Radioresistance is a major hurdle in the treatment of head and neck squamous cell carcinoma (HNSCC). Here, we report that concomitant treatment of HNSCCs with radiotherapy and mevalonate pathway inhibitors (statins) may overcome resistance. Proteomic profiling and comparison of radioresistant to radiosensitive HNSCCs revealed differential regulation of the mevalonate biosynthetic pathway. Consistent with this finding, inhibition of the mevalonate pathway by pitavastatin sensitized radioresistant SQ20B cells to ionizing radiation and reduced their clonogenic potential. Overall, this study reinforces the view that the mevalonate pathway is a promising therapeutic target in radioresistant HNSCCs.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717759PMC
http://dx.doi.org/10.1002/1878-0261.12535DOI Listing

Publication Analysis

Top Keywords

mevalonate pathway
16
head neck
8
mevalonate
5
pathway activity
4
activity determinant
4
determinant radiation
4
radiation sensitivity
4
sensitivity head
4
neck cancer
4
cancer radioresistance
4

Similar Publications

It is established that reverse hydroxamate analogs of fosmidomycin inhibit the growth of by inhibiting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate pathway, which is absent in humans. Recent biochemical studies have demonstrated that novel reverse fosmidomycin analogs with phenylalkyl substituents at the hydroxamate nitrogen exhibit inhibitory activities against DXR at the nanomolar level. Moreover, crystallographic analyses have revealed that the phenyl moiety of the -phenylpropyl substituent is accommodated in a previously unidentified subpocket within the active site of DXR.

View Article and Find Full Text PDF

Apo structure of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate synthase DXPS: Dynamics and implications for inhibitor design.

Biochem Biophys Res Commun

January 2025

Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. Electronic address:

The enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) catalyses the first step of the MEP pathway, a key process for isoprenoid biosynthesis in bacteria that is absent in humans, making it a promising drug target. We present the structure of Mycobacterium tuberculosis DXPS in its apo form, obtained through a soaking method that removes thiamine diphosphate (ThDP) and metals from pre-formed crystals. The apo structure had three regions with absence of electron density near the active site that are unique to the apo form of the enzyme.

View Article and Find Full Text PDF

Effects of simvastatin on the mevalonate pathway and cell wall integrity of Staphylococcus aureus.

J Appl Microbiol

January 2025

Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba, Avenida Limeira, 901, Areião, Piracicaba, SP 13414-903, Brazil.

Aims: To investigate the effects of simvastatin as an antimicrobial, considering its influence on the mevalonate pathway and on the bacterial cell wall of Staphylococcus aureus.

Methods And Results: S. aureus ATCC 29213 and 33591 were exposed to simvastatin in the presence of exogenous mevalonate to determine whether mevalonate could reverse the inhibition.

View Article and Find Full Text PDF

Coenzyme Q (CoQ) is a critical component of the mitochondrial respiratory chain. CoQ deficiencies often cause a variety of clinical syndromes, often involving encephalopathies. The heterogeneity of clinical manifestations implies different pathomechanisms, reflecting CoQ involvement in several biological processes.

View Article and Find Full Text PDF

Bisphosphonate-mineralized nano-IFNγ suppresses residual tumor growth caused by incomplete radiofrequency ablation through metabolically remodeling tumor-associated macrophages.

Theranostics

January 2025

Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

Radiofrequency ablation (RFA), as a minimally invasive surgery strategy based on local thermal-killing effect, is widely used in the clinical treatment of multiple solid tumors. Nevertheless, RFA cannot achieve the complete elimination of tumor lesions with larger burden or proximity to blood vessels. Incomplete RFA (iRFA) has even been validated to promote residual tumor growth due to the suppressive tumor immune microenvironment (TIME).

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!