Dalton's Lymphoma Research Articles

In vitro study of the antioxidant, antiproliferative, and anthelmintic properties of some medicinal plants of Kokrajhar district, India.

Alstonia scholaris, Cardiospermum halicacabum, Hydrocotyle sibthorpioides, and Hypericum japonicum are important folk medicinal plants used by tribal communities of Bodoland region of Assam to treat helminth infections. Because of their ethnomedicinal values, the present study was designed to investigate the antioxidant, antiproliferative, and anthelmintic activities of the plants. The antioxidant activity was measured by total antioxidant capacity, total phenolics (TPC), total flavonoid (TFC), FRAP, DPPH, ABTS, and TBARS assay. Antiproliferative and apoptosis-inducing activities of plants were conducted in Dalton's lymphoma (DL) cells. Cells were treated for 24h with different doses (25-200mg/mL) of plant extracts. Anthelmintic study was conducted by treating the Paramphistomum sp. at different doses of plant extracts. Phytochemical and antioxidant studies showed rich TPC, TFC, and free radical scavenging activity in H. japonicum and H. sibthorpioides. Both the antiproliferative and anthelmintic bioassays showed a dose-dependent efficacy in all plants. H. japonicum showed the strongest anthelmintic activity (LC50 0.21mg/mL) followed by H. sibthorpioides (5.36mg/mL), C. halicacabum (13.40mg/mL), and A. scholaris (18.40mg/mL). Evidently, H. sibthorpioides showed the strongest antiproliferative and apoptosis-inducing activities among all the plants. The study observed a positive correlation between the antioxidant properties and antiproliferative and anthelmintic activities of the plants. We, therefore, conclude that the phytocompounds present in the crude extracts along with antioxidant molecules may have combined effects contributing to the antiproliferative and anthelmintic activities of the plants.

Unconventional π-hole and Semi-coordination regium bonding interactions directed supramolecular assemblies in pyridinedicarboxylato bridged polymeric Cu(II) Compounds: Antiproliferative evaluation and theoretical studies

Two pyridinedicarboxylato bridged 1D coordination polymers of copper(II) viz.; {[Cu(2,5-PDC)(Hdmpz)2]·H2O}n (1) and {[Cu(2,3-PDC)]·10H2O}n (2) (where, Hdmpz = 3,5-dimethyl pyrazole, PDC = pyridinedicarboxylate) have been isolated and characterized using TGA, elemental analysis, spectroscopic (IR, electronic) and single crystal X-ray diffraction techniques. Crystal structure analysis of the compounds 1 and 2 reveals that unconventional CH⋯π(carbonyl) and intramolecular O⋯C π-hole interactions provide stability to the crystal structures, respectively. Such CH⋯π(carbonyl) and intramolecular O⋯C π-hole interactions are scarcely reported in the literature. Theoretical calculations have been performed to analyze the unconventional non-covalent interactions observed in the solid-state structures of 1 and 2 using NCI plot and QTAIM computational tools. We have also theoretically explored the semi-coordination (regium) Cu-Oaxial bonds present in the compound 2. The polymers have been further investigated for potential antiproliferative activities considering cell viability and apoptosis assays against Dalton’s lymphoma (DL) cancer cell lines and the results were compared with cisplatin (reference drug) in the same experimental conditions. The compounds significantly induce cytotoxicity in DL cells with nominal cytotoxicity in normal PBMC cells. The molecular doking simulation performed with the antiapoprotic protiens reveals strong binding affinities of the compounds with the active sites of the target proteins. To establish structure activity relationship (SAR), pharmacophore studies have been carried out to investigate the key pharmacophore features of the structures of the compounds responsible for biological activities.

Targeting PD-1 in CD8+ T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma.

We fabricated bilirubin-bovine serum albumin (BR-BSA) nanocomplexes as candidates for the delivery of 5-fluoro-2-deoxyuridine (5FUdr) against experimental murine lymphoma. BR was attached to 5FUdr via acid-labile ester bonds mimicking small-molecule drug conjugates. The construct was self-assembled with BSA through strong noncovalent interactions with high drug occupancy in the core and labeled with folic acid (FA) to target cancer cells. The BR-5FUdr-BSA-FA nanoconstruct exhibits excellent biocompatibility, prevents nephrotoxicity, and is tolerated by red blood cells and mononuclear cells. The construct also showed increased accumulation in lymph nodes and tumor cells. BR-5FUdr-BSA-FA caused prolonged growth inhibition and apoptosis, enhanced mitochondrial reactive oxygen species generation, and minimized the viability of parental and doxorubicin-resistant Dalton's lymphoma cells. Treatment of tumor-bearing mice with BR-5FUdr-BSA-FA significantly increased the life span of the animals, improved their histopathological parameters, and downregulated PD-1 expression, suggesting the potential of the construct for 5FUdr delivery to treat lymphoma.

Achyranthes aspera L. leaf extract induced anticancer effects on Dalton's Lymphoma via regulation of PKCα signaling pathway and mitochondrial apoptosis

Ethnopharmacological relevanceEpidemiological studies promote the inclusion of natural-products in diet due to their inhibitory effects on various types of cancer. Among them, Achyranthes aspera L. (Family Amaranthaceae) is a medicinal plant in Ayurvedic pharmacopeia, found in India, Southeast Asia, America, and Sub-Saharan Africa. It is endowed with anti-inflammatory, anti-oxidant, and anti-cancer activities. However, its potential effect on Non-Hodgkin lymphomas (NHLs), has not yet been clarified. Aim of the studyIn the present study, we aimed to investigate the effect of Achyranthes aspera L. leaf extracts on highly aggressive murine NHL called Dalton's Lymphoma (DL) in vitro and in vivo. Material and methodsGC-HRMS analysis was carried out for the identification of compounds present in A. aspera leaf extract. The cytotoxicity of various A. aspera leaf extracts was evaluated on DL cells by MTT assay. Chromatin condensation, nuclear fragmentation, and morphological changes were observed by microscopy technique. Flow cytometry was used to measure the changes in mitochondrial membrane potential (ΔΨm) and apoptosis. In addition, the expressions of apoptosis-related proteins were detected by western blotting. Meanwhile, the in vivo anti-tumor effect of leaf extract was tested in DL induced Balb/c mice. ResultGC-HRMS analysis of A. aspera methanolic leaf extract (AAML) revealed the presence of ten pharmacologically active compounds. The results showed that AAML suppressed cell proliferation, decreased mitochondrial membrane potential, changed the morphological structure, and induced apoptosis. Moreover, AAML could promote the release of cytochrome c by regulating Bcl-2 family proteins and then activated caspase-9/ -3 to triggered cell apoptosis. At the same time in DL cells treated with AAML, the protein kinase Cα (PKCα) pathway was inhibited in a concentration-dependent manner. Remarkably, in vivo, AAML mediated suppression of DL growth in Balb/c mice was accompanied by attenuation of the PKCα pathway and induction of apoptosis. Our result suggested that AAML promotes mitochondrial apoptotic cascade in DL cells by suppressing the PKCα signaling pathway. ConclusionThe study suggests that AAML could potently suppress DL progression by promoting apoptosis via mitochondrial-cascade and attenuation of the PKCα signaling pathway.

Pyrazole (1, 2-diazole) induce apoptosis in lymphoma cells by targeting BCL-2 and BCL-XL genes and mitigate murine solid tumour development by regulating cyclin-D1 and Ki-67 expression

Pyrazole or 1,2-Diazole is a five-membered heteroaromatic ring with two nitrogen atoms which is widely used in pharmacological research and organic synthesis. Several natural and synthetic pyrazole derivatives possess anti-cancer potential and some of them have underwent clinical trials. In this aspect, an investigation into the efficiency of the pyrazole nucleus to inhibit the growth and progression of various cancer cell lines/ experimental tumours would help in giving a better clarity to the anti-cancer behaviour of pyrazole containing drugs. This paper investigates the efficiency of pyrazole against Dalton's Lymphoma Ascites (DLA) cell line. Pyrazole inhibited the growth of DLA cells in vitro by committing them towards apoptosis. In vitro results were consistent in DLA induced murine solid tumour in vivo systems. Drug-treatment improved survival, reduced tumour loads, stabilized body weights and improved the haematological and serum biochemical parameters of DLA solid tumour bearing mice, thereby improving their overall survivability. Drug administration contained the aggravation of solid tumour by targeted downregulation of Cyclin-D1 and Ki-67. In addition, the mRNA expression levels of anti-apoptotic genes, BCL-2 and BCL-XL were downregulated in solid tumours, corroborating the in vitro results that pyrazole encourage apoptotic cell death in DLA cells. The new findings establish pyrazole as a potential anti-cancer drug candidate. The results must encourage future investigations into the efficacy of the drug against various cancer types.

Differential Effects of p-Coumaric Acid in relieving Doxorubicin induced Cardiotoxicity in Solid Tumour Bearing and Non-tumor Bearing Mice

The cardioprotective potential of p-coumaric acid (pCA) against Doxorubicin (Dox)-mediated cardiotoxicity in normal animals has been previously documented. The present study sought to examine the effect of pCA on the cardiotoxic and anti-tumor activity of Dox in non-tumor vs. Daltons Lymphoma Ascites (DLA) induced solid tumor model. Male Swiss Albino mice were pretreated and co-treated with pCA (100 mg/kg b.w.), after which Dox (16 mg/kg b.w. cumulative) was administered for a period of 28 days. Levels of serum cardiac diagnostic markers, lipid peroxidation products, and liver marker enzymes were significantly increased (P<0.05) in the Dox only treated groups. Partial restoration of the antioxidant system in the pCA pre/co-treated groups was observed. Cardiac damage was elevated in the Dox only tumor group; evident from changes in the heart/body weight ratio, haematological and biochemical analyses. Dox treated groups showed a significant reduction in tumor progression. pCA treatment did not appear to impede/enhance the efficacy of Dox-mediated anti-tumor activity in the tumor supergroup. This study leads us to conclude that pCA can be explored as a potent molecule to combat Dox-induced cardiotoxicity by the virtue of its proven antioxidant properties with no interference in the anti-tumor activity of Dox at the given dose.

Development of a PAMAM Dendrimer for Sustained Release of Temozolomide against Experimental Murine Lymphoma: Assessment of Therapeutic Efficacy.

Enhanced drug localization at the tumor sites with minimal toxicity was demonstrated using dendrimer-conjugated temozolomide for treating experimental lymphoma, developed as a solid tumor. Herein, we have constructed a polyamidoamine (PAMAM) dendrimer conjugated with temozolomide to enhance the stability of the active drug metabolites, derived from the prodrug temozolomide. Our results suggest that the active drug (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide) (MTIC) (derived from temozolomide) showed stable and sustained release from the dendrimer-temozolomide conjugate, suggesting the suitability of the construct for therapy. Besides growth inhibition and direct killing, the dendrimer-temozolomide construct induced extensive apoptosis not only in parental Dalton lymphoma tumor cells but also in the doxorubicin-resistant form of the tumor cells. Dendrimer-temozolomide conjugation significantly reduced the solid tumor growth and increased the lifespan with better prognosis, including improved histopathology of the treated mice, while untreated littermates developed extensive metastasis and succumbed to death.

Surface functionalization of ZnO nanoparticles with functionalized bovine serum albumin as a biocompatible photochemical and antimicrobial agent

The present study reports the surface functionalization of ZnO nanoparticles with functionalized bovine serum albumin (BSA) as a biocompatible system. Sol gel method was adopted for the synthesis of zinc oxide nanoparticles (ZnO NPs). BSA was functionalized with 2-oxo-2H-chromene-3-carboxylic acid (3-CCA) by the DCC (Dicyclohexyl carbodiimide) coupling method. The presence of hydroxyl functional groups in the biopolymer makes it easier to get coupled with carboxylic acid group of the dye. Finally, the ZnO NPs are incorporated into the biomacromolecular system, BSA, which was functionally modified. The various characterizations done for the surface functionalized ZnO NPs are ultraviolet (UV)/visible, Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), X-ray diffraction analysis (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The antimicrobial resistance of the surface functionalized ZnO NP product were also investigated. The present study also demonstrates the cytotoxicity of this system against Dalton's lymphoma ascites (DLA) cell lines in vitro.

Methyl Jasmonate Cytotoxicity and Chemosensitization of T Cell Lymphoma In Vitro Is Facilitated by HK 2, HIF-1α, and Hsp70: Implication of Altered Regulation of Cell Survival, pH Homeostasis, Mitochondrial Functions.

Methyl jasmonate (MJ) displays antineoplastic potential against numerous neoplastic cells. However, several mechanistic aspects of its antineoplastic action against malignancies of T cell origin remain elusive. The present investigation reports the novel targets of MJ and mechanistic pathways of MJ-mediated antineoplastic and chemosensitizing action against tumor cells derived from murine T-cell lymphoma, designated as Dalton’s lymphoma (DL). The present study demonstrates that MJ directly docks to HIF-1α, hexokinase 2, and Hsp70 at prominent binding sites. MJ exhibits tumoricidal action against tumor cells via induction of apoptosis and necrosis through multiple pathways, including declined mitochondrial membrane potential, enhanced expression of ROS, altered pH homeostasis, an elevated level of cytosolic cytochrome c, and modulated expression of crucial cell survival and metabolism regulatory molecules. Additionally, this study also reports the chemosensitizing ability of MJ against T cell lymphoma accompanied by a declined expression of MDR1. This study sheds new light by demonstrating the implication of novel molecular mechanisms underlying the antitumor action of MJ against T-cell lymphoma and hence has immense translational significance.

Tumor Decelerating and Chemo-Potentiating Action of Methyl Jasmonate on a T Cell Lymphoma In Vivo: Role of Altered Regulation of Metabolism, Cell Survival, Drug Resistance, and Intratumoral Blood Flow.

Methyl jasmonate (MJ), a natural oxylipin, possesses a broad spectrum of antineoplastic potential in vitro. However, its tumor growth impeding and chemo-potentiating action has not been adequately investigated in vivo. Using a murine thymus-derived tumor named Dalton’s Lymphoma (DL), in the present study, we examined if intra-tumoral administration of MJ can cause tumor growth impedance. We also explored the associated molecular mechanisms governing cell survival, carbohydrate & lipid metabolism, chemo-potentiation, and angiogenesis. MJ administration to tumor-transplanted mice caused deceleration of tumor growth accompanying prolonged survival of the tumor-bearing mice. MJ-dependent tumor growth retardation was associated with the declined blood supply in tumor milieu, cell cycle arrest, augmented induction of apoptosis and necrosis, deregulated glucose and lipid metabolism, enhanced membrane fragility of tumor cells, and altered cytokine repertoire in the tumor microenvironment. MJ administration modulated molecular network implicating Hsp70, Bcl-2, TERT, p53, Cyt c, BAX, GLUT-1, HK 2, LDH A, PDK-1, HIF-1α, ROS, MCT-1, FASN, ACSS2, SREBP1c, VEGF, cytokine repertoire, and MDR1, involved in the regulation of cell survival, carbohydrate and fatty acid metabolism, pH homeostasis, and drug resistance. Thus, the present study unveils novel molecular mechanisms of the tumor growth decelerating action of MJ. Besides, this preclinical study also establishes the adjunct therapeutic potential of MJ. Hence, the present investigation will help to design novel anti-cancer therapeutic regimens for the treatment of hematological malignancies.

Antiproliferative and apoptosis-inducing properties of selected medicinal plants of Assam, India

Background and Aim: Ethnomedicine is a common practice of disease treatment among tribal communities of India. The present study investigated the antiproliferative and apoptosis-inducing activities of seven medicinal plants traditionally used by the Bodo tribe of Assam. Materials and Methods: The phytochemical and antioxidant activities of plants were investigated following standard protocols. Antiproliferative and apoptosis-inducing activities were evaluated in Dalton's lymphoma (DL) cells. Plant extract-treated cells were stained with acridine orange/ethidium bromide solutions to see the antiproliferative and apoptosis-inducing properties of plants. Results: The study showed high phenolic and flavonoid contents in all the plants. Phlogacanthus tubiflorus displayed the strongest antioxidant activity. Plant extracts showed concentration-dependent antiproliferative activity. Hydrocotyle sibthorpioides showed the strongest antiproliferative and apoptosis-inducing activities. DL cells treated with plant extracts displayed apoptotic features. Furthermore, docking study revealed 2-methyl-5-(1-adamantyl) pentan the best binding affinity with anti-apoptotic proteins. Conclusion: The present study revealed potential antiproliferative and apoptosis-inducing properties in H. sibthorpioides. However, further study needs to be carried out to investigate bioactive compounds responsible for their pharmacological properties.

Synthesis, cytotoxic, anticancer and antimicrobial activities of some metal complexes of a novel tetradentate Schiff base ligand, (E)-3-((2-((E)-(1-(2-hydroxyphenyl)ethylidene)amino)ethyl)imino)-N-phenylbutanamide

A novel tetradentate Schiff base ligand, (E)-3-((2-((E)-(1-(2-hydroxyphenyl)ethylidene)amino)ethyl)imino)-N-phenylbutanamide (HEAc) and its VO(IV), Cr(III), Mn(II), Fe(III), Co(II), Ni(II) and Cu(II) complexes have been synthesized. Ligand, HEAc was characterized analytically and spectroscopically. Physico-chemical methods like elemental analysis, molar conductance, magnetic susceptibility measurement and IR- and UV–vis spectral measurements were employed for the characterization of the complexes. The cytotoxic activities of ligand and its Cr(III), Mn(II), Fe(III), Co(II), Ni(II) and Cu(II) complexes have been evaluated. In-vitro cytotoxicity studies on ligand and its metal complexes showed potential cytotoxicity against Dalton’s Lymphoma Ascites (DLA) cell lines. Antitumour activities of this Cu(II) complex was studied using Daltons Lymphoma Ascites cell-induced solid tumour model and Ehrlich's Ascites Carcinoma cell-induced ascites tumour model. Treatment with the Cu(II) complex at three different concentrations (15, 10 and 5 mg/kg body weight) subdued the solid tumour growth in experimental mice and increased the mean survival rate and the life span of Ascites tumour bearing mice in a concentration dependent manner. The copper complex showed highest antitumor activity and cytotoxicity with an IC50 value of 47 μg/ml. It was observed that all the metal complexes were more potent bactericides and fungicides than the free ligand, HEAc and copper complex showed high antimicrobial activity than the others.

4-Anilino Quinazoline Derivatives: Molecular Docking and Evaluation of In vitro Cytotoxic Activity

A novel scaffold of 4-anilino quinazoline derivatives was designed on the basis of known inhibitor of quinazoline based drugs. The designed derivatives were synthesized using optimized reaction condition. Their structures were confirmed by FT-IR, 1H-NMR, 13C-NMR and Mass spectral data. The structures of synthesized compounds were subjected to in silico molecular docking using AutoDock software against the target Poly (ADP-ribose) polymerase-1 (PARP-1) enzyme. The compounds were evaluated for their in vitro cytotoxic activity against Daltons Lymphocyte Ascites (DLA) Cell lines. Molecular docking study of the newly synthesized compounds showed good binding mode in the active site of PARP-1. The docking results were compared with the standard drug Doxorubicin. Doxorubicin showed binding energy of -8.94 kcal/mol and formed one hydrogen bond with Asn767 with a distance of 1.98 Å. Compound SMOQ2 showed the least binding energy, i.e., 11.87kcal/mol and formed one hydrogen bond with Arg 878 with a distance of 1.895.A° Compound DMUQ5 showed binding energy of -11.42 kcal/mol and produced two hydrogen bonds with Arg 878 and Asn 767. Among the synthesized compounds, compounds SMOQ2 and DMUQ5 showed significant binding affinity compared to the standard drug Doxorubicin. The in vitro cytotoxic evaluation indicated that compounds SMOQ2 and DMUQ5 showed significant cytotoxic activity against Daltons Lymphoma Ascites cell line.

Nimbolide induces cell death in T lymphoma cells: Implication of altered apoptosis and glucose metabolism.

Nimbolide is a tetranortriterpenoid derived from the leaves and flowers of Azadirachta indica (Neem). It exhibits anticancer activity against a variety of cancers by modulating various crucial features, including cell proliferation, apoptosis, and invasion and metastasis. More importantly, the cytotoxic effect of nimbolide has also been observed against T cell lymphoma, but the underlying mechanisms are still unexplored. So far, no study has been conducted to observe the effect of nimbolide on cancer cell metabolism. Therefore, the present investigation was designed to explore the molecular mechanisms of the antitumor potential of nimbolide against T cell lymphoma, a neoplastic disorder of thymic origin. In addition, we also unraveled the anti-glycolytic activity of nimbolide against T lymphoma cells with possible molecular mechanisms. Our results showed the cytotoxic action of nimbolide against three different cell lines of T cell lymphoma, namely Dalton's lymphoma, HuT-78, and J6. Nimbolide-induced apoptosis in T lymphoma cells by altering the level of reactive oxygen species, p53, Bcl2, Bax, and cytochrome c, with subsequent cleavage of caspase 3. Remarkably, nimbolide inhibited the expression of hypoxia-inducible factor-1α, glucose transporter 3, hexokinase II, and pyruvate dehydrogenase kinase 1, which led to the suppression of glycolysis with concomitant activation of oxidative phosphorylation. Hence, the results of the present investigation demonstrate that nimbolide exerts tumoricidal activity against T lymphoma cells via augmentation of apoptosis and reversal of altered cell metabolism. Thus, the present study provides a new insight for the therapeutic utilization of nimbolide against T cell lymphoma.

Sustained release of curcumin from fibrin matrix induces cancer cell death and immunomodulation

Despite the role of curcumin in controlling inflammation, angiogenesis, and cancer in human cells, its therapeutic use is limited. The reasons are quick metabolic breakdown, low aqueous solubility, and bioavailability. This study describes the advantages of clinical-grade curcumin-incorporated fibrin matrix either in lyophilized off-the-shelf wafer or injectable hydrogel forms, as a biodegradable local delivery system. To produce the curcumin-fibrin wafer, used clinical-grade fibrin sealant in a modified composition. To fabricate wafer, we premixed the curcumin with either fibrinogen or thrombin, before clotting into a hydrogel. Sustained release of active curcumin from fibrin wafer, suspended in culture medium at 37 °C lasted for seven days. Upon premixing albumin with thrombin and subsequently adding curcumin into the mixture improved the loading concentration and stability. Dose- and time-dependent apoptotic function of curcumin on cancer cell lines upon release from fibrin wafer, were demonstrated in vitro. In vivo immuno-modulation and a nontoxic response to curcumin released from fibrin into the peritoneal cavity of mice were established. The cytotoxic effect of released curcumin was demonstrated; showing both a preventive and therapeutic role against tumor growth. In vivo studies used Dalton's Lymphoma Ascites (DLA) mice model. Both implanted fibrin wafer and injected hydrogel can breakdown by a physiological process and get cleared by the fibrinolytic mechanism. The lyophilized fibrin wafer could function as a hemostat, adhere to surgical cancer tissues, and arrest bleeding. The potential of curcumin in preventing solid tumor metastasis may be explored upon the sustained delivery of the molecule from the fibrin wafer.

Energetically significant cooperative π-stacked ternary assemblies in Ni(II) phenanthroline compounds involving discrete water clusters: Anticancer activities and theoretical studies

Two new coordination compounds viz. [Ni(phen)2(NO3)](NO3)·4H2O (1) and [Ni(phen)2(H2O)Cl]Cl·4H2O (2) (phen = 1,10-phenanthroline) have been synthesized and characterized using elemental analysis, TGA, PXRD, electronic, FT-IR spectroscopy and single crystal X-ray diffraction techniques. Crystal structure analysis reveals the formation of discrete water and anion-water clusters that contribute to the layered assemblies of the compounds. Moreover, the enclathration of (H2O)4 cluster in the layered assembly of 2 also provides rigidity to the crystal structure. Unconventional anion-π interaction is also observed in compound 1 involving the π-system of the chelate ring of coordinated phen. Detailed structural investigation reveals the presence of biologically relevant cooperative π-stacked (π–π)1/(π–π)2/(π–π)1 ternary assemblies in both the compounds. Interestingly, DFT calculations reveal that (π-π)2 binding mode in 2 is energetically significant than in compound 1 which is further analyzed by NCI plot index computational tool. The compounds have been screened for anticancer activities considering cell cytotoxicity and apoptosis in Dalton's lymphoma (DL) malignant cancer cell line. The complexes significantly inhibit cell viability by inducing apoptotic cell death in cancer cell lines with negligible cytotoxicity in normal cells. DNA ladder assay results in the degradation of genomic DNA into small inter-nucleosomal fragments (damage DNA) which is a biochemical hallmark of DL cells undergoing apoptosis. Lactate dehydrogenase (LDH) leakage assay also reveals the release of the intracellular enzyme LDH from DL cells indicating the irreversible cell death involving cell membrane damage. The molecular docking simulations reveal that the compounds interact and accommodated well with the active site of anti-apoptotic BCL proteins. Structure activity relationship (SAR) analysis based on pharmacophore modelling reveal that the molecular features of the compounds play important roles in the biological activities.

Energetically significant anti-parallel π-stacking and unconventional anion-π interactions in phenanthroline based Ni(II) and Cu(II) coordination compounds: Antiproliferative evaluation and theoretical studies

Two new coordination compounds of Ni(II) and Cu(II), viz. [Ni(phen)2Cl(H2O)] 4-NO2bz·3H2O (1) and [Cu(phen)2Cl]Cl·5H2O (2) (phen = 1,10-phenanthroline, 4-NO2bz = 4-nitrobenzoate) have been synthesized and characterized by single crystal X-ray diffraction, elemental analysis, FT-IR, electronic spectroscopy, TGA and EPR. The detailed crystal structure analysis of the Werner Type Clathrate 1 reveals the self-assembled unconventional enclathration of 4-NO2bz moieties in supramolecular Ni(II) hosts. In addition to the conventional discrete (H2O)n clusters in the crystal structure of 2, the layered architecture involves enclathration of single guest water molecules in the Cu(II) supramolecular hosts. We have theoretically analysed the biologically relevant anti-parallel π-stacking interactions in compound 1 and two types of anion–π interactions involving coordinated and uncoordinated chloride ions in compound 2. MEP surface analysis and DFT calculations reveal that the anti-parallel π-stacking interaction in 1 is energetically significant and enhanced upon complexation of the ligands to the Ni(II) centre. Remarkably, studies also reveal that in addition to the conventional anion⋯π interaction involving the chloride anion in the lattice, the unusual Cl(chlorido)⋯π interaction observed in the crystal assembly of 2 is also energetically significant. The antiproliferative potential of the compounds 1 and 2 have been studied in Dalton’s Lymphoma (DL) malignant cancer cell lines considering MTT cell viability and apoptosis assays. The compounds 1 and 2 exhibited significant concentration dependent increase in cell cytotoxicity and apoptosis in DL cells with negligible cytotoxicity in normal (PBMC) cells.

Energetically significant nitrile⋯nitrile and unconventional C–H⋯π(nitrile) interactions in pyridine based Ni(II) and Zn(II) coordination compounds: Antiproliferative evaluation and theoretical studies

Two new coordination compounds viz. [Ni(2,6-PDC)(Hdmpz)(H2O)2]∙H2O (1) and [Zn(3-CNpy)2Cl2] (2) (2,6-PDC = 2,6-pyridinedicarboxylate, Hdmpz = 3,5-dimethylpyrazole, 3-CNpy = 3-cyanopyridine) have been synthesized and characterized using elemental analysis, thermogravimetric analysis, electronic, infrared spectroscopy and single crystal X-ray diffraction techniques. Crystal structure analyses reveal the presence of supramolecular assemblies involving interesting dimers with unconventional contacts in the compounds. DFT (Density Functional Theory) calculations on the supramolecular dimers in the crystal structure of 1 reveal that the sum of contributions of anion–π, π–π and other long range interactions due to the approximation of the bulk monomers is energetically significant. Molecular Electrostatic Potential (MEP) surface and Quantum Theory of Atoms in Molecules (QTAIM) analyses on the interesting supramolecular dimers of the crystal structures of 2 reveal the presence of unconventional anion⋯π contacts involving coordinated chlorido ligands and C–H⋯π(nitrile) interactions involving the π-system of the nitrile moiety of 3-cyanopyridine. Remarkably, Atoms in Molecules analysis also confirms the existence of energetically significant unconventional anti-parallel nitrile⋯nitrile interaction in the crystal structure of 2. Cell cytotoxicity of the compounds performed in Dalton's lymphoma (DL) malignant cancer cell line showed effective potency with negligible cytotoxicity in normal cells (~12%). It is interesting that compound 1has excellent cytotoxic potency with IC50 closer to cisplatin and can bind different biological targets with similar signalling pathways. Structure activity relationship (SAR) analyses of 1 and 2 based on pharmacophore modelling reveal that the molecular features associated with the structures of the compounds play important role in the biological activities.

Modulatory Effect of Rutin on the Antitumor Activity and Genotoxicity of Cisplatin in Tumor-Bearing Mice

Purpose: Cisplatin is a cancer chemotherapeutic drug that has been extensively used in the treatment of a variety of cancers. However, the full usage of cisplatin is limited due to its treatment associated development of multiple side effects in the host. In the present study, the modulatory effect of rutin, a type of flavonoid, on the cisplatin mediated antitumor activity and allied genotoxicity in ascites Dalton’s lymphoma (DL)-bearing mice were investigated. Methods: The antitumor activity was determined by calculating the percent increase in the life span of mice, cell viability and scanning electron microscopy (SEM) of DL cells. Further, the modulatory effect of rutin on the cisplatin-induced genotoxic effects in the same DL-bearing mice was assessed by the analysis of micronuclei, chromosomal aberration and sperm abnormality. Results: The combination treatment of mice with rutin and cisplatin showed a considerable increase in the life span of the DL-bearing mice depicting better antitumor efficacy. SEM of these DL cells showed severe membrane deformities in DL cells such as fusion of cell membrane, membrane blebbing, cell shrinkage, membrane folding and loss in microvilli from the tumor cell surface which may lead to cell death. Cisplatin alone treatment caused an increase in the frequency of chromosomal aberrations, micronuclei and sperms abnormality. However, the combination treatment of DL-bearing mice with rutin and cisplatin comparatively reduced these genotoxic effects. Conclusion: The overall findings suggest that rutin enhances the cisplatin-mediated antitumor activity and cytotoxicity against DL cells and at the same time diminishes the genotoxic effects induced by cisplatin in the DL-bearing mice.

Edible Sword Bean Extract Induces Apoptosis in Cancer Cells In Vitro and Inhibits Ascites and Solid Tumor Development In Vivo

Antitumor potential of edible sword bean (Canavalia gladiata (L.)) extract has been evaluated against Daltons lymphoma ascites (DLA) using in vitro and in vivo studies. Methanolic extraction was carried out and in vitro studies were performed against both DLA and A549, lung cancer cell lines. The results revealed that sword bean extract inhibited cell growth and induced apoptosis as evidenced by cytotoxic assay, Hoechst 33342 staining and acridine orange/ethidium bromide dual staining. In vivo studies performed on DLA induced solid as well as ascitic tumors models showed administration of sword bean extract (10 mg/kg B.wt.) could significantly inhibit ascitic and solid tumor development in mice. Therefore, our overall results revealed that C. gladiata treatment could significantly inhibit tumor development and induce apoptosis in tumor cells.