Apoptotic Mode Of Cell Death Research Articles

Betanin-encapsulated starch nanoparticles: synthesis and cytotoxic effect on colon cancer.

Colorectal cancer (CRC) is a common and life-threatening neoplastic disease that continues to pose a formidable challenge to global health. The present work was performed to evaluate the anticancer properties of betanin and betanin (BT) loaded starch nanoparticles (S-BT). The BT and S-BT were characterized by DLS, SEM, UV spectroscopy, XPS and FTIR. The cytotoxic effect was assessed by MTT and LDH assay. The apoptotic potential of BT and S-BT was assessed by DCFDA, Rh123, AO/EB and DAPI staining methods. Cell cycle arrest was depicted using flow cytometry. The antimetastatic potential of BT and S-BT was evaluated by wound healing assay. The S-BT showed a spherical morphology with a size of 175nm. The betanin contained SNPs were found to have strong encapsulation efficiency and favorable release profiles. Both BT and S-BT exhibited cytotoxicity in SW480 cells but S-BT displayed increased cytotoxicity when compared to BT alone. Loss of mitochondrial membrane potential, nuclear fragmentation, chromatin condensation and generation of ROS, all indicative of apoptotic mode of cell death, were revealed by fluorescence imaging. The cells were arrested in the G2M phase. Moreover, both BT and S-BT were able to inhibit the migratory potential of SW480 cells. Overall, our results indicated that both BT and S-BT were able to induce anticancer effects; and, S-BT was found to have increased therapeutic efficacy when compared to BT alone.

Deciphering the cytotoxic potential of acamprosate and acamprosate loaded mesoporous silica nanoparticles in hepatocellular carcinoma: an in vitro and in silico approach

Hepatocellular carcinoma (HCC) is a healthcare concern that causes most cancer-linked deaths around the world. This work was aimed at unraveling the anticancer potential of acamprosate and development of mesoporous silica nanoparticle (MSN) drug delivery system to increase the therapeutic efficacy of acamprosate. For this purpose, the MSNs were synthesized and encapsulated with acamprosate (MSN-Acamp). The MSN and MSN-Acamp were characterized by DLS, Zeta potential, UV spectroscopy, SEM, FTIR, XRD, DFT, and XPS. Biological effects were evaluated by MTT and lactate dehydrogenase assays. The apoptotic mode of cell death was evaluated by fluorescence imaging and DNA fragmentation assay. Cell cycle assessment and Annexin V-FITC/PI staining were performed to depict the phase of cell arrest and stage of apoptotic cells respectively. The acamprosate was found to exhibit cytotoxic effect and MSN-Acamp exhibited an increased cytotoxicity. Apoptotic mode of cell death was revealed by fluorescence imaging as nuclear fragmentation, production of reactive oxygen species (ROS), loss of membrane potential in mitochondria, and chromatin condensation/fragmentation were found. The docking results revealed that acamprosate had a considerable binding affinity with Bcl-2, Mcl-1, EGFR, and mTOR proteins. Overall, our results indicated that acamprosate and MSN-Acamp had a potent apoptotic effect and MSNs are propitious drug carriers to increase therapeutic effect in HCC.

Visible and Red Light-Triggered Anticancer Profile of a Ferrocene-Re(I)-Tricarbonyl Conjugate: Experimental and Theoretical Studies.

We have red-shifted the light absorbance property of a Re(I)-tricarbonyl complex via distant conjugation of a ferrocene moiety and developed a novel complex ReFctp, [Re(Fctp)(CO)3Cl], where Fctp = 4'-ferrocenyl-2,2':6',2″-terpyridine. ReFctp showed green to red light absorption ability and blue emission, indicating its potential for photodynamic therapy (PDT) application. The conjugation of ferrocene introduced ferrocene-based transitions, which lie at a higher wavelength within the PDT therapeutic window. The time-dependent density functional theory and excited state calculations revealed an efficient intersystem crossing for ReFctp, which is helpful for PDT. ReFctp elicited both PDT type I and type II pathways for reactive oxygen species (ROS) generation and facilitated NADH (1,4-dihydro-nicotinamide adenine dinucleotide) oxidation upon exposure to visible light. Importantly, ReFctp showed effective penetration through the layers of clinically relevant 3D multicellular tumor spheroids and localized primarily in mitochondria (Pearson's correlation coefficient, PCC = 0.65) of A549 cancer cells. ReFctp produced more than 20 times higher phototoxicity (IC50 ∼1.5 μM) by inducing ROS generation and altering mitochondrial membrane potential in A549 cancer cells than the nonferrocene analogue Retp, [Re(CO)3(tp)Cl], where tp = 2,2':6',2″-terpyridine. ReFctp induced apoptotic mode of cell death with a notable photocytotoxicity index (PI, PI = IC50dark/IC50light) and selectivity index (SI, SI = normal cell's IC50dark/cancer cell's IC50light) in the range of 25-33.

PTSA-induced synthesis, in silico and nano study of novel ethylquinolin-thiazolo-triazole in cervical cancer.

Aim: p-Toluenesulfonic acid-(PTSA) and grinding-induced novel synthesis of ethylquinolin-thiazolo-triazole derivatives was performed using green chemistry. Materials & methods: Development of a nanoconjugate drug-delivery system of ethylquinolin-thiazolo-triazole was carried out with D-α-tocopheryl polyethylene glycol succinate (TPGS) and the formulation was further characterized by transmission electron microscopy, atomic force microscopy, dynamic light scattering and in vitro drug release assay. The effect of 3a nanoparticles was assessed against a cervical cancer cell line (HeLa) through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect on apoptosis was determined. Results & discussion: The 3a nanoparticles triggered the apoptotic mode of cell death after increasing the intracellular reactive oxygen level by enhancing cellular uptake of micelles. Furthermore, in silico studies revealed higher absorption, distribution, metabolism, elimination and toxicity properties and bioavailability of the enzyme tyrosine protein kinase. Conclusion: The 3a nanoparticles enhanced the therapeutic potential and have higher potential for targeted drug delivery against cervical cancer.

Fabrication of etoposide-loaded folic-acid-clocked mesoporous nanoparticles: Investigation of lung cancer proliferation and induction of apoptosis and ferroptosis

Etoposide (EPT) offers significant benefits in the tumor therapy domain. EPT may cause ferroptosis in lung cancer cells; however, its limited bioavailability and low water solubility inhibit its potential applications. Therefore, we investigated the properties of EPT-loaded folic acid clocked with mesoporous silica nanoparticles (MSNs) (FA-MSN@EPT) that target lung tumor cells. We assessed the capacities of MSN@EPT and FA-MSN@EPT to induce ferroptosis in lung cancer cells by measuring ferroptosis-related ferritin (Fe2+), malondialdehyde, and glutathione levels. Enhanced ferroptosis, inhibition of A549 and H1299 cell proliferation, migration, invasion, and considerable improvements in the EPT bioavailability were noted when the fabricated MSN@EPT and FA-MSN@EPT were utilized. Furthermore, the apoptotic mode of cell death was investigated by acridine orange and ethidium bromide (AO-EB) and 4′,6-diamidino-2-phenylindole (DAPI) staining and flow cytometry using annexin V-FITC and propidium iodide staining. This opens new possibilities for the clinical treatment of various tumors and offers a possible therapeutic option for lung cancer.

Polydiacetylene/lipid-coated red-emissive silica nanorods for the sustained release and ameliorated anticancer efficacy of a Ru(arene) complex bearing piperlongumine natural product.

A suitable drug delivery strategy for metallodrugs is as significant as the strategies adopted for an efficient metallodrug design. In this study, piperlongumine, which is isolated from long pepper, is coordinated with a Ru(II)-p-cymene moiety to obtain an organoruthenated complex containing the natural product (Ru(pip)). The isolated complex shows higher cytotoxicity in MCF-7 breast cancer cells than in THP-1 leukemia and HepG2 liver cancer cells. The IC50 value of the complex in non-cancerous HEK-239 cells is also almost equal to that in MCF-7 cells. Next, with an aim to modulate the antiproliferative activity of Ru(pip) using a drug delivery strategy, the complex is loaded into mesoporous silica nanorods (MSNRs), which have a higher surface area than spherical silica nanoparticles. Furthermore, the outer surface of the loaded nanorods is covered with a polydiacetylene-lipid (PL) hybrid bilayer. Given the unique optical properties of polydiacetylene, the PL coating modifies non-fluorescent MSNRs into red-emissive particles (PL-Ru(pip)@MSNRs), which can be useful for diagnostic applications. The release profile studies reveal that the ene-yne conjugation in the PL coating ensures the sustained release of the complex from nanoparticles in both physiological and simulated cancer cell media. While Ru(pip) exhibits both necrotic and apoptotic modes of cell death, PL-Ru(pip)@MSNRs preferably induce the apoptotic mode of cell death in MCF-7 and THP-1 cells. Also, the nanoformulation exhibits a higher percentage of cell cycle arrest in the G0/G1 phase than Ru(pip), as measured by flow cytometry analysis. In contrast, the in vitro antioxidant potency of the complex is decreased after being loaded into PL-coated silica nanoparticles.

Cu(II) flavonoids as potential photochemotherapeutic agents.

Flavonoids, naturally derived polyphenolic compounds, have received significant attention due to their remarkable biochemical properties that offer substantial health benefits to humans. In this work, a series of six Cu(II) flavonoid complexes of the formulation [Cu(L1)(L2)](ClO4) where L1 is 3-hydroxy flavone (HF1, 1 and 4), 4-fluoro-3-hydroxy flavone (HF2, 2 and 5), and 2,6-difluoro-3-hydroxy flavone (HF3, 3 and 6); L2 is 1,10-phenanthroline (phen, 1-3) and 2-(anthracen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip, 4-6) were successfully synthesized, fully characterized and also evaluated for their in vitro photo-triggered cytotoxicity in cancer cells. The single-crystal X-ray diffraction structure of complex 2 shows square pyramidal geometry around the Cu(II) center. The complexes 1-6 showed quasi-reversible cyclic voltammetric responses for the Cu(II)/Cu(I) couple at ∼-0.230 V with a very large ΔEp value of ∼350-480 mV against the Ag/AgCl reference electrode in DMF-0.1 M tetrabutylammonium perchlorate (TBAP) at a scan rate of 50 mV s-1. The complexes were found to have considerable binding propensity for human serum albumin (HSA) and calf thymus DNA (ct-DNA). The complexes displayed remarkable dose-dependent photocytotoxicity in visible light (400-700 nm) in both A549 (human lung cancer) and MCF-7 (human breast cancer) cell lines while remaining significantly less toxic in darkness. They were found to be much less toxic to HPL1D (immortalized human peripheral lung epithelial) normal cells compared to A549 and MCF-7 cancer cells. Upon exposure to visible light, they generate reactive oxygen species, which are thought to be the main contributors to the death of cancer cells. In the presence of visible light, the complexes predominantly elicit an apoptotic mode of cell death. Complex 6 preferentially localizes in the mitochondria of A549 cells.

Hydrolytically Stable TiIV-Hydrazone-Based Metallodrugs: Protein Interaction and Anticancer Potential.

In this work, three titanium(IV) [TiIV(L1-3)2] (1-3) complexes have been reported using three different tridentate dibasic ONO donor hydrazone ligands, pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)-hydrazide (H2L1), furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)-hydrazide (H2L2), and thiophene-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)-hydrazide (H2L3) tethered with heterocyclic moieties. Elemental analysis, FT-IR, UV-vis, NMR, HR-ESI-MS, and single-crystal X-ray analysis have been used to characterize H2L1-3 and 1-3. In solid structures of 1-3, two ligand molecules with N2O4 donor sets give distorted octahedral geometries to the metal center. The aqueous stability of 1-3 was investigated and well correlated to their perceived pharmacological results. During the investigation, all three complexes were found to be hydrolytically stable in a 90% DMSO-d6/10% D2O (v/v) medium up to 48 h. Furthermore, the interaction of 1-3 with bovine serum albumin (BSA) was tested using fluorescence and absorption techniques. The complexes showed static quenching with a biomolecular quenching constant of Kq ∼ 1013 proposing a high affinity of complexes for BSA. Finally, the anticancer potential of 1-3 was tested against HeLa, A549, and NIH-3T3 cell lines. Among all, 1 with an IC50 value of 11.6 ± 1.1 μM against HeLa cells was found to be the most cytotoxic in the series. Furthermore, it has been found that the compounds induce an apoptotic mode of cell death, which is confirmed by the live cell confocal microscopy and flow cytometry techniques.

Combinatorial Implications of Nrf2 Inhibitors with FN3K Inhibitor: In vitro Breast Cancer Study.

Platinum derivatives are chemotherapeutic agents preferred for the treatment of cancers including breast cancer. Oxaliplatin is an anticancer drug that is in phase II studies to treat metastatic breast cancer. However, its usage is constrained by chemoresistance and dose-related side effects. The objective of this study is to examine the combinatorial efficacy of brusatol, an Nrf2 blocker, with oxaliplatin (a proven FN3K blocker in our study) in mitigating breast cancer growth in vitro. We performed cytotoxicity assays, combination index (CI) analysis, colony formation assays, apoptosis assays, and Western blotting. Results of our study described the chemosensitizing efficacy of brusatol in combination with lowdose oxaliplatin against breast cancer through synergistic effects in both BT-474 and T47D cells. A significant mitigation in the migration rate of these cancer cells was observed with the combination regimen, which is equivalent to the IC-50 dose of oxaliplatin (125 μM). Furthermore, ROS-mediated and apoptotic modes of cell death were observed with a combinatorial regimen. Colony formation of breast cancer cell lines was mitigated with a combinatorial regimen of bursatol and oxaliplatin than the individual treatment regimen. FN3K expression downregulated with oxaliplatin in T47D cells. The mitigation of FN3K protein expression with a combination regimen was not observed but the Nrf2 downstream antioxidant signaling proteins were significantly downregulated with a combination regimen similar to individual drug regimens. Our study concluded the combination efficacy of phytochemicals like brusatol in combination with low-dose oxaliplatin (FN3K blocker), which could enhance the chemosensitizing effect in breast cancer and minimize the overall dose requirement of oxaliplatin.

Gold nanoblackbodies-based multifunctional nanocomposite for multimodal cancer therapy

Multifunctional nanocomposites are of potential use to achieve complete tumor elimination and, thus, to avoid tumor recurrence. Herein, polydopamine (PDA)-based gold nanoblackbodies (AuNBs) loaded with indocyanine green (ICG) and Doxorubicin (DOX) termed as A-P-I-D nanocomposite were investigated for multimodal plasmonic photothermal-photodynamic-chemotherapy. Upon near-infrared (NIR) irradiation, A-P-I-D nanocomposite showed enhanced photothermal conversion efficiency of 69.2% compared to bare AuNBs (62.9%) due to the presence of ICG, along with ROS (1O2) generation as well as enhanced DOX release. On assessment of therapeutic effects on breast cancer (MCF-7) and melanoma (B16F10) cell lines, A-P-I-D nanocomposite showed significantly lower cell viabilities of 45.5% and 24% compared to 79.3% and 76.8% for AuNBs. Fluorescence images of stained cells revealed characteristic signs of apoptotic mode of cell death, with almost complete damage on A-P-I-D nanocomposite + NIR treated cells. Further, on evaluation of photothermal performance through breast tumor-tissue mimicking phantoms, A-P-I-D nanocomposite provided required thermal ablation temperatures within the tumor along with the potential for the elimination of residual cancerous cells through photodynamic therapy and chemotherapy. Overall, this study demonstrates that A-P-I-D nanocomposite + NIR provides better therapeutic outcome on cell lines and enhanced photothermal performance on breast tumor-tissue mimicking phantoms to be a promising agent for multimodal cancer therapy.

A study on the anticancer activity of imidazolyl benzamide derivative-IMUEB on a 549 lung cancer cell line.

Cancer is a deadly disease, which is due to the uncontrolled division of cells with abnormal or unusual characteristics. It is a consequence of lethal mutations occurring due to various chemical and physical carcinogens, affecting many cellular signalling pathways and leading to uncontrolled proliferation. In this study, we analyzed the effect of 4-(1H-imidazol-1-yl)-N-(2-(3-(4-methylbenzyl) ureido) ethyl)benzamide (IMUEB), an imidazole derivative, on A549 cells (lung cancer cells). The MTT and LDH assays were performed to measure the cytotoxicity of IMUEB against A549 cells. Apoptotic mode of cell death of A549 cells was determined by fluorescence imaging by using different stains. Flow cytometry was performed to detect the cell cycle arrest. Western blotting was performed to determine the levels of apoptotic protein. Wound healing assay was performed to find the effect of IMUEB on cell migration. In silico molecular docking of IMUEB was performed to predict its affinity towards apoptotic proteins and metastasis related enzymes. The MTT assay showed an increase in cytotoxicity with increasing concentrations of IMUEB. In addition, it was found that IMUEB arrests cell cycle at G1 phase as detected by flow cytometry analysis and induces apoptosis. The treatment with IMUEB drastically decreased the migratory potential of A549 cells as evaluated by migration and invasion assay. By Western blotting analysis, it was found that the concentration of caspase-3 was increased after the treatment with IMUEB. Altogether, our results indicate that IMUEB shows antitumor activity by inhibiting proliferation and inducing apoptosis in A549 cells.

Click synthesis of pyrrolidine-based 1,2,3-triazole derivatives as antifungal agents causing cell cycle arrest and apoptosis in Candida auris

The emergence of multidrug-resistant fungal pathogens such as Candida auris is one of the major reasons WHO has declared fungal infections as a public health threat. Multidrug resistance, high mortality rates, frequent misidentification, and involvement in hospital outbreaks of this fungus demand the development of novel therapeutic drugs. In this direction, we report the synthesis of novel pyrrolidine-based 1,2,3-triazole derivatives using Click Chemistry (CC) and evaluation of their antifungal susceptibility against C. auris following Clinical and Laboratory Standards Institute (CLSI) guidelines. The fungicidal activity of the most potent derivative (P6) was further quantitatively confirmed by the MUSE cell viability assay. For insight mechanisms, the effect of the most active derivative on cell cycle arrest was studied using MuseTM Cell Analyzer and apoptotic mode of cell death was determined by studying phosphatidylserine externalization and mitochondrial depolarization. In vitro susceptibility testing and viability assays showed that all the newly synthesized compounds have antifungal activity with P6 being the most potent derivative. Cell cycle analysis revealed that P6 arrested the cells in S-phase in a concentration dependent manner and the apoptotic mode of cell death was confirmed by the movement of cytochrome c from mitochondria to cytosol with membrane depolarization. The hemolytic assay confirmed the safe use of P6 for further in vivo studies.

Eco-Friendly Preparation of Silver Nanoparticles and Their Antiproliferative and Apoptosis-Inducing Ability against Lung Cancer.

In the present study, the anti-proliferative and apoptotic potential of Tabebuia roseo-alba in lung cancer was assessed. Silver nanoparticles (AgNPs) of T. roseo-alba were synthesized using an ethanolic extract and characterized by adopting various parameters. Herein, the eco-friendly, cost-effective, and green synthesis of AgNPs was evaluated using an ethanolic extract of T. roseo-alba. The as-synthesized AgNPs were then characterized using various characterization techniques, such as UV-visible spectroscopy (UV-vis), X-ray powder diffraction (XRD), dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The AgNPs are crystalline, spherical, and highly stable AgNPs of varying sizes in the range of 5-20 nm. The anticancer activity of the ethanolic extract of T. roseo-alba and its AgNPs was determined using an MTT assay. The results indicated that, although both samples showed prominent anti-proliferative activity on lung cancer cell lines, the AgNPs of T. roseo-alba were found to be more potent than the ethanolic extract. Further, apoptosis induction ability was evaluated by FITC Annexin V and PI staining, the results of which demonstrated the efficiency of the ethanolic extract of T. roseo-alba and its AgNPs in causing oxidative stress and subsequent cellular death. This was subsequently further confirmed by measuring the mitochondrial membrane potential after staining the cells with JC1. The apoptotic mode of cell death was further confirmed by DNA fragmentation and caspase assays using Western blot analysis.

Investigation on anticancer activity of new Ni(II) cuminaldehyde based benzhydrazone complexes

The research aims to find an efficacious anticancer agents of three new Ni(II) complexes containing cuminaldehyde based benzhydrazide ligands(L) with lesser side-effects. The complexes possessing the composition of [Ni(L)2] were characterized by analytical and spectral techniques(FT-IR, UV–vis, NMR, and HRMS). The square planar geometry of the complex 3 was authenticated by single-crystal X-ray diffraction and reveals the bidentate mode of coordination of the ligands in either side of the nickel (II) ion via imidolate oxygen and azomethine nitrogen resembling a butterfly. The cytotoxic efficiency of the complexes in inhibiting the growth of human cervical cancer cells (HeLa) and human colon carcinoma (HT-29) has been studied along with the cell viability assay against the non-cancerous fibroblast (L929) under in vitro condition by MTT assay. The results showed that all the three complexes displayed good cytotoxicity against the cancer cells with low IC50 values in the range 77.23 μM − 44.05 μM. In particular, complex 3 displayed excellent cytotoxicity against HT-29 cancer cells out of the three complexes with the IC50 value of 44.05 μM. This may be due to the electron releasing group (–OCH3) in the complex 3 which increases lipophilicity and enhances the permeability through the cell membrane. Further, the apoptotic mode of cell death in the cancer cells was assessed via AO–EB and Hoechst 33258 staining methods. In addition, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and flow cytometry methods were demonstrated to confirm the cell death in cancer cells through apoptosis.

Indole curcumin combats metastatic HBV-positive hepatocellular carcinoma by inhibiting cell proliferation, migration, and matrix metalloproteinase-9 activity.

Chemical modification of the natural products and molecules can lead us toward drugs with lesser off-target effects for chemotherapeutic use against cancers. In this study, we explored the effect of an indole analog of the molecule curcumin, for the first time against HBV-positive hepatocellular carcinoma (HCC) cells in vitro. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase assays were used to measure the cytotoxic effects of indole curcumin against Hep3B cells. The mode of cell death was established through acridine orange/ethidium bromide fluorescence staining, propidium iodide fluorescence staining, and the comet assay. The effect of the compound on cell migration behavior was studied through wound healing assay, whereas the effect on matrix metalloproteinase (MMP) activity was evaluated using gelatin zymography. In silico molecular docking was performed to predict the affinity of indole curcumin toward probable intracellular interacting partners. Indole curcumin had an antiproliferative effect on Hep3B cells, induced apoptotic mode of cell death, inhibited cell migration in time- and dose-dependent assays, and decreased MMP-9 activity levels. Molecular docking results suggest that the interaction of PI3K with indole curcumin may have led to downregulation of MMP-9 expression, thereby contributing to the overall reduction in MMP-9 activity. Our study establishes that indole curcumin is an effective cytotoxic and antimetastatic agent against hepatitis virus-B positive HCC cells. Hence, it can be a possible candidate for the treatment of hepatocarcinoma induced/promoted by the presence of chronic hepatitis B infection.

Cucurbitacin B, Purified and Characterized From the Rhizome of Corallocarpus epigaeus Exhibits Anti-Melanoma Potential.

The ethnomedicinal plant from the Cucurbitaceae family, Corallocarpus epigaeus, or its bioactive derivatives have been widely utilized in traditional medicine owing to their distinct applications against various human ailments and have lured the interest of ethnobotanists and biochemists. Here, we report for the first time, the anti-cancer potential of a bio-active fraction isolated from the dried rhizome of C. epigaeus, and the bioactive principle identified as cucurbitacin B (Cu-B). The purification processes involving the utilization of multiple organic extracts of C. epigaeus rhizome powder, yielded Cu-B from the Ethyl acetate Cytotoxic Fraction (ECF), obtained by the chromatographic separation of the ethyl acetate extract. Amongst the various cancer lines tested, melanoma cells exhibit maximal sensitivity towards the Cu-B-containing ECF fraction. Cu-B induces an apoptotic mode of cell death initiated intrinsically as well as extrinsically in A375 melanoma cells whilst remaining comparatively less toxic to normal skin fibroblasts. In vivo studies involving a NOD-SCID murine model of human melanoma demonstrate the ability of Cu-B to attenuate tumor growth, while being pharmacologically safe in vivo, as assessed in Swiss albino mice. Furthermore, Cu-B inhibits MEK 1/2 as well as the constitutive and EGF-induced ERK 1/2 activation, indicating a definitive involvement of MAPK signal transducers in regulating Cu-B-mediated anti-melanoma activity. Together, our study demonstrates the anti-melanoma potential of C. epigaeus-derived Cu-B, which indicates the Cucurbitaceae succulent as a prospective source for deriving potent and pharmacologically safe anti-cancer compounds.

Enhanced in vitro therapeutic efficacy of triphenyltin (IV) loaded vitamin E TPGS against breast cancer therapy

Triphenyltin (Ph3SnL (IV) is a synthetic hydrophobic compound functionalized with a diazo and amino group having potentials to use in anticancer chemotherapy, but its hydrophobic property hindrance the therapeutic efficacy for wider use against cancer treatment. Therefore, in our present work we aimed to develop TPGS micelles loaded with Ph3SnL (IV) to enhanced the therapeutic efficacy in breast cancer cells as compare to docetaxel. Solvent casting method was employed to develop TPGS-Ph3SnL1 (IV), TPGS-Ph3SnL5 (IV) and TPGS-DTX micelles to increase the aqueous solubility of hydrophobic drugs. The size of TPGS-Ph3SnL1 (TSD-30-F) and TPGS-Ph3SnL5 (TSD-34-F) micelles were initially evaluated by dynamic light scattering which were found to be below 50 nm. The morphological characteristics of micelles were observed by TEM, SEM and AFM respectively. Further, drug encapsulation and in vitro drug release profiles of micelles were assessed using dialysis bag diffusion technique under sink condition at pH7.4 at 37 °C over 72 h and analysed through UV–visible spectrophotometry. The anticancer efficacy of TSD-30-F, TSD-34-F and DTX-F were tested against two breast cancer cell lines (MCF-7 and MDA-MB-231) and cervical cancer cell line (HeLa) by MTT assay. IC50 values of TSD-30-F and TSD-34-F displayed very high activity towards breast cancer cells as compared to DTX-F, while moderate in case of HeLa cells. Acridine orange/ethidium bromide as well as flow cytometry observation delineates that micelles induced apoptotic mode of cell death after elevating intracellular reactive oxygen level. Higher cellular uptake of micelles in breast cancer cells was evaluated through TPGS-coumarin6 as compared to coumarin6 without TPGS. Therefore, our study suggests that TPGS micelles may increase therapeutics efficacy of Ph3SnL (IV) in breast cancer cells and can be a promising candidate for targeted drug delivery against breast cancer cells.

Fluorophore Tagged Mixed Ligand Copper(II) Complexes: Synthesis, Structural Characterization, Protein Binding, DNA Cleavage and Anticancer Activity

AbstractTwo fluorophore tagged copper(II) complexes [Cu(phen)(L)(ClO4)2] (1) and [Cu(bpy)(L)(H2O)(ClO4)](ClO4) (2), (where L=2‐amino‐1H‐benzo[de]isoquinoline‐1,3‐(2H)dione (L), phen=1,10‐phenanthroline and bpy=2,2′‐bipyridine) have been synthesized and structurally characterized. Structures of the copper complexes 1 and 2 were confirmed by single‐crystal X‐ray structure determination. The coordination geometry around the copper center of complexes 1 and 2 is distorted octahedral. The plasmid DNA cleavage activity of the complexes has been investigated by agarose gel electrophoresis and the study reveals that both the complexes have high plasmid DNA photo‐cleavage activity. The binding interaction ability of the metal complexes with bovine serum albumin (BSA) was investigated using fluorescence spectroscopy. The cytotoxicity of the complexes has been evaluated by MTT (3‐[4,5‐dimethylthiazole‐2‐yl]‐2,5‐diphenyltetrazolium bromide) assay against A549 (adenocarcinoma human alveolar basal epithelial cells) and MCF‐7 (breast cancer cell line) cell lines in comparison with cis‐platin. Complexes 1 and 2 have exhibited better cytotoxic activity than cis‐platin against A549 and MCF‐7 cell lines. The cellular uptake study and localization of the complexes within the cells have been investigated by fluorescence microscopy. The cell staining and flow cytometry experiments suggest that complexes induce an apoptotic mode of cell death.

Synthesis and antiproliferative activity of novel organometallic cobalt(III) complex encapsulated in polydiacetylene-phospholipid nanoformulation

Organometallic complexes are considered as promising anticancer agents with the aim to overcome the limitations of platinum drugs but until very recently the development of organometallic cobalt-based anticancer active compounds has remained scarce. Two novel half-sandwich Cobalt(III)-pentamethylcyclopentadienyl complexes containing Schiff base ligands of the general formula [Cp*Co(NN)CH3CN](ClO4)2(Cp*Co(L1) and Cp*Co(L2)), where Cp* is pentamethylcyclopentadiene and NN is bis(anthracen-9-ylmethylene)benzene-1,2-diamine (L1) or bis(4-isopropylbenzylidene)benzene-1,2-diamine (L2), have been synthesized and characterized by elemental analysis, spectroscopic techniques, DFT method and cyclic voltammogram analysis. The facile reduction behaviour of complexes illustrates the observed potency of their oxidative DNA cleavage. Cp*Co(L1) complex displays oxidative DNA cleavage in presence of ascorbic acid more prominent than Cp*Co(L2) by generating OH radicals. Cp*Co(L1) complex shows remarkable cytotoxicity (IC50: ∼0.5 μM) towards A549 lung and HeLaS3 cervical cancer cells but moderate to normal human lung fibroblast cells (IC50: 6.02 μM). Also, the cytotoxic potency of Cp*Co(L1) is significantly higher than its analogue complex as well as cis-platin due to its redox behaviour and enhanced hydrophobicity of the ligand moieties. The AO/EB staining assay reveals that the complexes are able to induce late apoptotic mode of cell death in lung and cervical cancer cells. In order to improve the biocompatibility and anticancer activity of Cp*Co(L1) complex, it is encapsulated into polymer-supported liposomes and the size and morphology of nanoformulation is characterized by suitable techniques. The toxic effect of the complex after being encapsulated into liposome is reduced towards normal cells. However, the nanoformulation is less active in lung and cervical cancer cells compared to non-encapsulated complex.

Cytotoxicity, Antimicrobial, and In Silico Studies of Secondary Metabolites From Aspergillus sp. Isolated From Tecoma stans (L.) Juss. Ex Kunth Leaves.

Endophytes are prolific producers of privileged secondary metabolites with diverse therapeutic potential, although their anticancer and antimicrobial potential still have a room for further investigation. Herein, seven known secondary metabolites namely, arugosin C (1), ergosterol (2), iso-emericellin (3), sterigmatocystin (4), dihydrosterigmatocystin (5), versicolorin B (6), and diorcinol (7) were isolated from the rice culture of Aspergillus sp. retrieved from Tecoma stans (L.) Juss. ex Kunth leaves. Their anticancer and antimicrobial activities were evaluated in MTT and agar well diffusion assays, respectively. The cytotoxicity results showed that metabolite 3 displayed the best viability inhibition on the MCF-7 breast cancer cells with IC50 = 225.21 µM, while 5 on the HepG2 hepatocellular carcinoma cells with IC50 = 161.81 µM. 5 demonstrated a 60% apoptotic mode of cell death which is virtually correlated to its high docking affinity to Hsp90 ATP binding cleft (binding score −8.4 Kcal/mol). On the other side, metabolites 4 and 5 displayed promising antimicrobial activity especially on Pseudomonas aeruginosa with MIC = 125 μg/ml. The observed effect may be likely related to their excellent in silico inhibition of the bacterial DNA-gyrase kinase domain (binding score −10.28 Kcal/mol). To the best of our knowledge, this study is the first to report the promising cytotoxic and antibacterial activities of metabolites 3, 4, and 5 which needs further investigation and renovation to therapeutic leads.