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1.
Pharmaceutics ; 15(9)2023 Aug 23.
Article in English | MEDLINE | ID: mdl-37765157

ABSTRACT

The glucose-lowering drug metformin has been reported to have anticancer properties through unknown mechanisms. Other unknown factors that may influence its anticancer potential include the glycemic status of the patient. Therefore, the objective of this study is to determine the effect of different glucose environments on the antiproliferative potency and the cellular mechanism of action of metformin. Human breast cancer cells, MCF-7, were incubated in low, normal, elevated, and high glucose environments and treated with metformin. The antiproliferative potential of metformin and its effect on protein expression as well as its ability to induce cellular apoptosis and autophagy under different glucose environments, were determined using different molecular techniques. Metformin significantly inhibited cellular proliferation in a time- and glucose-concentration-dependent manner. In comparison to elevated glucose, low normal glucose alone induced a significant level of autophagy that was further increased in the presence of metformin. While glucose concentration did not appear to have an effect on the antiproliferative potency of metformin, the cellular basis of action was shown to be glucose-dependent. The antiproliferative mechanism of action of metformin in elevated and low normal glucose environments is mTOR-dependent, whereas, in the high glucose environment, the antiproliferative mechanism is independent of mTOR. This is the first study to report that both the antiproliferative potency and the cellular mechanism of action aredependent on the concentration of glucose.

2.
Future Sci OA ; 9(5): FSO859, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37180606

ABSTRACT

Aim: The current study aimed to investigate the potential antiproliferative activity of metformin, the effective concentration range, and the mechanism of action. Materials & methods: Human breast cancer cells, MCF-7 were treated with a serial dilution of metformin (10-150 µM) for 24 and 48 h. Potential antiproliferative activity of metformin and its ability in inducing cellular apoptosis and autophagy were also investigated. Results: Metformin inhibited MCF-7 proliferation in a concentration and time dependent manner, with 80 µM as the most effective concentration. Compared with nontreated cells, metformin induced significant levels of autophagy and apoptosis, which were confirmed by the reduction of mTOR and BCL-2 protein expression. Conclusion: The study confirms the antiproliferative activity of metformin, which may likely occur through AMPK signaling pathway.


The antidiabetic drug, metformin is tested in this work for its possible ability to inhibit the growth of breast cancer cells. Using different concentrations of the drug over different time points, the results showed that the drug was able to inhibit cancer growth through different mechanisms. The results also showed that the drug inhibits cancer growth by stimulating program cell death (apoptosis), as well as autophagy, where the cell breaks old and abnormal cellular substances.

3.
Biochem Biophys Res Commun ; 589: 29-34, 2022 01 22.
Article in English | MEDLINE | ID: mdl-34883287

ABSTRACT

Autophagy is a highly conserved process of cellular self-digestion that involves the formation of autophagosomes for the delivery of intracellular components and dysfunctional organelles to lysosomes. This process is induced by different signals including starvation, mitochondrial dysfunction, and DNA damage. The molecular link between autophagy and DNA damage is not well understood yet. Importantly, tumor cells utilize the mechanism of autophagy to cope with genotoxic anti-cancer drug therapy. Another mechanism of drug resistance is provided to cancer cells via the execution of the EMT program. One of the critical transcription factors of EMT is Zeb1. Here we demonstrate that Zeb1 is involved in the regulation of autophagy in several breast cancer cell models. On the molecular level, Zeb1 likely facilitates autophagy through the regulation of autophagic genes, resulting in increased LC3-II levels, augmented staining with Lysotracker, and increased resistance to several genotoxic drugs. The attenuation of Zeb1 expression in TNBC cells led to the opposite effect. Consequently, we propose that Zeb1 augments the resistance of breast cancer cells to genotoxic drugs, at least partially, via autophagy. Collectively, we have uncovered a novel function of Zeb1 in the regulation of autophagy in breast cancer cells.


Subject(s)
Autophagy , Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Mutagens/toxicity , Zinc Finger E-box-Binding Homeobox 1/metabolism , Autophagy/drug effects , Autophagy/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Cell Line, Tumor , DNA Damage , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Microtubule-Associated Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Up-Regulation/drug effects , Up-Regulation/genetics , Zinc Finger E-box-Binding Homeobox 1/genetics
4.
ACS Chem Neurosci ; 11(24): 4073-4091, 2020 12 16.
Article in English | MEDLINE | ID: mdl-33280374

ABSTRACT

Sirtuins are class III histone deacetylase (HDAC) enzymes that target both histone and non-histone substrates. They are linked to different brain functions and the regulation of different isoforms of these enzymes is touted to be an emerging therapy for the treatment of neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). The level of sirtuins affects brain health as many sirtuin-regulated pathways are responsible for the progression of NDs. Certain sirtuins are also implicated in aging, which is a risk factor for many NDs. In addition to SIRT1-3, it has been suggested that the less studied sirtuins (SIRT4-7) also play critical roles in brain health. This review delineates the role of each sirtuin isoform in NDs from a disease centric perspective and provides an up-to-date overview of sirtuin modulators and their potential use as therapeutics in these diseases. Furthermore, the future perspectives for sirtuin modulator development and their therapeutic application in neurodegeneration are outlined in detail, hence providing a research direction for future studies.


Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Parkinson Disease , Sirtuins , Alzheimer Disease/drug therapy , Drug Discovery , Humans , Neurodegenerative Diseases/drug therapy
5.
Future Med Chem ; 12(10): 939-947, 2020 05.
Article in English | MEDLINE | ID: mdl-32270704

ABSTRACT

A new medicine will take an average of 10-15 years and more than US$2 billion before it can reach the pharmacy shelf. Traditionally, drug discovery relied on natural products as the main source of new drug entities, but was later shifted toward high-throughput synthesis and combinatorial chemistry-based development. New technologies such as ultra-high-throughput drug screening and artificial intelligence are being heavily employed to reduce the cost and the time of early drug discovery, but they remain relatively unchanged. However, are there other potentially faster and cheaper means of drug discovery? Is drug repurposing a viable alternative? In this review, we discuss the different means of drug discovery including their advantages and disadvantages.


Subject(s)
Drug Development , Artificial Intelligence , Drug Evaluation, Preclinical , Humans
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