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Background: Among various materials designed for anticancer drug transport, sulfide nanoparticles are uniquely intriguing owing to their spectral characteristics. Exploration of newer nanoscale copper sulfide particles with dysprosium doping is reported herein. It leads to a change in the physicochemical properties of the sulfide nanoparticles and hence the difference in drug release and cytotoxicity., Objective: We intend to purport the suitably engineered cobalt sulfide and dysprosium-doped cobalt sulfide nanoparticles that are magnetic and NIR-absorbing, as drug delivery vehicles. The drug loading and release are based on the supramolecular drug complex formation on the surface of the nanoparticles., Method: The nanomaterials are synthesized employing hydrothermal procedures, coated with a biocompatible poly-β-cyclodextrin, and characterized using the methods of diffractometry, microscopy, spectroscopy, thermogravimetry and magnetometry. The sustained drug release is investigated in vitro . 5-Fluorouracil is loaded in the nanocarriers. The empty and 5-fluorouracil-loaded nanocarriers are screened for their anti-breast cancer activity in vitro on MCF-7 cells., Results: The size of the nanoparticles is below 10 nm. They show soft ferromagnetic characteristics. Further, they show broad NIR absorption bands extending up to 1200 nm, with the dysprosium-doped material displaying greater absorbance. The drug 5-fluorouracil is encapsulated in the nanocarriers and released sustainably, with the expulsion duration extending over 10 days. The IC 50 of the blank and the drug-loaded cobalt sulfide are 16.24 ± 3.6 and 12.2 ± 2.6 μg mL -1 , respectively. For the drug-loaded, dysprosium-doped nanocarrier, the IC 50 value is 9.7 ± 0.3 μg mL -1 ., Conclusion: The ultrasmall nanoparticles possess a size suitable for drug delivery and are dispersed well in the aqueous medium. The release of the loaded 5-fluorouracil is slow and sustained. The anticancer activity of the drug-loaded nanocarrier shows an increase in efficacy, and the cytotoxicity is appreciable due to the controlled release. The nanocarriers show multi-functional characteristics, i.e. , magnetic and NIR-absorbing, and are promising drug delivery agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Platinum complexes are commonly used for cancer chemotherapy; however, they are not only highly-priced but also have various side effects. It is, therefore, important to design affordable anticancer drugs with minimal side effects., Methods: We synthesized a new gold(I) complex, PF6{(BDPEA)(TPPMS) digold(I)} (abbreviated as PBTDG) and tested its cytotoxicity in MCF-7 breast cancer cells. We also evaluated the effects of PBTDG on mitochondrial membrane potential, generation of reactive oxygen species (ROS) and apoptosis in breast cancer cells., Results: The IC 50 values for PBTDG and sorafenib were found to be 1.48 μM and 4.45 μM, respectively. Exposure to PBTDG caused significant and concentration-dependent depletion of ATP and disruption of mitochondrial membrane potential. PBTDG induced 2.6, 3.6, and 5.7-fold apoptosis for 1 μM, 3 μM, and 10 μM concentrations, respectively. The induction of apoptosis by the same concentrations of sorafenib was 1.2, 1.3, and 1.6-fold, respectively. The low concentration of PBTDG (1 μM) induced the generation of ROS by 99.83%, which was significantly higher than the ROS generation caused by the same concentration of sorafenib (73.76%). The ROS induction caused by higher concentrations (5 μM) of PBTDG and sorafenib were 104.95% and 122.11%, respectively., Conclusion: The lower concentration of PBTDG produced similar cytotoxicity and apoptotic effects that were caused by a comparatively higher concentration of known anticancer drug (sorafenib). The anticancer effects of PBTDG are attributed to its tendency to disrupt mitochondrial membrane potential, induction of apoptosis and generation of ROS. Further studies are warranted to test the anticancer effects of PBTDG in animal models of cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy due to the overexpression of ATP-binding cassette drug-efflux transporters, namely P-glycoprotein (P-gp)/ATP-binding cassette subfamily B member 1. In this study, derivatives of N-alkylated monoterpene indole alkaloids such as N-(para-bromobenzyl) (NBBT), N-(para-methylbenzyl) (NMBT), and N-(para-methoxyphenethyl) (NMPT) moieties were investigated for the reversal of P-gp-mediated MDR in drug-resistant KB colchicine-resistant 8-5 (KB-ChR-8-5) cells. Among the three indole alkaloid derivatives, the NBBT exhibited the highest P-gp inhibitory activity in a dose-dependent manner. Further, it significantly decreased P-gp overexpression by inactivating the nuclear translocation of the nuclear factor kappa B p-50 subunit. In the cell survival assay, doxorubicin showed 6.3-fold resistance (FR) in KB-ChR-8-5 cells compared with its parental KB-3-1 cells. However, NBBT significantly reduced doxorubicin FR to 1.7, 1.3, and 0.4 and showed strong synergism with doxorubicin for all the concentrations studied in the drug-resistant cells. Furthermore, NBBT and doxorubicin combination decreased the cellular migration and showed increased apoptotic incidence by downregulating Bcl-2, then activating BAX, caspase 3, and p53. The present findings suggest that NBBT could be a lead candidate for the reversal of P-gp- mediated multidrug resistance in cancer cells., (© 2023 Wiley Periodicals LLC.)

Background: Recent studies suggest that numerous naturally occurring agents have the potential to kill cancer cells via mitochondrial dysfunction. Solanum nigrum is a herb widely used in alternative medical systems. This study aimed to investigate the cytotoxic effect of Solanum nigrum water extract (SNWE) against Michigan Cancer Foundation-7 (MCF-7) and MD Anderson-Metastatic Breast Cancer-231 (MDA-MB-231) cells., Methods: We used an MTT reduction assay for cytotoxicity analysis. To explore the mode of action, the cellular adenosine triphosphate (ATP) levels and mitochondrial membrane potential were analyzed using a colorimetric ATP assay and Rhodamine-123 fluorescent staining, respectively, during SNWE treatment for 72 h., Results: The cytotoxic effect was significant in both cell lines, with IC50 values of 4.26 µg/mL and 5.30 µg/mL in MCF-7 and MDA-MB-231 cells, respectively. The 24, 48, and 72 h treatments of 100 µg/mL SNWE showed 0.85 ± 0.07, 0.38 ± 0.1, and 0.20 ± 0.1 nM ATP in MCF-7 cells and 0.94 ± 0.07, 0.84 ± 0.2 and 0.46 ± 0.2 nM in MDA-MB-231 cells, respectively. The SNWE treatment altered the mitochondrial membrane potential (ΔΨm) in a concentration-dependent manner in both the breast cancer cell lines, to 29.6 ± 4.1% in MCF-7 and 28.7 ± 4.17% in MDA-MB-231 cells, when compared with healthy mitochondria (100% ΔΨm)., Conclusions: The cytotoxic effects of Solanum nigrum against breast cancer cells are associated with energy metabolism. Additional studies are warranted to test the anticancer effect of Solanum nigrum using an animal model of breast cancer., Competing Interests: The authors declare no conflict of interest. HAK is serving as one of the Guest Editors and Editorial Board Members of this journal. We declare that HAK had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to SN., (© 2023 The Author(s). Published by IMR Press.)

In this study, we prepared a β-cyclodextrin polymer (β-CDP) co-loaded quercetin (QCT) and doxorubicin (DOX) nanocarrier (β-CDP/QD NCs) by freeze-dried method to combat P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in KB-Ch R 8-5 cancer cells. Various microscopic and spectroscopic techniques were employed to characterize the prepared nanocarrier. The molecular docking studies confirm the effective binding interactions of QCT and DOX with the synthesized β-CD polymer. The in vitro drug release study illustrates the sustainable release of DOX and QCT from the β-CDP nanocarrier. Further, we noticed that the QCT released from the β-CDP nanocarrier improved the intracellular availability of DOX via modulating P-gp drug efflux function in KB-Ch R 8-5 cells and MCF-7/DOX cancer cells. Cell uptake results confirmed the successful internalization of DOX in KB-Ch R 8-5 cells compared with free DOX. Cell-based assays such as nuclear condensation, alteration in the mitochondrial membrane potential (MMP), and apoptosis morphological changes confirmed the enhanced anticancer effect of β-CDP/QD NCs in the resistant cancer cells. Hence, QCT and DOX co-loaded β-CDP may be considered effective in achieving maximum cell death in the P-gp overexpressing MDR cancer cells., 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 © 2023 Elsevier B.V. All rights reserved.)

Cancer often develops multidrug resistance (MDR) when cancer cells become resistant to numerous structurally and functionally different chemotherapeutic agents. MDR is considered one of the principal reasons for the failure of many forms of clinical chemotherapy. Several factors are involved in the development of MDR including increased expression of efflux transporters, the tumor microenvironment, changes in molecular targets and the activity of cancer stem cells. Recently, researchers have designed and developed a number of small molecule inhibitors and derivatives of natural compounds to overcome various mechanisms of clinical MDR. Unfortunately, most of the chemosensitizing approaches have failed in clinical trials due to non-specific interactions and adverse side effects at pharmacologically effective concentrations. Nanomedicine approaches provide an efficient drug delivery platform to overcome the limitations of conventional chemotherapy and improve therapeutic effectiveness. Multifunctional nanomaterials have been found to facilitate drug delivery by improving bioavailability and pharmacokinetics, enhancing the therapeutic efficacy of chemotherapeutic drugs to overcome MDR. In this review article, we discuss the major factors contributing to MDR and the limitations of existing chemotherapy- and nanocarrier-based drug delivery systems to overcome clinical MDR mechanisms. We critically review recent nanotechnology-based approaches to combat tumor heterogeneity, drug efflux mechanisms, DNA repair and apoptotic machineries to overcome clinical MDR. Recent successful therapies of this nature include liposomal nanoformulations, cRGDY-PEG-Cy5.5-Carbon dots and Cds/ZnS core-shell quantum dots that have been employed for the effective treatment of various cancer sub-types including small cell lung, head and neck and breast cancers., (© 2022. The Author(s).)

Background: In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed., Methods: We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385., Results: PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity., Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable., (© 2021. The Author(s).)

Aim: To investigate anticancer activity of the DNA binding domain of SMAR1 (His 5) in vitro and in vivo., Materials & Methods: His 5 was conjugated to hydrothermally synthesized carbon nanospheres (CNs). Anticancer activity of CNs-His 5 was evaluated in vitro and in vivo., Results: CNs- His 5 significantly reduced cyclin D1 levels in MDA-MB-231 cells. Tumor bearing Balb/c mice injected with CNs-His 5 showed approximately 62% tumor regression and significantly reduced 18 FDG uptake. Caspases assay and IHC staining confirmed tumor growth inhibition, which could be attributed to apoptotic, antiproliferative and antiangiogenic activities of His 5., Conclusion: DNA binding domain of the SMAR1 protein (His 5) has potent anticancer activity and its CNs mediated delivery could control breast tumor in mice model.

P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P-gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P-gp. Dietary flavonoids exhibit better interactions with homology modeled human P-gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P-gp transport function and they significantly reduced resistance in cytotoxicity assays to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer.

In this study, we investigated the efficacy of an LNA (locked nucleic acid)-modified DNA aptamer named RNV66 targeting VEGF against various breast cancer cell lines. Our results demonstrate that RNV66 efficiently inhibits breast cancer cell proliferation both in vitro and in vivo. Introduction of LNA nucleotides were crucial for higher efficacy. Furthermore, the binding interaction of RNV66 with VEGF was investigated using molecular dynamic simulations leading to the first computational model of the LNA aptamer-VEGF complex blocking its interaction with VEGF-receptor.

Silibinin (SIL) is a plant derived flavonoid isolated from the fruits and seeds of the milk thistle (Silybum marianum). Silibinin possesses a wide variety of biological applications including anticancer activities but poor aqueous solubility and poor bioavailability limit its potential and efficacy at the tumor sites. In the present study, silibinin was encapsulated in Eudragit® E (EE) nanoparticles in the presence of stabilizing agent polyvinyl alcohol (PVA) and its anticancer efficacy in oral carcinoma (KB) cells was studied. Silibinin loaded nanoparticles (SILNPs) were prepared by nanoprecipitation technique and characterized in terms of size distribution, morphology, surface charge, encapsulation efficiency and in vitro drug release. MTT assay revealed higher cytotoxic efficacy of SILNPs than free SIL in KB cells. Meanwhile, reactive oxygen species (ROS) determination revealed the significantly higher intracellular ROS levels in SILNPs treated cells compared to free SIL treated cells. Therefore, the differential cytotoxicity between SILNPs and SIL may be mediated by the discrepancy of intracellular ROS levels. Moreover, acridine orange (AO) and ethidium bromide (EB) dual staining and reduced mitochondrial membrane potential (MMP) confirmed the induction of apoptosis with nanoparticle treatment. Further, the extent of DNA damage (evaluated by comet assay) was significantly increased in SILNPs than free SIL in KB cells. Taken together, the present study suggests that silibinin-loaded nanoparticles can be used as an effective drug delivery system to produce a better chemopreventive response for the treatment of cancer., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Caffeic acid (3,4-dihydroxy cinnamic acid) (CA) is naturally found in fruits, vegetables, olive oil, and coffee. This study was undertaken to evaluate the anticancer effect of caffeic acid on HT-1080 human fibrosarcoma cell line. The antiproliferative effect of caffeic acid was determined by MTT assay, and the oxidative stress was determined by lipid peroxidation, changes in the enzymatic, and non-enzymatic antioxidant status. To understand the mode of antiproliferative effect of CA, the authors observed intracellular ROS levels by DCFH-DA method, mitochondrial membrane potential alterations by Rh-123 staining, oxidative DNA damage by comet assay, and apoptotic morphological changes by AO/EtBr-staining method. The results show that caffeic acid enhances lipid peroxidative markers such as TBARS, CD, and LHP in HT-1080 cell line. Caffeic acid enhances the ROS levels, which is evidenced by the increased DCF fluorescence. Further, caffeic acid treatment altered the mitochondrial membrane potential in HT-1080 cells. Similarly, the authors observed increased oxidative DNA damage (% Tail DNA, % Tail length, Tail moment, and olive tail moment), and apoptotic morphological changes in caffeic acid-treated groups. These data suggest that caffeic acid exhibits potent anticancer effect in HT-1080 cell line, and that it may be used as an anticancer agent.

Cucurbiturils are magnificent macrocycles that are used as precise molecules for the fabrication of supramolecular chemotherapeutic agents through host-guest molecular recognition. In the present work, the host-guest complex of cucurbit[6]uril (CB[6]) with 5-fluorouracil (Flu, an anticancer drug) is synthesized and its structural study was carried out using UV, XRD, and TG/DTA techniques. The UV-Vis spectrum of the inclusion complex exhibited maximum absorbance with a blue shift at 302 nm whereas the maximum absorbance for free CB[6] was observed at 318 nm. This notable shift in wavelength proves the formation of the inclusion complex of CB[6] with fluorouracil. The host-guest complex of fluorouracil with CB[6] shows sharp endothermic peaks at 403.30C with a heat flow of -0.5 mW/mg the peak covers partially an area of 528.2 J/g, The large variations observed in the DSC curves of the complex compared with free host CB[6] confirm the formation of a stable host-guest complex. The XRD pattern of the host-guest complex is different from the parent compound and this reaffirms the formation of host-guest complex. The cytotoxic effect of 5-fluorouracil and the host-guest complex of CB[6] with fluorouracil on KB cells was determined by MTT assay and the cytotoxicity of anticancer drug Flu towards cancer cells significantly increases by encapsulating 5-fluorouracil into the hydrophobic cavity of CB[6], The ROS generation study was carried out by measurement of intracellular ROS using fluorescent and chemiluminescent probe. The ROS generation of anticancer drugs against cancer cells is significantly increased by encapsulating 5-fluorouracil into the hydrophobic cavity of CB[6], The inclusion complex of cucurbituril with fluorouracil treatment in KB cells showed higher anticancer potential than fluorouracil treatment in KB cells when compared to the control. The IC50 value of 5-flurouracil was found to be higher compared to the inclusion complex of cucurbituril with fluorouracil. The interesting results obtained, might open new avenues for the use of CB[6] host-guest complexes in anticancer and drug delivery studies. [ABSTRACT FROM AUTHOR]

Abstract: Resveratrol (RSV), a grape phytochemical, has drawn greater attention because of its beneficial effects against cancer. However, RSV has some drawbacks such as unstabilization, poor water solubility and short biological half time, which limit the utilization of RSV in medicine, food and pharmaceutical industries. In this study, we have encapsulated RSV in gelatin nanoparticles (GNPs) and studied its anticancer efficacy in NCI-H460 lung cancer cells. SEM and DLS studies have revealed that the prepared RSV-GNPs possess spherical shape with a mean diameter of 294nm. The successful encapsulation of RSV in GNPs has been achieved by the cross-linker glutaraldehyde probably through Schiff base reaction and hydrogen bond interaction. Spectrophotometric analysis revealed that the maximum of 93.6% of RSV has been entrapped in GNPs. In vitro drug release kinetics indicated that there was an initial burst release followed by a slow and sustained release of RSV from GNPs. The prepared RSV-GNPs exhibited very rapid and more efficient cellular uptake than free RSV. Further, RSV-GNPs treatment showed greater antiproliferative efficacy than free RSV treatment in NCI-H460 cells. It has been found that greater ROS generation, DNA damage and apoptotic incidence in RSV-GNPs treated cells than free RSV treatment. Erythrocyte aggregation assay showed that the prepared RSV-GNPs formulation elicit no toxic response. HPLC analysis revealed that RSV-GNPs was more bioavailable and had a longer half-life than free RSV. Hence, GNPs carrier system might be a promising mode for controlled delivery and for improved therapeutic index of poorly water soluble RSV. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to develop PTX-PLGA nanoparticles and to study its anticancer efficacy in NCI-H460 cells in vitro. DLS results revealed that prepared PTX-PLGA had an average size of 211nm. TEM analysis showed that prepared PTX-PLGA nanoparticles were spherical in shape with 150nm. Drug encapsulation assay showed that 65% PTX was encapsulated in PLGA. It was noticed that anticancer potential of PTX-PLGA nanoparticles was greater than that of PTX treatment alone. Further, PLGA-PTX exhibits increased intracellular ROS levels, altered MMP, increased DNA damage, enhanced TBARS and apoptotic morphological changes in NCI-H460 cells when compared to bulk PTX treatment alone. Our results indicate that PTX-PLGA demonstrated increased anticancer property in cancer cells than PTX treatment alone. [Copyright &y& Elsevier]

Abstract: Ferulic acid (FA) is a phenolic phytonutrient, which possesses strong anticancer effect. However, its prominent application in cancer is limited due to poor bioavailability at the tumor site. The aim of the present study was to develop FA-PLGA nanoparticles and to study its anticancer efficacy in NCI-H460 cells in vitro. FA-PLGA nanoparticles were prepared by double emulsion method and characterized by dynamic light scattering (DLS) and the prepared FA-PLGA had an average size of 483nm. Transmission electron microscope (TEM) analysis showed the prepared FA-PLGA nanoparticles were spherical in shape with 200nm. Drug encapsulation assay showed that 76% FA was encapsulated in PLGA. Further, FA-PLGA exhibits increased intracellular reactive oxygen species (ROS) levels, altered mitochondrial transmembrane potential (MMP), increased DNA damage, enhanced TBARS and apoptotic morphological changes in NCI-H460 cells when compared to FA treatment alone. Our results indicate that FA-PLGA demonstrated increased anticancer property in cancer cells than FA treatment alone. [Copyright &y& Elsevier]