Codelivery of Gemcitabine and MUC1 Inhibitor Using PEG-PCL Nanoparticles for Breast Cancer Therapy.

In breast cancer therapy, Gemcitabine (Gem) is an antineoplastic antimetabolite with greater anticancer efficacy and tolerability. However, effectiveness of Gem is limited by its off-target effects. The synergistic potential of MUC1 (mucin 1) inhibitors and Gem-loaded polymeric nanoparticles (NPs) was discussed in this work in order to reduce dose-related toxicities and enhance the therapeutic efficacy. The double emulsion solvent evaporation method was used to prepare poly(ethylene glycol) methyl ether-block-poly-caprolactone (PEG-PCL)-loaded Gem and MUC 1 inhibitor NPs. The average size of Gem and MUC 1 inhibitor-loaded NPs was 128 nm, with a spherical shape. Twin-loaded NPs containing Gem and the MUC1 inhibitor decreased IC50 and behaved synergistically. Furthermore, in vitro mechanistic studies, that is, loss of MMP, clonogenic assay, Annexin V FITC assay, and Western blotting to confirm apoptosis with simultaneous induction of autophagy using acridine orange (AO) staining were performed in this study. Furthermore, the investigated NPs upon combination exhibited greater loss of MMP and decreased clonogenic potential with simultaneous induction of autophagy in MCF-7 cells. Annexin V FITC clearly showed the percentage of apoptosis while Western blotting protein expression analysis revealed an increase in caspase-3 activity with simultaneous decrease in Bcl-2 protein expression, a hallmark of apoptosis. The effectiveness of the Ehrlich ascites solid (EAT) mice treated with Gem-MUC1 inhibitor NPs was higher than that of the animals treated alone. Overall, the combined administration of Gem and MUC1 inhibitor-loaded NPs was found to be more efficacious than Gem and MUC1 inhibitor delivered separately.

Nano-Based Drug Delivery of Anticancer Chemotherapeutic Drugs Targeting Breast Cancer.

BACKGROUND: Chemotherapeutic drugs are principally intended to treat breast cancer. However, sooner or later, tumor drug resistance developed. These chemo drugs are effective but with numerous side effects. Breast cancer care may be extremely difficult since recurring cancer is frequently pre-treated with powerful agents. Cancer cells acquire high resistance to earlier therapies, necessitating alternative and more powerful drugs. Nanoparticles (NPs) as a medication delivery technology can overcome medication resistance in breast cancer and significantly reduce the effective dose. The off-targeted nature of chemo drugs can be resolved by encapsulating or attaching chemo drugs in nanocarriers, specifically targeting breast cancer cells. OBJECTIVES: This review highlights various chemo drugs for breast cancer and their encapsulation or bioconjugation with nanoparticles for its targeted delivery. CONCLUSION: Nanoparticles may subsist valuable abet in breast cancer management in this regard. Given that traditional chemotherapy approaches have been demonstrated to have several side effects and defects during treatment, the NPs-mediated drug delivery mechanism is a possible contender for replacement as a new technique.

Computational Design for Identification of Human Anti-MUC1 Heteroclitic Peptides in the Treatment of HER2-Positive Breast Cancer through Neural Network Training and Monomeric based Design.

AIMS: Generation of the human anti-MUC1 peptide through neural network training and monomeric design method. Analyzing 9-mer peptide potential computationally for treatment of HER2-positive breast cancer. BACKGROUND: With the advancements of cancer genome atlas project (TCGA), cancer dependancy project (DepMap) and human protein atlas (HPA), large-scale datasets are generated for oncology studies. However, after development of redefined breast cancer drug targets, there are key issues in successful breast cancer treatments that needed to be pursued which paved the pathway for new approaches or strategies. In that respect, our research data aimed to represent a new aspect of breast cancer drug development studies. OBJECTIVE: Extract human MUC1 sequences from various databases. Perform neural networking method for novel peptides sequences. Analyze the potentiality of generated heteroclitic peptide sequences for suitable vaccine candidate for breast cancer treatment. METHODS: Input scaffolds of protein database (PDB) files for human MUC1 were retrieved and loaded into Evo design server with monomeric based design option. Further, neural network training approaches were followed and other computational tools were used for alignment-independent prediction of protective antigens and subunit vaccines potency of designed heteroclitic peptides. RESULTS: Study findings revealed two human anti-MUC1 heteroclitic peptides of 9mers (WAVWTYVSV, FMSFYIMNL), which showed the lowest energy cluster and sequence identity, normalized relative error rate of secondary structure, solvent accessibility, backbone torsion angles for neural networking and RMSD values in evolutionary profiling, and online MHCPred IC50 interaction values. VaxiGen v2.0 server revealed subunit vaccine potency values of in-silico designed two heteroclitic peptides were 0.1551 (WAVWTYVSV) and 0.3508 (FMSFYIMNL) with a threshold value of 0.5 followed by AllerTOP v2.0 for their allergenicity nature in immunogenic reactions. CONCLUSION: Computationally designed heteroclitic peptide WAVWTYVSV indicated promising values which can be utilised as drug delivery or tumour marker candidate in the treatment of human breast cancer by eliciting lyse of tumor cells.

Monoclonal antibodies in breast cancer: A critical appraisal.

In breast cancer, mAbs can play multifunctional roles like targeting cancer cells, sometimes directly attacking them, helping in locating and delivering therapeutic drugs to targets, inhibiting cell growth and blocking immune system inhibitors, etc. Monoclonal antibodies are also one of the important successful treatment strategies especially against HER2 but they have not been explored much for other types of breast cancers especially in triple negative breast cancers. Monoclonal antibodies impact the feasibility of antigen specificity, bispecific and trispecific mAbs have opened new doors for more targeted specific efficacy. Monoclonal antibodies can be used diversly and with efficacy as compared to other methods of treatment thus maining it a suitable candidate for breast cancer treatment. However, mAbs treatment also causes various side effects such as fever, trembling, fatigue, headache and muscle pain, nausea/vomiting, difficulty in breathing, rashes and bleeding. Understanding the pros and cons of this strategy, we have explored in this review, the current and future potential capabilities of monoclonal antibodies with respect to diagnosis and treatment of breast cancer. DATA AVAILABILITY: Not applicable.

Biodegradable PEG-PCL Nanoparticles for Co-delivery of MUC1 Inhibitor and Doxorubicin for the Confinement of Triple-Negative Breast Cancer.

Combating triple-negative breast cancer (TNBC) is still a problem, despite the development of numerous drug delivery approaches. Mucin1 (MUC1), a glycoprotein linked to chemo-resistance and progressive malignancy, is unregulated in TNBC. GO-201, a MUC1 peptide inhibitor that impairs MUC1 activity, promotes necrotic cell death by binding to the MUC1-C unit. The current study deals with the synthesis and development of a novel nano-formulation (DM-PEG-PCL NPs) comprising of polyethylene glycol-polycaprolactone (PEG-PCL) polymer loaded with MUC1 inhibitor and an effective anticancer drug, doxorubicin (DOX). The DOX and MUC1 loaded nanoparticles were fully characterized, and their different physicochemical properties, viz. size, shape, surface charge, entrapment efficiencies, release behavior, etc., were determined. With IC50 values of 5.8 and 2.4 nm on breast cancer cell lines, accordingly, and a combination index (CI) of < 1.0, DM-PEG-PCL NPs displayed enhanced toxicity towards breast cancer cells (MCF-7 and MDA-MB-231) than DOX-PEG-PCL and MUC1i-PEG-PCL nanoparticles. Fluorescence microscopy analysis revealed DOX localization in the nucleus and MUC1 inhibitor in the mitochondria. Further, DM-PEG-PCL NPs treated breast cancer cells showed increased mitochondrial damage with enhancement in caspase-3 expression and reduction in Bcl-2 expression.In vivo evaluation using Ehrlich Ascites Carcinoma bearing mice explicitly stated that DM-PEG-PCL NPs therapy minimized tumor growth relative to control treatment. Further, acute toxicity studies did not reveal any adverse effects on organs and their functions, as no mortalities were observed. The current research reports for the first time the synergistic approach of combination entrapment of a clinical chemotherapeutic (DOX) and an anticancer peptide (MUC1 inhibitor) encased in a diblock PEG-PCL copolymer. Incorporating both DOX and MUC1 inhibitors in PEG-PCL NPs in the designed nanoformulation has provided chances and insights for treating triple-negative breast tumors. Our controlled delivery technology is biodegradable, non-toxic, and anti-multidrug-resistant. In addition, this tailored smart nanoformulation has been particularly effective in the therapy of triple-negative breast cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s10924-022-02654-4.

Chemotherapeutic Strategies for Combating Staphylococcus aureus Infections.

Staphylococcus aureus is a prominent human pathogen that causes nosocomial and community acquired infections. The accelerating emergence and prevalence of staphylococcal infections have grotesque health consequences which are mostly due to its anomalous capability to acquire drug resistance and scarcity of novel classes of antibacterials. Many combating therapies are centered on primary targets of S. aureus which are cell envelope, ribosomes and nucleic acids. This review describes various chemotherapeutic strategies for combating S. aureus infections including monotherapy, combination drug therapy, phage endolysin therapy, lysostaphins and antibacterial drones. Monotherapy has dwindled in due course of time, but combination therapy, endolysin therapy, lysostaphin and antibacterial drones are emerging alternatives which efficiently conquer the shortcomings of monotherapy. Combinations of more than one antibiotic agents or combination of adjuvant with antibiotics provide a synergistic approach to combat infections causing pathogenic strains. Phage endolysin therapy and lysostaphin are also presented as possible alternatives to conventional antibiotic therapies. Antibacterial Drones go a step further by specifically targeting the virulence genes in bacteria, giving them a certain advantage over existing antibacterial strategies. But the challenge remains on the better understanding of these strategies for executing and implementing them in the health sector. In this day and age, most of the S. aureus strains are resistant to an ample number of antibiotics, so there is an urgent need to overcome such multidrug-resistant strains for the welfare of our community.

A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells.

We have synthesized a novel quinazolinone chalcone derivative (QC) and first time reported its in-vitro and in-vivo anticancer potential. It inhibited the cell proliferation of different cancer cell lines like PC-3, Panc-1, Mia-Paca-2, A549, MCF-7 and HCT-116. It induces apoptosis as measured by several biological endpoints such as apoptotic body formation, evident by Hoechst and scanning electron microscopy, enhanced annexinV-FITC binding of the cells, increased sub-G0 cell fraction, loss of mitochondrial membrane potential (Δψm), reduction of Bcl-2/Bax ratio, activation of caspase-9, caspase-3 and PARP-1 (poly-ADP Ribose polymerase) cleavage in HCT-116 cells. In spite of apoptosis, QC significantly hammers the downstream and upstream signaling cascade of PI3K/Akt/mTOR pathway and cell cycle regulator Skp-2, p21 and p27. Interestingly, QC induces the S and G2/M phase of HCT-116 cells at experimental doses. QC inhibits the tumor growth of Ehrlich ascites carcinoma (EAC), Ehrlich tumor (ET, solid) and sarcoma-180(solid) mice models. Furthermore, it was found to be non-toxic as no animal mortality (0/7) occurred during experimental doses. The present study provides an insight of anticancer potential of QC, which may be useful in managing and treating cancer.

Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer.

Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110α and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo.

Design and Synthesis of Antitumor Heck-Coupled Sclareol Analogues: Modulation of BH3 Family Members by SS-12 in Autophagy and Apoptotic Cell Death.

Sclareol, a promising anticancer labdane diterpene, was isolated from Salvia sclarea. Keeping the basic stereochemistry-rich framework of the molecule intact, a method for the synthesis of novel sclareol analogues was designed using palladium(II)-catalyzed oxidative Heck coupling reaction in order to study their structure-activity relationship. Both sclareol and its derivatives showed an interesting cytotoxicity profile, with 15-(4-fluorophenyl)sclareol (SS-12) as the most potent analogue, having IC50 = 0.082 µM against PC-3 cells. It was found that SS-12 commonly interacts with Bcl-2 and Beclin 1 BH3 domain proteins and enhances autophagic flux by modulating autophagy-related proteins. Moreover, inhibition of autophagy by autophagy inhibitors protected against SS-12-induced apoptosis. Finally, SS-12 effectively suppressed tumor growth in vivo in Ehrlich's ascitic and solid Sarcoma-180 mouse models.