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Breast cancer continues to pose a substantial global health challenge, emphasizing the critical need for the advancement of novel therapeutic approaches. Key players in the regulation of apoptosis, a fundamental process in cell death, are the B-cell lymphoma 2 (Bcl-2) family proteins, namely Bcl-2 and Bax. These proteins have garnered attention as highly promising targets for the treatment of breast cancer. Targeting the overexpressed anti-apoptotic Bcl-2 protein in breast cancer, Gefitinib (GEF), an EGFR (Epidermal Growth Factor Receptor) inhibitor, emerges as a potential solution. This study focuses on designing Gefitinib-loaded polymeric mixed micelles (GPMM) using poloxamer 407 and TPGS (D-alpha tocopherol PEG 1000 succinate) for breast cancer therapy. In silico analyses unveil strong interactions between GEF- Bcl-2 and TPGS-Pgp-2 receptors, indicating efficacy against breast cancer. Molecular dynamics simulations offer insights into GEF and TPGS interactions within the micelles. Formulation optimization via Design of Experiment ensures particle size and entrapment efficiency within acceptable ranges. Characterization tools such as zeta sizer, ATR-FTIR, XRD, TEM, AFM, NMR, TGA, and DSC confirms particle size, structure, functional groups, and thermodynamic events. The optimized micelles exhibit a particle size of 22.34 ± 0.18 nm, PDI of 0.038 ± 0.009, and zeta potential of -0.772 ± 0.12 mV. HPLC determines 95.67 ± 0.34% entrapment efficiency and 1.05 ± 0.12% drug loading capacity. In-vitro studies with MDA-MB-231 cell lines demonstrate enhanced cytotoxicity of GPMM compared to free GEF, suggesting its potential in breast cancer therapy. Cell cycle analysis reveals apoptosis induction through key apoptotic proteins. Western blot results confirm GPMM's ability to trigger apoptosis in MDA-MB-231 cells by activating caspase-3, Bax, Bcl-2, and Parp. In conclusion, these polymeric mixed micelles show promise in selectively targeting cancer cells, warranting future in-vivo studies for optimized clinical application against breast cancer., 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 © 2024 Elsevier B.V. All rights reserved.)

Dasatinib (DST) is a tyrosine kinase inhibitor with established antiproliferative activity in Triple-negative breast cancer. Conventional treatment strategies with DST have several pitfalls related to the development of resistance, lower cellular uptake and unwanted adverse effects. To address these issues, we have prepared P-selectin-targeted nanoparticles of DST with fucoidan (FUC) as a ligand. Poly lactide-co-glycolide nanoparticles of DST were coated with chitosan (CH) and FUC via electrostatic interaction (DST-CH-FUC-NPs). The mean particle size of 210.36 ± 0.66 nm and a polydispersity index of 0.234 ± 0.013 was observed for DST-CH-FUC-NPs. TEM and FTIR analysis proved CH coating followed by an FUC layer on nanoparticles. DST-CH-FUC-NPs showed a sustained release profile up to 120 h and 2.9 times less hemolytic potential than free DST suspension. DST-CH-FUC-NPs demonstrated 8-fold higher cytotoxicity compared to free DST in MDA-MB-231 cells. Rhodamine-CH-FUC- NPs showed 19 times and 3 times higher cellular uptake than free Rhodamine and Rhodamine-CH-NPs, respectively. DST-CH-FUC-NPs also displayed increased ROS production and mitochondrial membrane potential damage. Apoptosis study revealed a 7.5-fold higher apoptosis index for DST-CH-FUC-NPs than free DST. Subsequently, the DST-CH-FUC-NPs showed increased inhibition of cell migration, where approximately 5 % wound closure was noted. Further, DST-CH-FUC-NPs confirmed higher disruption of lysosomal membrane integrity, which is well correlated with apoptosis results. In addition, developed NPs were nontoxic on MCF 10 A normal cells. All these findings suggest that fabricated DST-CH-FUC-NPs are promising biocompatible carriers for tumor-targeted delivery and enhanced efficacy of dasatinib., 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.)

Structural tailoring of the flavone framework (position 7) via organopalladium-catalyzed C-C bond formation was attempted in this study. The impact of substituents with varied electronic effects (phenyl ring, position 2 of the benzopyran scaffold) on the antitumor properties was also assessed. Resultantly, the efforts yielded a furyl arm bearing benzopyran possessing a 4-fluoro phenyl ring (position 2) ( 14 ) that manifested a magnificent antitumor profile against the Ishikawa cell lines mediated through dual inhibition of PARP and tubulin [(IC 50 (PARP1) = 74 nM, IC 50 (PARP2) = 109 nM) and tubulin (IC 50 = 1.4 µM)]. Further investigations confirmed the ability of 14 to induce apoptosis as well as autophagy and cause cell cycle arrest at the G2/M phase. Overall, the outcome of the study culminated in a tractable dual PARP-tubulin inhibitor endowed with an impressive activity profile against endometrial cancer.

A new colchinoid compound, identified as N -deacetyl- N -formylcornigerine ( 1 ), named glorigerine was isolated from the roots of Gloriosa superba , along with two known compounds. The structures of isolated compounds were elucidated by 1 D and 2 D NMR and HRMS experiments. Glorigerine ( 1 ) differed from cornigerine ( 6 ) by the presence of an N -formyl group instead of the N -acetyl group. Glorigerine ( 1 ) was found to have moderate cytotoxicity when tested against four human cancer cell lines.

We present N-imidazopyridine-noscapinoids, a new class of noscapine derivatives that bind to tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. The N-atom of the isoquinoline ring of noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a] pyridine pharmacophore to rationally develop a series of N-imidazopyridine-noscapinoids (7-11) with high tubulin binding affinity. The predicted ΔG binding of the N-imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than noscapine with ΔG binding -22.49 kcal/mol. The cytotoxicity of N-imidazopyridine-noscapinoids was evaluated using hormone dependent MCF-7, triple negative MDA-MB-231 breast cancer cell lines and primary breast cancer cells. The cytotoxicity of these compounds (represented as IC 50 concentration) ranges between 4.04 and 33.93 μM against breast cancer cells without affecting normal cells (IC 50 value > 952 μM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after drug administration. We conclude that N-imidazopyridine-noscapinoids possess excellent potential as a promising drug for treating breast cancers., 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.)

The concern impeding the success of chemotherapy in leukemia treatment is descending efficacy of drugs because of multiple drug resistance (MDR). The previous failure of traditional treatment methods is primarily responsible for the present era of innovative agents to treat leukemia effectively. The treatment option is a chemotherapeutic agent in most available treatment strategies, which unfortunately leads to high unavoidable toxicities. As a result of the recent surge in marketed products, theranostic nanoparticles, i.e., multifunctional targetable liposomes (MFTL), have been approved for improved and more successful leukemia treatment that blends therapeutic and diagnostic characteristics. Since they broadly offer the required characteristics to get past the traditional/previous limitations, such as the absence of site-specific anti-cancer therapeutic delivery and ongoing real-time surveillance of the leukemia target sites while administering therapeutic activities. To prepare MFTL, suitable targeting ligands or tumor-specific antibodies are required to attach to the surface of the liposomes. This review exhaustively covered and summarized the liposomal-based formulation in leukemia treatment, emphasizing leukemia types; regulatory considerations, patents, and clinical portfolios to overcome clinical translation hurdles have all been explored., 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 Inc. All rights reserved.)

Richness in nutrients with an ample of the myco-bioactive molecules makes Pleurotus osteratus preferential mushroom. In this paper, we conducted a preliminary study on bio-assay-guided fractionation of dichloromethane:ethanol crude extract (1:1, v/v) of P. osteratus (CD) against human breast cancer cell line (MDA-MB-231). Later, CD and its potent hexane (H) and ethyl acetate (EA) fraction were screened against a panel of a human cancer cell lines. H fraction possesses higher cytotoxicity followed by EA and CD. Literature review revealed that polyphenol and ergosterol are the biomarkers found in P. osteratus and could responsible for its cytotoxic potential. Accordingly, hyphenated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based polyphenol and ergosterol-targeted myco-metabolite profiling of CD, H, and EA fractions were carried out. Despite being significantly rich in polyphenol and ergosterol content, EA fraction showed moderate cytotoxicity. Considering this, liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF/MS)-based untargeted myco-metabolite profiling of CD, H and EA fractions was further conducted to identify a new biomarker. Tentatively, 20 myco-metabolites were identified, belonging to the class of steroids, alkaloid, terpenoid, fatty alcohol, and polyketide. The myco-metabolite variabilities among potent samples in correlation to their in vitro anti-cancer activity was explored using the different chemometric tools: principal component analysis (PCA), hierarchical clustering analysis (HCA), and partial least square (PLS). A probable synergistic action among identified myco-metabolites (betulin, solanocapsine, ophiobolin F, linoleoyl ethanolamide, (13R,14R)-7-labdene-13,14,15-triol, asterosterol, cholest-5-ene, (3b,6b,8a,12a)-8,12-epoxy-7(11)-eremophilene-6,8,12-trimethoxy-3-ol, beta-obscurine, myxalamid B, momordol, and avocadyne 4-acetate) may be responsible for the observed cytotoxicity potential of H fraction of P. osteratus., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

As a part of natural defense, plants initiate the secretion of gum containing numerous pharmacologically active essential metabolites. A fraction of such gum-resin from Araucaria cunninghamii Mudie, when screened against human cancer cell lines, was found to be active. Further, it was subjected to an LCMS-DNP (Dictionary of Natural Products) based dereplication study followed by a detailed phytochemical investigation to obtain pure metabolites. Also, the gum resin of A. cunninghamii was found to be a rich source of abietanes and labdanes. The LCMS-DNP-based dereplication study identified many known metabolites, which were isolated for the first time from this plant as well as a new labdane diterpenoid ( 9 ). The compounds were characterized via spectroscopic techniques, which were subsequently compared with the already existing literature data. The metabolites were screened against seven human cancer cell lines. The anticancer activity was further supported by molecular docking studies.

Hematological malignancy like lymphoma originates in lymph tissues and has a propensity to spread across other organs. Managing such tumors is challenging as conventional strategies like surgery and local treatment are not plausible options and there are high chances of relapse. The advent of novel targeted therapies and antibody-mediated treatments has proven revolutionary in the management of these tumors. Although these therapies have an added advantage of specificity in comparison to the traditional chemotherapy approach, such treatment alternatives suffer from the occurrence of drug resistance and dose-related toxicities. In past decades, nanomedicine has emerged as an excellent surrogate to increase the bioavailability of therapeutic moieties along with a reduction in toxicities of highly cytotoxic drugs. Nanotherapeutics achieve targeted delivery of the therapeutic agents into the malignant cells and also have the ability to carry genes and therapeutic proteins to the desired sites. Furthermore, nanomedicine has an edge in rendering personalized medicine as one type of lymphoma is pathologically different from others. In this review, we have highlighted various applications of nanotechnology-based delivery systems based on lipidic, polymeric and inorganic nanomaterials that address different targets for effectively tackling lymphomas. Moreover, we have discussed recent advances and therapies available exclusively for managing this malignancy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

To strategically design and frame the novel 9-Br-Trimethoxybenzyl noscapine (BTN) with rigorous binding affinity with tubulin, the structure of noscapine (an antitussive plant alkaloid) was amended with a 3,4,5-trimethoxybenzyl group linked at the seventh position on the lower isobenzofuran unit. Molecular modelling and cellular studies were used to assess the single and combined effects of BTN and docetaxel (DOX). Based on MM-GBSA, the individual calculated free energies of binding (ΔG bind, pred ) for BTN and DOX with tubulin was found to be -25.69 and -38.17 kcal/mol, respectively, and -29.11 and -36.60 kcal/mol based on MM-PBSA. Furthermore, the ΔG bind, pred of BTN was dramatically reduced (-30.02 and -33.54 kcal/mol using MM-GBSA and MM-PBSA) in presence of DOX on its binding pocket. Parenthetically, the ΔG bind, pred of DOX was substantially decreased (-39.17 and -35.80 kcal/mol using MM-GBSA and MM-PBSA) in the presence of BTN on its binding pocket. The synergistic activity of both compounds on tubulin dimmer was also analysed using purified tubulin, where a combined regimen of BTN and DOX attenuated tubulin intensity to a higher value (50%) particularly in comparison to the single regimen. In comparison to the single regimen, the combination of BTN and DOX effectively prevents cell cycle progression during the G2/M phase and induces breast cancer cell death. Female athymic nude mice were xenografted with MCF-7 cells and the efficacy of (150 mg/kg/day), DOX (1.5 mg/kg/week, i.v.), or in combination (BTN 300 mg/kg/day + DOX 1.0 mg/kg/week, i.v) were evaluated., (Copyright © 2021. Published by Elsevier Ltd.)

A series of chalcone linked-1,2,3-triazoles was synthesized via cellulose supported copper nanoparticle catalyzed click reaction in water. The structures of all the compounds were analyzed by IR, NMR and Mass spectral techniques. All the synthesized products were subjected to 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay against a panel of four human cancer cell lines (MCF-7, MIA-Pa-Ca-2, A549, HepG2) to check their anticancer potential. Compound 6h was found to be most active against all the tested cancer cell lines with IC 50 values in the range of 4-11 μM and showed better or comparable activity to the reference drug against all the tested cell lines. Cell cycle analysis revealed that compound 6h induces apoptosis and G2/S arrest in MIA-Pa-Ca-2 cells. Compound 6h triggers mitochondrial potential loss in pancreatic cancer MIA-Pa-Ca-2 cells. Further, Compound 6h also triggers caspase-3 and PARP-1 cleavage, which increases in dose dependent manner., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Nanotechnology-based drug products are emerging as promising agents to enhance the safety and efficacy of established chemotherapeutic molecules. Carbon nanotubes (CNTs), especially multiwalled CNTs (MWCNTs), have been explored for this potential owing to their safety and other desired attributes. Docetaxel (DTX) is an indispensable anticancer agent, which has wide applicability in variety of cancers. However, the potential of DTX is still not completely harvested due to problems like poor aqueous solubility, low tissue permeability, poor bioavailability, high first pass metabolism, and dose-related toxicity. Hence, it was proposed to attach DTX to MWCNTs and coadminister it along with piperine with an aim to enhance the tissue permeation, anticancer activity, and bioavailability. The Fourier transform infrared, UV, and NMR spectroscopic data confirmed successful conjugation of DTX to MWCNTs and adsorption of piperine onto MWCNTs. The codelivery MWCNT-based system offered drug release moderation and better cancer cell toxicity than that of plain DTX as well as DTX-CNT conjugate. The pharmacokinetic profile of DTX was exceptionally improved by the conjugation, in general, and coadministration with piperine, in specific vis-à-vis plain drug. Hence, the dual approach of MWCNTs conjugation and piperine coadministration can serve as a beneficial option for enhancement of the performance of DTX in cancer chemotherapy.

Docetaxel is one of the promising drugs and employed for the management of variety of cancers. However, challenges like poor-bioavailability, low tissue-permeability, compromised aqueous solubility and dose-dependent side-effects limit its clinical applications. Whereas, PLGA-based polymeric micelles possess the ability to enhance the tissue permeability of drugs and increase their biocompatibility. Henceforth, it was aimed to fabricate the dextran-PLGA-based polymeric-micelles loaded with docetaxel to explore the potential benefits in drug delivery. Dextran was chemically linked to PLGA and the linkage was confirmed by FT-IR, UV and NMR-spectroscopy. Critical-micelle-concentration of amphiphilic polymer was determined and drug was encapsulated by diffusion technique and erythrocyte compatibility. The system was evaluated for drug release profile and in vitro cytotoxicity studies. The pharmacokinetic profile was studied in rats. The micelles obtained were of 96.5±2.5nm and offered drug encapsulation of order of 54.85±1.21%.The cytotoxicity of drug against MCF-7 and MDA-MB-231 cell lines was enhanced by approx. 100%. The pharmacokinetic profile was substantially modified and about 16-folds enhancement in bioavailability was observed vis-à-vis plain drug. The approach was not only able to control the drug release, but also offered promise to enhance the pharmacokinetic and pharmacodynamic potential of docetaxel and similar anticancer agents., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram-positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future.

Docetaxel has always attracted the researchers owing to its promises and challenges. Despite marked efficacy, concerns like poor aqueous solubility, lower bioavailability, poor tissue penetration and dose related side-effects offer further scope of research on docetaxel. The present study aims to explore the potential of C60-fullerenes in the delivery of docetaxel to cancerous cells. C60-fullerenes were carboxylated, acylated and conjugated with the drug. The chemical processes were monitored by UV, FT-IR and NMR spectroscopy. The conjugate was further characterized for drug loading, micromeritics, drug release, morphology and evaluated for in-vitro cytotoxicity, haemolysis and in-vivo pharmacokinetic profile. The developed nanoconstruct was able to enhance the bioavailability of docetaxel by 4.2 times and decrease the drug clearance by 50%. The developed system was able to control the drug release and was found to be compatible with erythrocytes. The cytotoxic potential on studied MCF-7 and MDA-MB231 cell lines was also enhanced by many folds, indicating marked promise in efficacy enhancement and dose reduction. The present findings are encouraging and offer a technique to enhance the delivery and efficacy potential of anticancer agents, especially belonging to BCS class IV., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Tubulin binding compounds represent one of the most attractive targets for anticancer drug development. They broadly fall into two categories viz., tubulin polymerization inhibitors, which block microtubule growth and destabilize microtubules like vinca alkaloids and cryptophycins, and the others, which polymerize microtubules into hyperstable forms represented by family of taxanes. In this context, we aimed at design and synthesis of cryptophycins based macrocyclic depsipeptides, which are synthetically more accessible, however have the basic information to target tubulins and establish structure activity relationship (SAR). Thus, a new class of cryptophycins based marocyclic depsipeptides with a truncated epoxide chain were synthesized as potential tubulin inhibitors. The resultant lead analogues 15a and 16a exhibited good anti-cancer activity, induced apoptosis, caused block/delay in cell cycle as well as significantly reduced the expression of α- and β-tubulins. Molecular modelling studies show that 15a and 16a bind in the same domain as that of cryptophycins., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A microwave assisted strategy for synthesis of series of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones has been developed and their biological evaluation as anticancer agents is described. The synthetic protocol involves simple procedure by oxidative coupling of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide with different aldehydes in presence of K2S2O8 offering 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one compounds in excellent yields. The in vitro anticancer activity screening against human cancer cell lines HeLa, CAKI-I, PC-3, MiaPaca-2, A549 gave good results. The in detailed mechanistic correlation studies of compound 3m revealed that the compound shows anticancer activity through apoptosis mechanism and also inhibits mTOR with nonomolar potency. The design was based on docking with mTOR protein. The concentration dependent cell cycle analysis, western blotting experiment and nuclear cell morphology studies have been described., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

This study describes the mechanism of trolox and tiron induced potentiation of cytotoxicity caused by Ery5, an analog of magnolol, in human myeloid leukemia HL-60 cells. Ery5 induced cytotoxicity in HL-60 cells by involving activation of bax and cleavage of caspase 3, which contributed towards activation of both apoptotic and autophagic pathways. Trolox and tiron, even at non-toxic concentrations, contributed to the cytotoxicity of Ery5 by activation of autophagic proteins like ATG7, ATG12 and LC3-II. Z-VAD-fmk mediated reduction in the cytotoxicity and expression of autophagic proteins, further suggested that autophagy induced by Ery5 is largely dependent upon caspases. Interestingly, Ery5 induced autophagy was accompanied by the downregulation of PI3K/AKT pathway whereas, trolox and tiron strongly enhanced this effect. In addition to that treatment of cells with Ery5, trolox and tiron individually, displayed a marked upregulation of Bax. The involvement of Bax in trolox and tiron induced enhancement of the cytotoxicity of Ery5 was confirmed, when siRNA induced silencing of Bax led to increased viability of the cells and exerted a strong inhibitory effect on LC3-II accumulation and p62 degradation in case of cells treated by the combination of Ery5 with trolox or tiron. Additionally, an important role of PARP in Ery5 mediated cell death has been suggested by PARP silencing experiments, however, potentiation of autophagic cytotoxicity by trolox and tiron did not seem to be dependent on PARP-1. Therefore, Bax seems to play a vital role in trolox and tiron mediated potentiation of autophagic cell death by Ery5 in HL-60 cells.

A pentacyclic triterpenediol (TPD) from Boswellia serrata has significant cytotoxic and apoptotic potential in a large number of human cancer cell lines. To enhance its anticancer potential, it was successfully formulated into solid lipid nanoparticles (SLNs) by the microemulsion method with 75% drug entrapment efficiency. SEM and TEM studies indicated that TPD-SLNs were regular, solid, and spherical particles in the range of 100-200 nm, and the system indicated that they were more or less stable upon storing up to six months. TPD loaded SLNs showed significantly higher cytotoxic/antitumor potential than the parent drug. TPD-SLNs have 40-60% higher cytotoxic and apoptotic potential than the parent drug in terms of IC(50), extent of apoptosis, DNA damage, and expression of pro-apoptotic proteins like TNF-R1, cytochrome-c, and PARP cleavage in HL-60 cells. Moreover, blank SLNs did not have any cytotoxic effect on the cancer as well as in normal mouse peritoneal macrophages. The in vivo antitumor potential of TPD-SLNs was significantly higher than that of TPD alone in Sarcoma-180 solid tumor bearing mice. Therefore, SLNs of TPD successfully increased the apoptotic and anticancer potential of TPD at comparable doses (both in vitro and in vivo). This work provides new insight into improvising the therapeutic efficacy of TPD by adopting novel delivery strategies such as solid lipid nanoparticles.

Purpose: Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein's expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored. Methods: The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer). Results: Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09 nm, 0.078 ± 0.009 and -4.29 ± 0.24 mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314 µg/ml at 24, 48, and 72 h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 0.85, 0.13, 0.008 µg/ml at 24, 48 and 72 h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells. Conclusion: The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models. [ABSTRACT FROM AUTHOR]

We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram-positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1α/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1α, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G1-S transition-phase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent. [ABSTRACT FROM AUTHOR]

Bioassay-guided fractionation of the fruits of Piper longum afforded two new minor amides, piperlongimin A (2) [2E-N-isobutyl-hexadecenamide] and piperlongimin B (4) [2E-octadecenoylpiperidine] together with five known compounds with moderate cytotoxic activity. The structures were elucidated on the basis of spectroscopic evidences. All these compounds inhibited cell proliferation of human leukemia, HL-60 cell lines, and displayed major apoptosis-inducing effects. [ABSTRACT FROM AUTHOR]

The in vitro anticancer screening of new compounds (III) (20 examples) against human cancer cell lines (HeLa, CAKI-I, PC-3, MiaPaca-2, A549) gives good results. [ABSTRACT FROM AUTHOR]

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ~33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads. [ABSTRACT FROM AUTHOR]