Effects of Garlic on Breast Tumor Cells with a Triple Negative Phenotype: Peculiar Subtype-Dependent Down-Modulation of Akt Signaling DOI Creative Commons
Federica Brugnoli,

Marcello Dell’Aira,

Paola Tedeschi

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(10), P. 822 - 822

Published: May 11, 2024

Breast cancer includes tumor subgroups with morphological, molecular, and clinical differences. Intrinsic heterogeneity especially characterizes breast tumors a triple negative phenotype, often leading to the failure of even most advanced therapeutic strategies. To improve treatment, use natural agents integrate conventional therapies is subject ever-increasing attention. In this context, garlic (Allium sativum) shows anti-cancerous potential, interfering proliferation, motility, malignant progression both non-invasive invasive cells. As could be at basis variable effects, main objective our study was evaluate anti-tumoral activity extract in cells phenotype. Established (TNBC) cell lines from patient-derived xenografts (PDXs) were used, revealing subtype-dependent effects on morphology, cycle, correlated peculiar down-modulation Akt signaling, crucial regulator solid tumors. Our results first demonstrate that TNBC are not unique suggest only more precise knowledge mechanisms activated by compound each will allow for inclusion personalized approaches cancer.

Language: Английский

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer DOI Creative Commons
Antonino Glaviano, Aaron Song Chuan Foo, Hiu Yan Lam

et al.

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Aug. 18, 2023

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Growth factor signalling to transcription factors the PAM axis regulated by multiple cross-interactions with several other pathways, dysregulation of can predispose cancer development. most frequently activated human often implicated resistance anticancer therapies. Dysfunction components this such as hyperactivity PI3K, loss function PTEN, gain-of-function AKT, are notorious drivers treatment disease progression cancer. In review we highlight major dysregulations cancer, discuss results AKT mTOR inhibitors monotherapy co-administation antineoplastic agents clinical trials strategy for overcoming resistance. Finally, mechanisms targeted therapies, including immunology immunotherapies also discussed.

Language: Английский

Citations

737
Role of protein phosphorylation in cell signaling, disease, and the intervention therapy DOI Creative Commons
Kun Pang, Wei Wang, Jiaxin Qin

et al.

MedComm, Journal Year: 2022, Volume and Issue: 3(4)

Published: Nov. 3, 2022

Abstract Protein phosphorylation is an important post‐transcriptional modification involving extremely wide range of intracellular signaling transduction pathways, making it therapeutic target for disease intervention. At present, numerous drugs targeting protein have been developed the treatment various diseases including malignant tumors, neurological diseases, infectious and immune diseases. In this review article, we analyzed 303 small‐molecule kinase inhibitors (PKIs) registered participated in clinical research obtained a database named Kinase Inhibitor Database (PKIDB), 68 approved by Food Drug Administration United States. Based on previous classifications kinases, divided these human kinases into eight groups nearly 50 families, delineated their main regulatory upstream downstream targets. These include: A, G, C (AGC) receptor guanylate cyclase (RGC) group, calmodulin‐dependent (CaMK) CMGC [Cyclin‐dependent (CDKs), Mitogen‐activated (MAPKs), Glycogen synthase (GSKs), dc2‐like (CLKs)] sterile (STE)‐MAPKs tyrosine (TK) kinase‐like (TKL) atypical other groups. Different families stimulate or inhibit others, forming intricate molecular network. This takes newly new PKIs as breakthrough point, aiming to clarify network relationship each pathway, well roles intervention, provide direction future drug development.

Language: Английский

Citations

64
The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions DOI
Mohammad Rafi Khezri, Reza Jafari, Keyvan Yousefi

et al.

Experimental and Molecular Pathology, Journal Year: 2022, Volume and Issue: 127, P. 104787 - 104787

Published: May 27, 2022

Language: Английский

Citations

61
Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors DOI

Liwen Hua,

Qiuyue Zhang, Xinyue Zhu

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(12), P. 8091 - 8112

Published: June 10, 2022

In recent years, with the successful development of proteolysis-targeting chimeric molecules (PROTACs), potential heterobifunctional to contribute reenvisioning drug design, especially small-molecule drugs, has been increasingly recognized. Inspired by PROTACs, diverse have reported simultaneously bind two or more and bring them into proximity interaction, such as ribonuclease-recruiting, autophagy-recruiting, lysosome-recruiting, kinase-recruiting, phosphatase-recruiting, glycosyltransferase-recruiting, acetyltransferase-recruiting chimeras. On basis principle, opportunities for advancing design linking effectors a protein interest (POI) emerged. Herein, we introduce other than summarize limitations existing molecules, list main challenges, propose perspectives future research directions, providing insight alternative strategies based on substrate-proximity-based targeting.

Language: Английский

Citations

47
Capivasertib: A Novel AKT Inhibitor Approved for Hormone-Receptor-Positive, HER-2-Negative Metastatic Breast Cancer DOI

Alexa J. Luboff,

David L. DeRemer

Annals of Pharmacotherapy, Journal Year: 2024, Volume and Issue: 58(12), P. 1229 - 1237

Published: April 2, 2024

To review the pharmacology, efficacy, and safety of capivasertib for treatment adults with hormone receptor-positive, HER2-negative (HR+/HER2-) locally advanced or metastatic breast cancer 1 more PIK3CA/AKT1/PTEN alterations.

Language: Английский

Citations

12
Targeting PI3K/AKT/mTOR Signaling to Overcome Drug Resistance in Cancer DOI
Muhammad Tufail,

Wendong Wan,

Canhua Jiang

et al.

Chemico-Biological Interactions, Journal Year: 2024, Volume and Issue: 396, P. 111055 - 111055

Published: May 17, 2024

Language: Английский

Citations

10
Structural Requirements of Isoform-Specific Inhibitors of Akt: Implications in the Development of Effective Cancer Treatment Strategies DOI
Tenzin Adon, Syamal D. Bhattacharya, SubbaRao V. Madhunapantula

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117334 - 117334

Published: Jan. 1, 2025

Language: Английский

Citations

1
Molecular Docking of Lactoferrin with Apoptosis-Related Proteins Insights into Its Anticancer Mechanism DOI Open Access

Lidia Esmeralda Ángel-Lerma,

Javier Carrillo‐Campos,

Luis Ignacio Siañez-Estrada

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2023 - 2023

Published: Feb. 26, 2025

Human Lactoferrin (hLf), a multifunctional glycoprotein, has been analyzed through molecular docking to evaluate its role in apoptosis regulation and potential as an anticancer agent. The results highlight XIAP (X-linked Inhibitor of Apoptosis Protein) Caspase-3 the most reliable targets, where hLf disrupts XIAP's inhibition Caspase-9, potentially restoring apoptotic signaling; also stabilizes Caspase-3, enhancing activation intrinsic extrinsic pathways. Weaker interactions were observed with Fas, Bcl-2, Akt. hLf's Fas signaling is likely due expression upregulation rather than direct binding. In contrast, binding Bcl-2 may disrupt anti-apoptotic function, interaction Akt suggests interference pro-survival signaling. These findings suggest that promote by caspase modulating key regulators, supporting use cancer treatment. However, further experimental validation needed confirm these their therapeutic implications.

Language: Английский

Citations

1
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK) DOI Creative Commons

Xueqin Huang,

Li You, Eugenie Nepovimová

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: July 24, 2023

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of that play vital roles in cell growth DNA damage repair. Dysfunction PIKK members aberrant stimulation the PI3K/AKT/mTOR signalling pathway linked to a plethora diseases including cancer. In recent decades, numerous inhibitors have made great strides cancer treatment, like copanlisib sirolimus. Notably, most (such as VX-970 M3814) response also shown good efficacy clinical trials. However, these drugs still require suitable combination therapy overcome drug resistance or improve antitumor activity. Based on aforementioned facts, we summarised PIKK, PI3K, AKT human malignancies mechanisms targeted therapy, order provide deeper insights into treatment.

Language: Английский

Citations

15
Study of Drug Targets Associated With Oncogenesis and Cancer Cell Survival and the Therapeutic Activity of Engineered Ashwagandha Extract Having Differential Withanolide Constitutions DOI Creative Commons
Franco Cavaleri,

Sukalpa Chattopadhyay,

Vrushalee Palsule

et al.

Integrative Cancer Therapies, Journal Year: 2024, Volume and Issue: 23

Published: Jan. 1, 2024

Ashwagandha ( Withania somnifera) has gained worldwide popularity for a multitude of health benefits inclusive cancer-preventive and curative effects. Despite numerous research data supporting the this wonder herb, actual use ashwagandha cancer treatment in clinics is limited. The primary reason inconsistent therapeutic outcome due to highly variable composition constitution active ingredients plant extract impacting ashwagandha’s pharmacology. We investigate here an engineered yield: (Oncowithanib) that unique fixed portion achieve consistent effective activity. Using MCF7 cell line, Oncowithanib was studied its anti-neoplastic efficacy drug targets associated with cycle regulation, translation machinery, survival apoptosis. Results demonstrate dose-dependent decline Oncowithanib-treated viability reduced colony-forming ability. Treated cells showed increased death as evidenced by enhancement Caspase 3 enzyme activity decreased expressions proliferation markers such Ki67 Aurora Kinase A. also found be expressional suppression key cellular kinases RSK1, Akt1, mTOR cells. Our findings indicate decreases propagation, sheds light on common might good candidates development therapeutics. Further in-depth investigations are required fully explore potency pharmacology novel extract. This study highlights importance standardization herbal extracts get disease indication.

Language: Английский

Citations

5