed cytotoxic activity against different tumor cell lines, especially in MCF-7 human breast adenocarcinoma cells, which showed IC 50 values of 3.06 and 0.98 μM for 24 and 48 h incubation, respectively. In wound-healing migration assays, CNFD promoted inhibition of cell migration. We have found typical hallmarks of apoptosis, such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of caspases-9 and-3 activation, increase of internucleosomal DNA fragmentation without affecting the cell membrane permeabilization, increase of ROS production, and loss of mitochondrial membrane potential induced by CNFD. Moreover, gene expression experiments indicated that CNFD increased the expression of the genes CDKN1A, FOS, MAX, and RAC1 and decreased the levels of mRNA transcripts of several genes, including CCND1, CDK2, SOS1, RHOA, GRB2, EGFR and KRAS. The CNFD treatment of MCF-7 cells induced the phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) and inactivation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). In a study using melanoma cells in a murine model in vivo, CNFD induced a potent anti-tumor activity. Herein, we describe, for the first time, the cytotoxicity and anti-tumor activity of CNFD and sequential mechanisms of apoptosis in MCF-7 cells. CNFD seems to be a promising candidate for anti-tumor therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

At present, nuclear condensation and fragmentation have been estimated also using Hoechst probes in fluorescence microscopy and flow cytometry. However, none of the methods used the Hoechst probes for quantitative spectrofluorometric assessment. Therefore, the aim of the present study was to develop a spectrofluorometric assay for detection of nuclear condensation and fragmentation in the intact cells. We used human hepatoma HepG2 and renal HK-2 cells cultured in 96-well plates treated with potent apoptotic inducers (i.e. cisplatin, staurosporine, camptothecin) for 6-48 h. Afterwards, the cells were incubated with Hoechst 33258 (2 µg/mL) and the increase of fluorescence after binding of the dye to DNA was measured. The developed spectrofluorometric assay was capable to detect nuclear changes caused by all tested apoptotic inducers. Then, we compared the outcomes of the spectrofluorometric assay with other methods detecting cell impairment and apoptosis (i.e. WST-1 and glutathione tests, TUNEL, DNA ladder, caspase activity, PARP-1 and JNKs expressions). We found that our developed spectrofluorometric assay provided results of the same sensitivity as the TUNEL assay but with the advantages of being fast processing, low-cost and a high throughput. Because nuclear condensation and fragmentation can be typical markers of cell death, especially in apoptosis, we suppose that the spectrofluorometric assay could become a routinely used method for characterizing cell death processes.

In the present study, nickel(II) complex with 2-[2-[2-(1H-benzimidazol-2-yl)ethylsulfanyl]ethyl]-1H-benzimidazole (tebb) of formula [Ni(tebb) 2 ](ClO 4 ) 2 has been prepared and its structure was proved by X-ray crystallography. The central nickel atom is in deformed octahedral vicinity. Four nitrogen atoms of two ligands form plane of octahedral and sulfur atoms are in apical positions. Perchlorate anions are outside the coordination sphere. The coordination compound was tested for its biological activities in an array of in vitro assays. It was found that the synthesized complex possesses interesting biological activity, which is most likely related to its cell-type related uptake kinetics. The synthesized complex is readily uptaken by malignant MDA-MB-231 and CACO-2 cells with the lowest uptake by healthy Hs27 fibroblasts. The lowest IC 50 values were obtained for MDA-MB-231 cells (5.2-12.7 μM), highlighting exceptional differential cytotoxicity (IC 50 values for healthy fibroblasts were 38.6-51.5 μM). Furthermore, it was found the complex is capable to cause hydrolytic DNA cleavage, promotes an efficient DNA fragmentation and to trigger an extensive formation of intracellular reactive oxygen species. Overall, current work presents a synthesis of Ni(II) coordination compound with interesting biological behavior and with a promising potential to be further tested in pre-clinical models., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1 , while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML.

Burkitt's lymphoma (BL) is the fastest growing human tumor. Current treatment consists of a multiagent regimen of cytotoxic drugs with serious side effjects including tumor lysis, cardiotoxicity, hepatic impairment, neuropathy, myelosuppression, increased susceptibility to malignancy, and death. Furthermore, therapeutic interventions in areas of BL prevalence are not as feasible as in high-income countries. Therefore, there exists an urgent need to identify new therapies with a safer profile and improved accessibility. Triclosan (TCS), an antimicrobial used in personal care products and surgical scrubs, has gained considerable interest as an antitumor agent due to its interference with fatty acid synthesis. Here, we investigate the antitumor properties and associated molecular mechanisms of TCS in BL-derived BJAB cells. Dose-dependent cell death was observed following treatment with 10-100 µM TCS for 24 h, which was associated with membrane phospholipid scrambling, compromised permeability, and cell shrinkage. TCS-induced cell death was accompanied by elevated intracellular calcium, perturbed redox balance, chromatin condensation, and DNA fragmentation. TCS upregulated Bad expression and downregulated that of Bcl2. Moreover, caspase and JNK MAPK signaling were required for the full apoptotic activity of TCS. In conclusion, this report identifies TCS as an antitumor agent and provides new insights into the molecular mechanisms governing TCS-induced apoptosis in BL cells.

I., Background: A combination of etoposide (VP-16) and cisplatin (CDDP) is the standard treatment for certain colon cancers. These drugs promote the death of cancer cells via direct and indirect induction of the most lethal DNA lesions - DNA double-stand breaks. However, cancer cells can reverse the DNA damaging effect of anticancer drugs by triggering DNA repair processes. In eukaryotic cells, the main DNA repair pathway responsible for DNA double-stand breaks repair is non-homologous end-joining (NHEJ). Inhibitors of DNA repair are of special interest in cancer research as they could break the cellular resistance to DNA-damaging agents and increase the efficiency of standard cancer treatments. In this study, we investigated the effect of two NHEJ inhibitors, SCR7 and NU7441, on the cytotoxic mechanism of VP-16/CDDP in a LoVo human colorectal adenocarcinoma cell line. SCR7 blocks Ligase IV-mediated joining by interfering with its DNA binding, whereas NU7441 is a highly potent and selective DNA-PK inhibitor.II., Methods and Results: Both inhibitors synergistically increased the cytotoxicity of CDDP and VP-16 when combined, but the effect of SCR7 was more pronounced. SCR7 and NU7441 also significantly increased VP-16; CDDP induced DNA double-stand breaks level and delayed drug-induced DSB repair, as seen on the comet assay and measured using H2AX foci. We also observed changes in cell cycle distribution and enhanced apoptosis ratio in colorectal adenocarcinoma cells treated with DNA repair inhibitors and VP-16/CDDP.III., Conclusions: Our data support the hypothesis that NHEJ inhibitors could be used in conjunction with standard therapy to provide effective clinical improvement and allow reduction in drug doses.

Background and Objective: Evidence point out promising anticancer activities of Dihydropyrimidinones (DHPM) and organoselenium compounds. This study aimed to evaluate the cytotoxic and antiproliferative potential of DHPM-derived selenoesters (Se-DHPM), as well as their molecular mechanisms of action., Methods: Se-DHPM cytotoxicity was evaluated against cancer lines (HeLa, HepG2, and MCF-7) and normal cells (McCoy). HepG2 clonogenic assay allowed verifying antiproliferative effects. The propidium iodide/ orange acridine fluorescence readings showed the type of cell death induced after treatments (72h). Molecular simulations with B-DNA and 49H showed docked positions (AutoDock Vina) and trajectories/energies (GROMACS). In vitro molecular interactions used CT-DNA and 49H applying UV-Vis absorbance and fluorescence. Comet assay evaluated DNA fragmentation of HepG2 cells. Flow cytometry analysis verified HepG2 cell cycle effects. Levels of proteins (β-actin, p53, BAX, HIF-1α, γH2AX, PARP-1, cyclin A, CDK-2, and pRB) were quantified by immunoblotting., Results: Among Se-DHPM, 49H was selectively cytotoxic to HepG2 cells, reduced cell proliferation, and increased BAX (80%), and p53 (66%) causing apoptosis. Molecular assays revealed 49H inserted in the CT-DNA molecule causing the hypochromic effect. Docking simulations showed H-bonds and hydrophobic interactions, which kept the ligand partially inserted into the DNA minor groove. 49H increased the DNA damage (1.5 fold) and γH2AX level (153%). Besides, treatments reduced PARP-1 (60%) and reduced pRB phosphorylation (21%) as well as decreased cyclin A (46%) arresting cell cycle at the G1 phase., Conclusion: Together all data obtained confirmed the hypothesis of disruptive interactions between Se-DHPM and DNA, thereby highlighting its potential as a new anticancer drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Naringenin (NGEN), a natural flavonoid has growth inhibition and apoptosis-inducing activities in several cancer cells. However, the cytotoxicity mechanisms of NGEN in cell death of lung cancer cells have not been fully defined. In present study, treatment of human lung adenocarcinoma A549 cells with NGEN resulted in time- and dose-dependent decreases in cell viability. Moreover, NGEN significantly induced apoptosis evidenced by morphological changes, DAPI staining, TUNEL assay and sub-G1 population increase. In NGEN-treated cells, intensely upregulated Bax and down-regulated Bcl-2 proteins were detected and the Bax protein associated with the mitochondrial membrane was analyzed by subcellular fractionation. Knockdown of the Bax expression by the shRNA method dramatically protected A549 cells against NGEN-induced apoptosis. Treatment with the inhibitors of caspase-3, -8, or -9 significantly reduced NGEN-induced apoptotic deaths. Taken together, our results demonstrate that NGEN-induced apoptosis may occur via a Bax-activated mitochondrial pathway in lung adenocarcinoma A549 cells., (© 2020 The Authors. Environmental Toxicology published by Wiley Periodicals LLC.)

Cancer, as a group, represents the most important cause of death worldwide. Unfortunately, the available therapeutic approaches of cancer including surgery, chemotherapy, radiotherapy, and immunotherapy are unsatisfactory and represent a great challenge as many patients have cancer recurrence and severe side effects. Methotrexate (MTX) is a well-established (antineoplastic or cytotoxic) chemotherapy and immunosuppressant drug used to treat different types of cancer, but its usage requires high doses causing severe side effects. Therefore, we need a novel drug with high antitumor efficacy in addition to safety. The aim of this study was the evaluation of the antitumor efficacy of zinc oxide nanoparticle (ZnO-NPs) and sorafenib alone or in combination on solid Ehrlich carcinoma (SEC) in mice. Sixty adult female Swiss-albino mice were divided equally into 6 groups as follows: control, SEC, MTX, ZnO-NPs, sorafenib, and ZnO-NPs+sorafenib; all treatments continued for 4 weeks. ZnO-NPs were characterized by TEM, zeta potential, and SEM mapping. Data showed that ZnO-NPs synergized with sorafenib as a combination therapy to execute more effective and safer anticancer activity compared to monotherapy as showed by a significant reduction ( P < 0.001) in tumor weight, tumor cell viability, and cancer tissue glutathione amount as well as by significant increase ( P < 0.001) in tumor growth inhibition rate, DNA fragmentation, reactive oxygen species generation, the release of cytochrome c, and expression of the apoptotic gene caspase-3 in the tumor tissues with minimal changes in the liver, renal, and hematological parameters. Therefore, we suggest that ZnO-NPs might be a safe candidate in combination with sorafenib as a more potent anticancer. The safety of this combined treatment may allow its use in clinical trials., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Ahmed Nabil et al.)

Background: The anti-cancer effect of the halophyte Arthrocnemum indicum, a member of Arthrocnemum family of salt-tolerant plants, was evaluated against colorectal cancer cell, CaCo2. However, the anti-cancer effect of another halophyte Arthrocnemum machrostachyum was not investigated yet. Herein, the anticancer effect of A. machrostachyum methanolic extract (AME) was evaluated against Ehrlich solid tumor (EST) in mice and the potential mechanism of action was also studied., Methods: Male Swiss albino mice (n = 28) were randomly divided into 4 groups (n = 7/group). Group 1 (negative control group); group 2 (EST) injected intramuscularly by 0.2 mL Ehrlich ascitic carcinoma (2 × 10 6 cells); and groups 3 and 4 injected intratumorally with AME (180 and 360 mg/kg body weight, respectively) at D12 trice weekly for 2 weeks. Gene expression, protein expression, DNA damage, and TNFa level in tumors were determined by real-time PCR, western blot, comet assay, and Elisa, respectively., Results: Treatment with AME induced anti-tumor effects against EST as indicated by 1) notable reduction in tumor size; 2) elevation in tissue necrosis and apoptosis, as confirmed histologically; 3) increased DNA fragmentation; 4) decreased expression of the apoptotic genes (p53, Bax and caspase 3), and increased expression of the anti-apoptotic marker Bcl2; 5) significantly upregulated cell cycle regulatory genes Cdc2 and connexin26, and; 6) decreased TNFa levels in tumor tissues. Interestingly, a high dose of AME exhibited a more potent anti-tumor effect against EST., Conclusion: These findings indicate that AME has a potent antitumor effect against EST and could be used as an adjuvant to anticancer drugs to combat tumor, but after application of further confirmatory clinical trials.

In this work, a new tridentate ligand, its some novel zinc halide/pseudohalide complexes and their antimicrobial and cytotoxic effects of them are described. Characterization data of these compounds have been achieved via several physical and micro analytical techniques. As typical one, X-ray crystal structure analysis of zinc azide complex was run showing zinc center is penta-coordinated by three nitrogen atoms from Schiff base ligand and two terminal azide nitrogen atoms as a distorted square pyramidal geometry. Hirshfeld surfaces analysis clears the important role of interactions related to azide groups (NH⋯N and CH⋯N hydrogen bonds) in the stabilization of its supramolecular structure. According to data obtained from thermal analysis (TG/DTG/DTA), all complexes are decomposed at four or more thermal stages below 1000 °C. Moreover antimicrobial activities of the compounds were screened against some gram positive and gram negative bacteria. Furthermore anticancer activities of the complexes were studied against MDA-MB468 and k562 as two cancer cell lines. In final, three zinc complexes were also synthesized in nano scale by sonochemical method and one of them was utilized as the precursor for preparation of nanostructure ZnO confirmed by XRD pattern and SEM image., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Malignant melanoma is a high aggressive malignancy in humans and causes 60-80% of deaths from skin cancer. Defect in an intrinsic pathway of apoptosis via overexpression of Mcl-1 is responsible for malignant melanoma development and progression, and also for resistance to chemotherapeutic agents. MIM1 is a specific low molecular Mcl-1 protein inhibitor that is able to induce Mcl-1-dependent cancer cells death. Here, we examined the effect of MIM1 as well as MIM1 and dacarbazine (DTIC) mixture on cell viability, apoptosis, and cell cycle progression in COLO829 melanoma cells. Cell viability was performed by the WST-1 assay. Analysis of apoptosis as well as cell cycle progression was determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results demonstrated that the MIM1 exhibited high cytotoxicity against melanotic melanoma cells and induced mitochondrial membrane breakdown, GSH depletion, and DNA fragmentation. Additionally, MIM1 enhanced the proapoptotic effect of DTIC toward melanoma cells; furthermore, a mixture of these drugs caused cell cycle arrest at G2/M phase in COLO829 cells. Taken together, these data provide, for the first time, evidence that a low molecular weight Mcl-1 inhibitor-MIM1 may be a promising agent with antitumor and proapoptotic properties toward melanoma cells., (© 2019 Société Française de Pharmacologie et de Thérapeutique.)

Breast cancer is the most common cancer in females, and the leading cause of cancer-related mortality in the world. Among the available treatment options for cancer, chemotherapy is the therapy for treating a variety of cancer patients. However, the therapeutic efficacy of current agents is minimal and these drugs do not retard the progression of disease pathology. Lack of appropriate therapy may increase the prevalence of disease in world. Hence, more effective strategies and novel therapies must be pursued for altering the progression of the disease acting through different mechanisms. There is a continuing need for new and improved therapy. Hence, Vitamin B17 is suggested a therapeutic potential for treating breast cancer. This study is to evaluate the potential therapy of vitamin B17 (Vit B17, amygdalin) against Ehrlish solid tumors, bearing mice (EST) induced DNA damage, NF-Kb, TNFα and apoptosis. Sixty female mice were randomly divided into four groups: (I, control group; II, VitB17 group; III, EST group; IV, EST+VitB17 group). EST induced group had elevated in the levels of serum ALT, AST, ALP, creatinine, urea, potassium ions, cholesterol, triglycerides, cytokine IFNγ, NF-kb, DNA damage, tumor TNF-α, VEGF expressions and had an associated reduction in serum albumin, total proteins, sodium ions, tumor NF-kb, Bcl2 and survivin expressions. Treatment of EST with vitamin B17 (EST+VitB17) modulates the changes in liver and kidney functions, electrolytes, cytokines, NF-kb and apoptosis in mice bearing EST. Hence, these findings suggest that vitamin B17 can be a reliable and novel therapy for breast cancer, further validate the neoplastic activity of Vitamin B17 as a potential therapy for other types of cancer is needed.

Acute myeloid leukemia (AML) is a blood cancer characterized by the formation of faulty defective myelogenous cells with morphological heterogeneity and cytogenic aberrations leading to a loss of their function. In an attempt to find an effective and safe AML treatment, vitamin E derivatives, including tocopherols were considered as potential anti-tumor compounds. Recently, other isoforms of vitamin E, namely tocotrienols have been proposed as potential potent anti-cancerous agents, displaying promising therapeutic effects in different cancer types. In this study we evaluated the anti-cancerous effects of γ-tocotrienol, on AML cell lines in vitro . For this purpose, AML cell lines incubated with γ-tocotrienol were examined for their viability, cell cycle status, apoptotic cell death, DNA fragmentation, production of reactive oxygen species and expression of proapoptotic proteins. Our results showed that γ-tocotrienol exhibits time and dose-dependent anti-proliferative, pro-apoptotic and antioxidant effects on U937 and KG-1 cell lines, through the upregulation of proteins involved in the intrinsic apoptotic pathway., Competing Interests: The authors declare no conflicts of interest.

The present study investigated the effect of cladribine (CLA) and six of its derivatives containing a formamidine group at position 6 (CLA-FDM, CLA-FPAZ, CLA-FPIR, CLA-FPIP, CLA-FHEX, and CLA-FMOR) on acute promyelocytic, lymphoblastic, and acute monocytic leukemia cells. The role of ATR kinase in deoxycytidine kinase (dCK) activation in response to DNA damage was assessed. The presence of DNA lesions was assessed by measurement phosphorylation of H2AX and by using the alkaline comet assay with proteinase K post-treatment following assessment of the cell cycle. Apoptotic events such as alterations in intracellular calcium concentration, caspase-3/7 activity and increased sub-G1 cell population were measured. CLA derivatives were highly effective against leukemic cells, showing high cytotoxicity, causing DNA fragmentation, and inducing DNA-protein cross-links in leukemic cells. CLA-FMOR showed the highest efficacy. CLA derivatives increased the levels of intracellular calcium ions, caspase-3/7 and the percentage of sub-G1 apoptotic cells and blocked cells in the S phase of the cell cycle to a greater extent than free CLA. The selective ATR inhibitor VE-821 significantly suppressed the increase in dCK activity and decreased basal dCK activity. The present results suggested that ATR kinase controls dCK activity in response to synthetic CLA derivatives.

A neutral bidentate ligand 2-(3-methyl-5-phenyl pyrazol-1-yl) benzthiazole (L) has been synthesized by refluxing equimolar proportions of 2-hydrazino benzthiazole and benzoyl acetone in ethanol. The ligand acts in a NN donor fashion and forms stable mononuclear, MoOX 3 L [L = Ligand, X = Cl (1), Br (2)] and binuclear Mo 2 O 4 X 2 L 2 [L = Ligand, X = Cl (3), Br (4)] complexes with molybdenum(V). The ligand and complexes are thoroughly characterized by elemental analyses, IR, UV-Vis spectroscopy, EPR study, magnetic susceptibility, thermogravimetry and cyclic voltammetry. Magnetic moment measurements reveal that the mononuclear complexes are paramagnetic while the binuclear complexes are diamagnetic in nature. EPR studies also confirm the presence of a mononuclear Mo(V) moiety in the complexes. Relevant Density Functional Theory (DFT) calculations have been carried out to determine the structures of the synthesized compounds. The binding mode and mechanism of interaction of the synthesized compounds with bovine serum albumin (BSA) were studied by concentration dependent absorption and fluorescence titration experiments. The ligand and complexes 1-4 are screened for their potential in vitro anticancer activities against three different human cancer cell lines, namely, cervix adenocarcinoma epithelial cells (HeLa), renal carcinoma cells (SK-RC-45) and breast adenocarcinoma cells (MCF-7). The oxomolybdenum(V) complexes are found to exhibit higher anticancer potency towards the cancer cells than the free ligand. Also, structure activity relationship (SAR) studies of this new series of oxomolybdenum(V) complexes indicate that the anticancer activity is to some extent dependent on the electronic effects of the halogen atom coordinated to the molybdenum centre., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Sunitinib is cardiotoxic, but the mechanisms are not entirely clear. We aimed to enlarge our knowledge about the role of mitochondria in cardiac toxicity of sunitinib in vitro and in vivo. For this reason, we studied the toxicity of sunitinib on cardiac H9c2 cells exposed for 24 h, permeabilized rat cardiac fibers exposed for 15 min and in mice treated orally with sunitinib for 2 weeks (7.5 mg/kg/day). In H9c2 cells exposed for 24 h, sunitinib was more cytotoxic under galactose (favoring mitochondrial metabolism) compared to glucose conditions (favoring glycolysis). Sunitinib dissipated the mitochondrial membrane potential starting at 10 μM under glucose and at 5 μM under galactose conditions. Sunitinib reduced activities of mitochondrial enzyme complexes of the electron transport chain (ETC), increased mitochondrial ROS accumulation and decreased the cellular GSH pool. Electron microscopy revealed swollen mitochondria with loss of cristae. Accordingly, sunitinib caused caspase 3 activation and DNA fragmentation in H9c2 cells. Co-exposure with mito-TEMPO (mitochondrial-specific ROS scavenger) for 24 h prevented ATP and GSH depletion, as well as the increases in H 2 O 2 and caspase 3/7 activity observed with sunitinib. In mice, treatment with sunitinib for two weeks increased plasma concentrations of troponin I and creatine kinase MB, indicating cardiomyocyte damage. The activity of enzyme complexes of the ETCwas decreased, mitochondrial ROS were increased and cleavage of caspase 3 was increased, suggesting cardiomyocyte apoptosis. In conclusion, mitochondrial damage with ROS accumulation appears to be an important mechanism of cardiotoxicity associated with sunitinib, eventually leading to apoptotic cell death., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We report on chemistry and cytotoxic studies of four new ruthenium (II) complexes containing uracil derivatives. All compounds are neutral, presenting the formula [Ru(PPh 3 ) 2 (2TU) 2 ] (1), [Ru(PPh 3 ) 2 (6m2TU) 2 ] (2), [Ru(dppb)(2TU) 2 ] (3) and [Ru(dppb)(6m2TU) 2 ] (4), where PPh 3  = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane, 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil. They were characterized using NMR, UV-vis and IR spectroscopies, microanalytical analysis and mass spectrometry. Furthermore, the crystal structures of 1-4 were determined by single-crystal X-ray diffraction. The coordination of 2-thiouracil derivatives with ruthenium increases regions able to carry out hydrogen bonds with the biological targets, such as DNA. We evaluated the interaction of the complexes with DNA by UV/Vis spectrophotometric titration, and as a result, the values of DNA-binding constants are in the range of 0.8-1.8 × 10 4  M -1 . Moreover, the interaction of the complexes with BSA was investigated. In vitro, activities against B16-F10 (mouse melanoma), HepG2 (human hepatocellular carcinoma), HL-60 (human promyelocytic leukemia) and K562 (human chronic myelocytic leukemia) and non-tumor cells: PBMC (human peripheral blood mononuclear cells activated with concanavalin A - human lymphoblast) were carried out. Cytotoxicity assays revealed that complexes (2) and (4) present biological activity against tumor cells comparable with oxaliplatin, the reference platinum drug, revealing that they are promising molecules for developing new antitumor compounds., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Novel thiourea (5a, 5b) and thiazolidinone derivatives (6a, 6b) were synthesized by hybridizing molecules starting from the compound 6-(4-phenylpiperazin-1-yl)pyridin-3-amine (4) which is known to show anticancer activity. The synthesis of the leading compound was carried out by using 1-(5-nitropyridin-2-yl)-4-phenylpiperazine (3) which was obtained by a novel method of the reaction of 2-chloro-5-nitropyridine (1) and N-phenylpiperazine (2). The structures of the compounds were confirmed using FTIR, 1 H NMR, 13 C NMR, HRMS spectroscopic methods and elemental analysis. The organic molecules were tested for their anticancer activities against prostate cancer (PC) cell lines: DU 145, PC-3 and LNCaP. As the compound 5a exerted the highest cytotoxic activity, IC 50 concentrations of compound 5a were further investigated in terms of morphology, colony-forming ability, RNA expression, fragmented DNA and cell cycle distributions of PC cell lines. Overall data revealed that compound 5a treatment induces apoptosis and DNA fragmentation in PC cell lines and inhibits cell cycle progression resulting in the accumulation of cells in either the G1 or the S phases., (© 2019 John Wiley & Sons A/S.)

We report the design, synthesis and biological studies on a group of mixed ligand Fe(III) complexes as anti-cancer drug candidates, namely their interaction with DNA, cytotoxicity and mechanism(s) of action. The aim is to obtain stable, efficient and selective Fe-complexes to be used as anti-cancer agents with less damaging side effects than previously reported compounds. Five ternary Fe(III) complexes bearing a tripodal aminophenolate ligand L 2- , H 2 L = N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-N-(2-pyridylmethyl)amine, and different aromatic bases NN = 2,2'-bipyridine [Fe(L)(bipy)]PF 6 (1), 1,10-phenanthroline [Fe(L)(phen)]PF 6 (2), or a phenanthroline derivative co-ligand: [Fe(L)(amphen)]NO 3 (3), [Fe(L)(amphen)]PF 6 (3a), [Fe(L)(Clphen)]PF 6 (4), [Fe(L)(epoxyphen)]PF 6 (5) (where amphen = 1,10-phenanthroline-5-amine, epoxyphen = 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, Clphen = 5-chloro-1,10-phenanthroline) and the [Fe(L)(EtOH)]NO 3 (6) complex are synthesized. The compounds are characterized in the solid state and in solution by elemental analysis, ESI-MS, magnetic susceptibility measurements and FTIR, UV-Vis, 1 H and 13 C NMR and fluorescence spectroscopies. [Fe(phen)Cl 3 ] and [Fe(amphen)Cl 3 ] were also prepared for comparison purposes. Spectroscopic binding studies indicate groove binding as the main interaction for most complexes with DNA, and for those containing amphen a B- to Z-DNA conformational change is proposed to occur. As determined via MTT analysis all compounds 1-6 are cytotoxic against a panel of three different cell lines (HeLa, H1299, MDA-MB-231). For selected compounds with promising cytotoxic activity, apoptosis was evaluated using cell and DNA morphology, TUNEL, Annexin V/7AAD staining and caspase3/7 activity. The compounds induce oxidative DNA damage on plasmid DNA and in cell culture as assessed by 8-oxo-Guanine and γH2AX staining. Comet assay confirmed the presence of genomic damage. There is also increased reactive oxygen species formation following drug treatment, which may be the relevant mechanism of action, thus differing from that normally assumed for cisplatin. The Fe(III)-complexes were also tested against strains of M. Tuberculosis (MTb), complex 2 depicting higher anti-MTb activity than several known second line drugs. Hence, these initial studies show prospective anti-cancer and anti-MTb activity granting promise for further studies., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Anticancer compounds from natural sources have drawn attention due to their structural diversity and relatively lesser side effects. Endophytic fungi are one such natural resource from, which plethoras of anticancerous compounds have been isolated., Purpose: The objective of the study was to isolate and characterize the bioactive metabolite from Chaetomium globosum that exhibits astonishing antiproliferative activity against cancerous cell lines., Methods: Flavipin was isolated by bioassay-guided fractionation and identified using FT-IR, EI-MS and NMR studies. MTT assay was used to determine the cytotoxicity. Fluorescent staining (AO/EB) and DNA fragmentation studies confirmed the occurrence of apoptosis. Real time PCR and Western blotting were used to analyze the expression of apoptosis related genes and its proteins, respectively., Results: Flavipin inhibited proliferation of A549, HT-29 and MCF-7 cancer cells in dose dependent manner with an IC 50 concentration of 9.89 µg/ml, 18 µg/ml and 54 µg/ml, respectively, whereas it was comparatively less sensitive (IC 50  = 78.89 µg/ml) against normal cell line (CCD-18Co). At IC 50 concentration cancerous cells exhibited cell shrinkage and fragmentation of DNA, which indicated that flavipin induced apoptotic cell death. In treated cells there is an up-regulation of p53 gene and its associated protein, whereas reciprocal expression was observed in BCL-2 gene and its protein. Furthermore, western blotting results also showed down-regulation of NFκB., Conclusion: This is the first report on the antiproliferative activity of flavipin isolated from endophytic C. globosum and also proposed that interaction of flavipin with NFкB could be a possible mechanism for this activity. Flavipin induced apoptosis at low concentrations in cancer cell lines (A549, HT-29) and exhibited itself as a potential anticancer agent., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Breast cancer is the most frequently diagnosed cancer among women worldwide. Here, recombinant human lactoferrin (rhLf) expressed in Pichia pastoris was tested for its potential cytotoxic activity on a panel of six human breast cancer cell lines. The rhLf cytotoxic effect was determined via a live-cell HTS imaging assay. Also, confocal microscopy and flow cytometry protocols were employed to investigate the rhLf mode of action. The rhLf revealed an effective CC 50 of 91.4 and 109.46 µg/ml on non-metastatic and metastatic MDA-MB-231 cells, with favorable selective cytotoxicity index values, 11.68 and 13.99, respectively. Moreover, rhLf displayed satisfactory SCI values on four additional cell lines, MDA-MB-468, HCC70, MCF-7 and T-47D (1.55-3.34). Also, rhLf provoked plasma membrane blebbing, chromatin condensation and cell shrinkage in MDA-MB-231 cells, being all three apoptosis-related morphological changes. Also, rhLf was able to shrink the microfilaments, forming a punctuated cytoplasmic pattern in both the MDA-MB-231 and Hs-27 cells, as visualized in confocal photomicrographs. Moreover, performing flow cytometric analysis, rhLf provoked significant phosphatidylserine externalization, cell cycle arrest in the S phase and apoptosis-induced DNA fragmentation in MDA-MB-231 cells. Hence, rhLf possesses selective cytotoxicity on breast cancer cells. Also, rhLf caused apoptosis-associated morphologic changes, disruption of F-actin cytoskeleton organization, phosphatidylserine externalization, DNA fragmentation, and arrest of the cell cycle progression on triple-negative breast cancer MDA-MB-231 cells. Overall results suggest that rhLf is using the apoptosis pathway as its mechanism to inflict cell death. Findings warranty further evaluation of rhLf as a potential anti-breast cancer drug option.

Leukemia is a type of blood cancer where abnormal and immature leucocytes are produced in the bone marrow. Methadone hydrochloride is a man-made drug that is commonly used in the maintenance treatment for drug addiction. The objective of this research was to determine the cytotoxic activity and apoptotic effects of methadone hydrochloride treatment towards two leukemia cell lines which are CCRF-CEM and HL-60. CCRF-CEM and HL-60 cells were treated with methadone hydrochloride for 24 and 48 hours to determine the cytotoxic activity. IC 50 at 24 hours obtained for CCRF-CEM was 121.6μmol/L while IC 50 for HL-60 cells was 97.18μmol/L. Result obtained from DNA fragmentation assay showed no characteristic DNA ladder pattern in CCRF-CEM leukemia cells treated with methadone hydrochloride. Characteristics DNA ladder pattern was observed in methadone hydrochloride treated HL-60 cells. Formation of comets was seen in methadone hydrochloride treated CCRF-CEM and HL-60 cells with varying degree of DNA damage. The comets formed by methadone hydrochloride treated HL-60 cells were more prominent as compared to methadone-treated CCRF-CEM cells. The expression of apoptotic-related proteins in methadone-treated CCRF-CEM and HL-60 cells were checked by incubating the cell lysate with Raybio® Human Apoptosis Antibody Array. Significant alterations in expression level of apoptosis-related proteins in methadone hydrochloride treated CCRF-CEM cells were found involving upregulation of caspase-8 expression and downregulation of survivin expression. Methadone hydrochloride induced apoptosis in HL-60 cells involved upregulation of Bid and caspase-8 expression and downregulation of Bcl-2, p21 and survivin expression.

Telomere length determines the replicative capacity of mammalian cells. Successive telomere reduction to a critically short length can lead to cellular senescence that irreversibly prevents cells from further cell division. A series of Cu complexes has been designed as selective artificial nucleases that degrade G-quadruplex telomeric DNA and exhibit selective DNA binding affinity and cleavage reactivity toward G-quadruplex telomeric DNA over duplex DNA. In contrast to protein-based nucleases that usually lack membrane permeability, significant cellular uptake and nuclear localization of these Cu complexes was observed. Rapid telomere reduction of cancer cells was also observed after only 1 day incubation, while the absence of DNA fragmentation indicates a low level of nonselective DNA cleavage. Robust telomere reduction by the designed Cu complexes is an S-phase-specific event that is associated with increased formation of the G-quadruplex structure during DNA replication.

Though the current therapies are effective at clearing an early stage prostate cancer, they often fail to treat late-stage metastatic disease. We aimed to investigate the molecular mechanisms underlying the anticancer effects of a natural triterpenoid, ganoderic acid DM (GA-DM), on two human prostate cancer cell lines: the androgen-independent prostate carcinoma (PC-3), and androgen-sensitive prostate adenocarcinoma (LNCaP). Cell viability assay showed that GA-DM was relatively more toxic to LNCaP cells than to PC-3 cells (IC 50 s ranged 45-55 µM for PC-3, and 20-25 µM for LNCaP), which may have occurred due to differential expression of p53. Hoechst DNA staining confirmed detectable nuclear fragmentation in both cell lines irrespective of the p53 status. GA-DM treatment decreased Bcl-2 proteins while it upregulated apoptotic Bax and autophagic Beclin-1, Atg5, and LC-3 molecules, and caused an induction of both early and late events of apoptotic cell death. Biochemical analyses of GA-DM-treated prostate cancer cells demonstrated that caspase-3 cleavage was notable in GA-DM-treated PC-3 cells. Interestingly, GA-DM treatment altered cell cycle progression in the S phase with a significant growth arrest in the G2 checkpoint and enhanced CD4 + T cell recognition of prostate tumor cells. Mechanistic study of GA-DM-treated prostate cancer cells further demonstrated that calpain activation and endoplasmic reticulum stress contributed to cell death. These findings suggest that GA-DM is a candidate for future drug design for prostate cancer as it activates multiple pathways of cell death and immune recognition., (© 2018 Wiley Periodicals, Inc.)

Novel fused chromenes ( 4 , 7 ⁻ 11 ) and pyrimidines ( 12 ⁻ 16 ) were designed, synthesized, and evaluated for their mammary gland breast cancer (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2) activities. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR, and mass spectroscopy. The preliminary results of the bioassay disclosed that some of the target compounds were proven to have a significant antiproliferative effect against the three cell lines, as compared to Doxorubicin, Vinblastine, and Colchicine, used as reference drugs. Particularly, compounds 7 and 14 exerted promising anticancer activity towards all cell lines and were chosen for further studies, such as cell cycle analysis, cell apoptosis, caspase 3/7 activity, DNA fragmentation, cell invasion, and migration. We found that these potent cytotoxic compounds induced cell cycle arrest at the S and G2/M phases, prompting apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. The structure-activity relationship (SAR) survey highlights that the antitumor activity of the desired compounds was affected by the hydrophobic or hydrophilic nature of the substituent at different positions.

Approximately 15% of globally diagnosed breast cancers are designated as triple negative breast cancer (TNBC). In this study, we investigated the effect of the natural compound, Bis(2- ethyl hexyl) 1H-pyrrole-3,4-dicarboxylate (TCCP), purified from Tinospora cordifolia on MDA-MB-231, a TNBC cell line. The pro-apoptotic nature of TCCP on MDA-MB-231 was determined by assessing various apoptotic markers. ROS generation, intracellular calcium, mitochondrial membrane potential (ΔΨm), MPTP, cardiolipin peroxidation and caspase activity were determined fluorometrically. BAX, BCL-2, cytochrome c, caspases, and p53 protein expressions were determined by immunoblotting. Further, the effect of TCCP on DNA and cell death was determined by DNA fragmentation assay, annexin-V staining, and cell cycle analysis. TCCP treatment caused endogenous ROS generation, increase in intracellular calcium and phosphorylation of p53 in a concentration-dependent manner, which was reverted upon pre-treatment with pifithrin-μ. This led to the downstream altered expression of Bcl-2 and Bax proteins, mitochondrial membrane depolarization, MPTP, and cardiolipin peroxidation. TCCP induced cytochrome c release into the cytosol, caspase activation, ultimately resulting in DNA fragmentation. Further, induction of apoptosis and morphological alterations were evident from the phosphatidylserine externalization and increase in sub G 1 population. The in vivo Ehrlich ascites tumor (EAT) mouse study revealed the effectiveness of TCCP in reducing the tumor burden and resulted in a ~2 fold increase in mice survival with minimal hepato-renal toxicity. Overall, TCCP was shown to be efficient in inducing ROS and mitochondrial-mediated apoptosis by restoring p53 activity in MDA-MB-231 cells and also induced EAT cell death in vivo thereby inhibiting tumor proliferation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Fucoidan from brown alga Fucus evanescens and its product of enzymatic hydrolysis have precisely established structure and possess significant biological activities. The aim of present study was to determine radiosensitizing activity of fucoidan from brown alga F. evanescens and its derivative in human melanoma, breast adenocarcinoma, and colorectal carcinoma cell lines and elucidate mechanism of their action. The fucoidan from F. evanescens and its derivative had a comparable radiosensitizing activity and increased the inhibiting effect of X-ray radiation on proliferation and colony formation of human cancer cells, with significant inhibition of melanoma cells. The molecular mechanism of this action was associated with the induction of apoptosis by activating the initiator and effector caspases, suppressing the expression of the anti-apoptotic protein, and enhancing the fragmentation of DNA. The obtained data confirm the prospects of using fucoidan's derivative in combination with radiation therapy for the improvement of the schemes of cancer therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In this study, two DNA-targeting agents, cisplatin and chlorambucil, were combined in a Pt(IV) prodrug, 1 , which was thoroughly characterized by means of spectroscopic and spectrometric techniques. Tested towards a panel of various human tumor cell lines, this compound showed superior in vitro antitumor potential than the reference drug cisplatin. In addition, an antitumor potential of 1 was found, which is comparable to that of oxaliplatin in 3D spheroid models of colon cancer cells. Mechanistic studies performed in colon cancer cells confirmed that the conjugation of chlorambucil to Pt(IV) cisplatin-based scaffold tunes the lipophilicity of the prodrug, consequently improving the ability of the compound to accumulate into cancer cells and to target DNA, ultimately leading to apoptotic cancer cell death., Competing Interests: The authors declare no conflicts of interest.

The potent antimalarial drug pyronaridine (PND) was tested for its potential as an anticancer drug. After exposing cancerous (17) and non-cancerous (2) cells to PND for 72 hr, PND was found to exhibit consistent and potent cytotoxic activity at low micromolar (μM) concentrations that ranged from 1.6 μM to 9.4 μM. Moreover, PND exerted a significant selective cytotoxicity index (SCI) on five out of seven breast cancer cell lines tested, with favorable values of 2.5 to 4.4, as compared with the non-cancerous breast MCF-10A cell line. By using the same comparison, PND exhibited a significant SCI on three out of four leukemia/lymphoma cell lines with promising values of 3.3 to 3.5. One breast cancer and one leukemia cell line were tested further in order to determine the likely mode of action of PND. PND was found to consistently elicit phosphatidylserine externalization, mitochondrial depolarization, and DNA fragmentation, in both the triple negative MDA-MB-231 breast cancer and HL-60 leukemia cell lines. In addition, PND treatment altered cell cycle progression in both cancer cells. Subsequent DNA mobility-shift assays, UV-Visible spectroscopic titrations, and circular dichroism (CD) experiments revealed that PND intercalates with DNA. The findings presented in this study indicates that PND induces apoptosis and interfered with cell cycle progression of cancer cell lines and these results indicate that this drug has the potential as a repurposed drug for cancer therapy., Competing Interests: The authors have declared that no competing interests exist.

Background: Nasopharyngeal cancer (NPC) is one of the subtypes of head and neck cancers. It occurs rarely, and its prevalence depends mainly on geographical location. Modern-day research is focused on coupling nanotechnology and traditional medicine for combating cancers. Gold nanoparticles (AuNPs) were synthesized from Solanum xanthocarpum (Sx) leaf extract using reduction method., Methods: Characterization of the synthesized AuNPs was done by different techniques such as ultraviolet-visible spectrum absorption, X-ray diffraction, dynamic light scattering, Fourier transform infrared spectroscopy, transmission electron microscopy, and energy-dispersive X-ray analysis., Results: All the results showed the successful green synthesis of AuNPs from Sx, which induced apoptosis of C666-1 cell line (NPC cell line). There was a decline in both cell viability and colony formation in C666-1 cells upon treatment with Sx-AuNPs. The cell death was proved to be caused by autophagy and mitochondrial-dependent apoptotic pathway., Conclusion: Thus, due to their anticancer potential, these nanoparticles coupled with Sx can be used for in vivo applications and clinical research in future., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Many oncologists contend that patient undergoing chemotherapy must avoid antioxidant supplementation as it may interfere with the activity of the drug. In the present investigation, we have explored the influence of vitamin E, a well-known antioxidant on Camptothecin (CPT), a potent anti-cancer drug induced cell apoptosis and death of cervical cancer cells. HeLa cells were treated with different concentrations of CPT in presence and absence of 100 μm vitamin E. Treated cells were subjected to cytotoxicity studies, catalase assay, DNA fragmentation assay, clonogenic assay and flow cytometry based apoptosis detection. Also, Raman spectroscopy a label free technique which provides global information, in conjunction with multivariate tools like PCA, PCLDA and FDA, was investigated to explore vitamin E supplementation induced alterations. Our data based on biochemical and biophysical experimental analysis reveals that CPT causes DNA damage along with protein and lipid alteration culminating in cell death. Importantly, Raman spectroscopic analysis could uniquely differentiate the cluster of control and vitamin E control from CPT and CPT + Vit E treated cells. We conclusively prove that presence of vitamin E at 100 μM concentration shows promising antioxidant activity and displays no modulatory role on CPT induced effect, thereby causing no possible hindrance with the efficacy of the drug. Vitamin E may prove beneficial to alleviate chemotherapy associated side effects in patients during clinical settings which may open the doors further for subsequent exploration in in vivo preclinical studies., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Asteriscus graveolens ( A. graveolens ) plants contain among other metabolites, sesquiterpene lactone asteriscunolide isomers (AS). The crude extract and its fractions affected the viability of mouse BS-24-1 lymphoma cells (BS-24-1 cells) with an IC50 of 3 μg/mL. The fraction was cytotoxic to cancer cells but not to non-cancerous cells (human induced pluripotent stem cells); its activity was accompanied by a concentration- and time-dependent appearance of apoptosis as determined by DNA fragmentation and caspase-3 activity. High levels of Reactive Oxygen Species (ROS) were rapidly observed (less than 1 min) after addition of the fraction followed by an increase in caspase-3 activity three hours later. Comparison of RNA-seq transcriptome profiles from pre-and post-treatment of BS-24-1 cells with crude extract of A. graveolens yielded a list of 2293 genes whose expression was significantly affected. This gene set included genes encoding proteins involved in cell cycle arrest, protection against ROS, and activation of the tumor suppressor P53 pathway, supporting the biochemical findings on ROS species-dependent apoptosis induced by A. graveolens fraction. Interestingly, several of the pathways and genes affected by A. graveolens extract are expressed following treatment of human cancer cells with chemotherapy drugs. We suggest, that A. graveolens extracts maybe further developed into selective chemotherapy.

Novel half-sandwich ruthenium(II) complexes with aminomethyl(diphenyl)phosphine derived from fluoroloquinolones (RuPCp, RuPSf, RuPLm, RuPNr) were being investigated as alternatives to well-established metal-based chemotherapeutics. All compounds were characterized by elemental analysis, selected spectroscopic methods (i.e., absorption and fluorescence spectroscopies, ESI-MS, NMR, circular dichroizm), X-ray diffractometry, ICP-MS, and electrochemical techniques. To overcome low solubility, serious side effects connected with systemic cytotoxicity of ruthenium complexes, and acquiring the resistance of cancer cells, polymeric nanoformulations based on Pluronic P-123 micelles loaded with selected Ru(II) complexes were prepared and characterized. Resulting micelles (RuPCp&#95;M, RuPNr&#95;M) enabled efficient drug accumulation inside human lung adenocarcinoma (A549 tumor cell line), proved by confocal microscopy and ICP-MS analysis, allowing cytotoxic action. Studied complexes exhibited promising cytotoxicity in vitro with IC50 values significantly lower than the reference drug - cisplatin. The fluorescence spectroscopic data (CT-DNA titration, in vitro cell staining) together with analysis of DNA fragmentation (pBR322 plasmid, comet assay) provided clear evidence for the interaction with DNA inducing apoptotic cell death., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Thiazolidine-2,4-dione ring system is used as a pharmacophore to build various heterocyclic compounds aimed to interact with biological targets. In the present study, benzylidene-2,4-thiazolidinedione derivatives (compounds 2-5) were synthesized and screened against cancer cell lines and the genotoxicity and cytotoxicity of the most active compound (5) was investigated on normal and lung cancer cell line., Methods: For in vitro cytotoxic screening, the MTT assay was used for HL60 and K562 (leukemia), MCF-7 (breast adenocarcinoma), HT29 (colon adenocarcinoma), HEp-2 (cervix carcinoma) and NCI-H292 (lung carcinoma) tumor cell lines and Alamar-blue assay was used for non-tumor cells (PBMC, human peripheral blood mononuclear cells) were used. Cell morphology was visualized after Giemsa-May-Grunwald staining. DNA content, phosphatidylserine externalization and mitochondrial depolarization were measured by flow cytometry. Genotoxicity was assessed by Comet assay., Results: 5-(2-Bromo-5-methoxybenzylidene)-thiazolidine-2,4-dione (5) presented the most potent cytotoxicity, especially against NCI-H292 lung cancer cell line, with IC 50 value of 1.26μg/mL after 72h incubation. None of the compounds were cytotoxic to PBMC. After 48h incubation, externalization of phosphatidylserine, mitochondrial depolarization, internucleosomal DNA fragmentation and morphological alterations consistent with apoptosis were observed in NCI-H292 cells treated with compound (5). In addition, compound (5) also induced genotoxicity in NCI-H292 cells (2.8-fold increase in damage index compared to the negative control), but not in PBMC., Conclusion: Compound 5 presented selective cytotoxic and genotoxic activity against pulmonary carcinoma (NCI-H292 cells)., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Context: Microorganisms produce a variety of pigments and many pigments from bacteria were reported to have therapeutic potential including anticancer effects., Aim: The aim of this study is to evaluate the anticancer potential a yellow pigment from newly isolated Pseudomonas stutzeri JGI 52., Materials and Methods: Serial dilution method was adopted for the isolation of pigmented bacteria from soil sources. Pigment extraction was carried out from bacterial isolates using methanol as the solvent and the pigment was purified by thin layer chromatography. Through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the effect of the pigment fraction on cancer cells was analyzed. Apoptosis induction was evaluated by caspase-3 activity assay, DNA fragmentation analysis, cell morphology observation by AO-EB staining under the fluorescence microscope, and cellular cytotoxicity was analysed by lactate dehydrogenase (LDH) release assay. Characterization of the purified pigment was by high-performance liquid chromatography and electrospray ionization-mass spectrometry analysis., Statistical Analysis: Significance of the results was confirmed by performing one-way analysis of variance., Results: The pigment (PY3) from P. stutzeri inhibited the proliferation of HeLa, HepG2, and Jurkat cells and found to be less toxic to lymphocytes and CHO cells. PY3 exhibited apoptotic potential in the cancer cell lines, as evidenced by cleavage of DNA, LDH release, activation of caspase-3, and decrease in cell count. Results of mass spectra indicated the presence of "fucoxanthinol" which was earlier reported as an anticancer compound from seaweeds., Conclusions: This study revealed that the pigment PY3 from P. stutzeri has anticancer potential and induced cell death by apoptosis. It was found to have the carotenoid fucoxanthinol, responsible for its observed anticancer activity., Competing Interests: There are no conflicts of interest.

Diterpenes are compounds with complex structure and due to their unique carbon skeleton and interesting biological activities, have been the focus of continuous studies for the development of new anticancer agents. The plants of the genus Calceolaria (Scrophulariaceae family), native of South America have also yielded several new diterpenes with the scopadulane skeleton, such as thyrsiflorin A. The present study was undertaken to investigate the effect of the semisynthetic compound, demalonyl thyrsiflorin A on human melanoma cells. In A375 cells compound demalonyl thyrsiflorin A showed a clear dose-response relationship in the range of 6.25-50μM concentrations. In addition, we demonstrated an apoptotic response after treatment of cancer cells with this semisynthetic phenolic labdane diterpene at 6.25 and 12.5μM concentrations that probably involves the reduction of Hsp70 expression and reactive oxygen species production. Alternatively, the inhibition of the caspase cascade at higher concentrations, 25 and 50μM, correlated with additional reactive oxygen species increase, probably switched the mode of demalonyl thyrsiflorin A-induced cell death from apoptosis to necrosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In the current study, neuroprotective significance of ellagic acid (EA, a polyohenol) was explored by primarily studying its antioxidant and antiapoptotic potential against arsenic trioxide (As 2 O 3 )-induced toxicity in SH-SY5Y human neuroblastoma cell lines. The mitigatory effects of EA with particular reference to cell viability and cytotoxicity, the generation of reactive oxygen species, DNA damage, and mitochondrial dynamics were studied. Pretreatment of SH-SY5Y cells with EA (10 and 20 μM) for 60 min followed by exposure to 2 μM As 2 O 3 protected the SH-SY5Y cells against the harmful effects of the second. Also, EA pre-treated groups expressed improved viability, repaired DNA, reduced free radical generation, and maintained altered mitochondrial membrane potential than those exposed to As 2 O 3 alone. EA supplementation also inhibited As 2 O 3 -induced cytochrome c expression that is an important hallmark for determining mitochondrial dynamics. Thus, the current investigations are more convinced for EA as a promising candidate in modulating As 2 O 3 -induced mitochondria-mediated neuronal toxicity under in vitro system., (© 2018 Wiley Periodicals, Inc.)

Piperazine scaffolds or 2-azetidinone pharmacophores have been reported to show anti-cancer activities and apoptosis induction in different types of cancer cells. However, the mechanistic studies involve in induction of apoptosis addressing these two moieties for human cervical cancer cells remain uncertain. The present study emphasizes on the anti-proliferating properties and mechanism involved in induction of apoptosis for these structurally related azoles derivatives in HeLa cancer cells. 1-Phenylpiperazine clubbed with 2-azetidione derivatives (5a-5h) were synthesized, characterized using various spectroscopic techniques and evaluated for their in-vitro anti-proliferative activities and induction of apoptosis. Further, we also evaluated oxidative stress generated by these synthetic derivatives (5a-5h). Cell viability studies revealed that among all, the compound N-(3-chloro-2-(3-nitrophenyl)-4-oxoazetidin-1-yl)-2-(4-phenylpiperazin-1-yl) acetamide 5e remarkably inhibited the growth of HeLa cells in a concentration dependent manner having IC 50 value of 29.44 ± 1.46 µg/ml. Morphological changes, colonies suppression and inhibition of migration clearly showed the antineoplasicity in HeLa cells treated with 5e. Simultaneously, phosphatidylserine externalization, DNA fragmentation and cell-cycle arrest showed ongoing apoptosis in the HeLa cancer cells induced by compound 5e in concentration dependent manner. Additionally, generation of intracellular ROS along with the decrease in mitochondrial membrane potential supported that compound 5e caused oxidative stress resulting in apoptosis through mitochondria mediated pathway. Elevation in the level of cytochrome c and upregulation in expression of caspase-3 clearly indicated the involvement of the intrinsic pathway of programmed cell death. In brief; compound 5e could serve as a promising lead for the development of an effective antitumor agent.

Phellinus rimosus is a host-specific wood-rotting polypore that has been reported to be used by some tribes in Kerala, India, for curing mumps. We isolated a novel polysaccharide-protein complex from Ph. rimosus (PPC-Pr) that possessed significant antitumor activity. In this study, we examined the antiproliferative and apoptotic properties of PPC-Pr using human colon cancer cell line HCT116 as a model system. HCT116 cells were cultured in the presence of PPC-Pr at various concentrations (100-1000 μg/mL) for 24-96 hours, and the percentage of cell viability was evaluated using a 3-(4-5 dimethylthiozol-2-yl) 2-5-diphenyl-tetrazolium bromide (MTT) assay. The results showed that PPC-Pr inhibited cell viability in a time- and concentration-dependent manner. The antiproliferative effect of PPC-Pr was associated with apoptosis on HCT116 cells. We analyzed the morphological changes in the PPC-Pr-treated HCT116 cells using fluorescent DNA-microscopy with 4',6-diamidino-2-phenylindole dihydrochloride hydrate (DAPI) and acridine orange-ethidium bromide (AO/EB) staining. With DAPI staining, the cells treated with PPC-Pr showed nuclear shrinkage and chromatin condensation. Apoptotic morphology in cellular bodies as well as chromatin condensation were also confirmed by AO/EB double staining. Oligonucleosomal DNA fragmentation in PPC-Pr-treated cells was evaluated using a comet assay. The comet assay showed that control cells had few nuclei with fragmented chromatin, whereas apoptotic nuclei were more frequent in PPC-Pr-treated cells. These investigations indicate that the polysaccharide-protein complex from Ph. rimosus possesses antiproliferative activity and induces marked apoptosis in tumor cells in vitro.

A newly synthesised zerumbone pendant derivative (ZPD) was studied in human cervical cancer cells (HeLa) for its anticancer properties. ZPD significantly inhibited the growth of human cervical cancer cells with a GI 50 value of 6.35 ± 1.30 μM, which also induced morphological changes and apoptosis in a dose-dependent manner. Our data indicated that ZPD actively encouraged programmed cell death in HeLa cells which were confirmed by DNA fragmentation, phosphatidylserine translocation, increased activity of caspase 3, upregulation of the expression of the pro-apoptotic protein Bax, cleaved PARP, cleaved caspase 3 and downregulation of anti-apoptotic protein Bcl-2. ZPD also inhibited cell migration of HeLa cells, decreasing the production of MMP-2,-9 and downregulation of expression of MMPs and pro-angiogenic factor VEGF. Also it is nontoxic to normal rat cardiac myoblasts. Overall, ZPD is a promising candidate for inducing cytotoxicity, apoptosis and anti-migratory effects in cervical cancer cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We investigated the cytotoxic potential of the cardenolide glycoside acovenoside A against non-small-cell lung cancer cells. Lung cancer is the leading cause of cancer-related mortality and the second most common cancer diagnosed. Epidemiological studies revealed a direct correlation between the regular administration of cardiac glycosides and a lower incidence of various cancers. Acovenoside A, isolated from the pericarps of Acokanthera oppositifolia, potently inhibited proliferation and induced cytotoxicity in A549 non-small-cell lung cancer cells with an IC 50 of 68 ± 3 nM after 48 h of exposure. Compared to the antineoplastic agent doxorubicin, acovenoside A was more potent in inhibiting the viability of A549 cancer cells. Moreover, acovenoside A exhibited selectivity against cancer cells, being significantly less toxic to lung fibroblasts and nontoxic for peripheral blood mononuclear cells. Analysis of the cell cycle profile in acovenoside A-treated A549 cells revealed mitotic arrest, due to accumulation of the G 2 /M regulators cyclin B 1 and CDK1, and cytokinesis failure. Furthermore, acovenoside A affected the mitochondrial membrane integrity and induced production of radical oxygen species, which resulted in induction of canonical apoptosis, manifested by caspase 3 activation and DNA fragmentation. Based on our results, acovenoside A warrants further exploration as a potential anticancer lead.

Endometrial cancer (EC) is one of the most common types of gynecologic cancer of the female genital tract; it considered being the fourth leading death factor among other types of cancer. Therefore, developing new anti-cancer agents are crucial for cancer treatment. Based on the potential of Schiff based complexes for the induction of apoptosis, Schiff base compounds, and their metal complexes displayed excellent anticancer properties. In this current study, antiproliferative activity of [L(BF 2 ) 2 ] as a novel binuclear boron-fluoride complex was examined to preliminary research in eight different cell lines, HELA, DU-145, PC3, DLD-1, ECC-1, PNT1-A, HT-29, and MCF-7, it was found to have a potent, suppressive effect on human endometrial adenocarcinoma cell line ECC-1. Based on this data, later investigated its apoptotic, cytotoxic, and genotoxic properties on human endometrial adenocarcinoma cell line ECC-1 in different concentrations. Apoptotic and cytotoxic tests such as single cell gel electrophoresis assay (comet assay), DNA fragmentation laddering, acridine orange test for DNA damage, and ELISA for apoptotic measurement was performed. We also gauged the oxidative status by evaluating total antioxidant status (TAS) and total oxidant status (TOS). Oxidative stress index (OSI) was calculated too. As a result [L(BF 2 ) 2 ] has been found to have a marvelous effect on ECC-1 cells, especially in damaging their DNA and cause a series of reactions lead to apoptosis. Taken together, it suggests that the [L(BF 2 ) 2 ] complex can induce the apoptotic pathway of endometrial cancer cells and is a possible candidate for future cancer treatment studies.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide. The limitations of cisplatin-based chemotherapy have prompted intense interest among scientists to search for alternative metal-based anticancer medicines. Gold(III) complexes have been among the most widely investigated since they showed higher cytotoxicity than cisplatin and promising in vitro and in vivo anticancer activities in CRC but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complexes [gold(III) porphyrin-adamantane chloride (SN1) and gold(III) porphyrin mono-acetate chloride (SN2)] with improved aqueous stability were synthesized. SN1 and SN2 reduced the survival of human CRC HT-29 and HCT-116 cell lines, caused cell cycle arrest in G 2 /M phase, and we observed downregulation of the expression of cyclin B1 and cyclin-dependent kinase 1 (Cdk1) along with up-regulation of the active form of p53, p21 and Bcl-2-associated X (Bax). Furthermore, SN1 and SN2 induced apoptosis by the intrinsic pathway, since they lead to the cleavage of caspase 9, caspase 3 and poly(ADP-ribose) polymerase (PARP), and up-regulating Bax. Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases (ERK) are important for cell survival and proliferation. SN1 and SN2 lead to decrease in the activity of Akt where the phosphorylated form decreased with time as well as they caused an important decrease in the phosphorylation of ERK and activity of NF-κB. Finally, SN1 and SN2 complexes affected p38/mitogen-activated protein kinase (MAPK) pathway then we recorded an increase in the cyclooxygenase-2 expression and its enzymatic product prostaglandin E 2 ., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study was conducted to investigate the anticancer effects and mechanism of Calophyllum inophyllum fruit extract against MCF-7 cells. C. inophyllum fruit extract was found to have markedly cytotoxic effect against MCF-7 cells in a dose-dependent manner with the IC 50 for 24 h of 23.59 µg/mL. Flow cytometry analysis revealed that C. inophyllum fruit extract mediated cell cycle at G 0 /G 1 and G 2 /M phases, and MCF-7 cells entered the early phase of apoptosis. The expression of anti-apoptotic proteins Bcl-2 was decreased whereas the expression of the pro-apoptotic protein Bax, cytochrome C and p53 were increased after treatment. C. inophyllum fruit extract led to apoptosis in MCF-7 cells via the mitochondrial pathway in a dose dependent manner. This is evidenced by the elevation of intracellular ROS, the loss of mitochondria membrane potential (Δψm), and activation of caspase-3. Meanwhile, dose-dependent genomic DNA fragmentation was observed after C. inophyllum fruits extract treatment by comet assay. This study shows that C. inophyllum fruits extract-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3. C. inophyllum fruit extract could be an excellent source of chemopreventive agent in the treatment of breast cancer and has potential to be explored as green anticancer agent.

Objectives: To examine if HIV nosode in 30c dilution (HIV 30c) has therapeutic potential against lung cancer cells (A549) as compared to WRL-68 normal cells and to elucidate its possible molecular mechanism of action on DNA replication and apoptosis., Methods: Effects of HIV 30c were thoroughly tested for its possible anticancer potential on A549 cells (lung cancer); WRL-68 normal liver cells served as control. Three doses, one at LD50 and two below LD-50, were used. Proliferation, migration and senescence assays were made and generation of reactive oxygen species (ROS) studied by routine techniques. The ability of HIV 30c to induce apoptosis in A549 cells and its possible signalling pathway were determined using immunoblots of relevant signal proteins and confocal microscopy, including studies on telomerase reverse transcriptase (TERT) and topoisomerase II (Top II) activities, intimately associated with cell division and DNA replication., Results: HIV 30c prevented cancer cell proliferation and migration, induced pre-mature senescence, enhanced pro-apoptotic signal proteins like p53, bax, cytochrome c, caspase-3 and inhibited anti-apoptotic signal proteins Bcl2, TERT and Top II, changed mitochondrial membrane potential and caused externalization of phosphatidyl serine. Thus, it induced apoptosis as also evidenced from increase in cells with distorted membrane morphology, nuclear condensation, DNA fragmentation, and ROS, typical of apoptosis in progress., Conclusion: HIV 30c nosode has therapeutic potential for inducing cytotoxic effects on A549 cells as manifested by changes in nuclear condensation, DNA fragmentation, ROS generation and MMP, and for its inhibitory action on cell proliferation, cell migration, expression of telomerase reverse transcriptase and Top II genes, and increasing expression of pro-apoptotic genes., (Copyright © 2017 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.)