Statins, the drugs used for the treatment of hypercholesterolemia, have come into the spotlight not only as chemoadjuvants, but also as potential stem cell modulators in the context of regenerative therapy. In our study, we compared the in vitro effects of all clinically used statins on the viability of human pancreatic cancer (MiaPaCa-2) cells, non-cancerous human embryonic kidney (HEK 293) cells and adipose-derived mesenchymal stem cells (ADMSC). Additionally, the effect of statins on viability of MiaPaCa-2 and ADMSC cells spheroids was tested. Furthermore, we performed a microarray analysis on ADMSCs treated with individual statins (12 μM) and compared the importance of the effects of statins on gene expression between stem cells and pancreatic cancer cells. Concentrations of statins that significantly affected cancer cells viability (< 40 μM) did not affect stem cells viability after 24 h. Moreover, statins that didn´t affect viability of cancer cells grown in a monolayer, induce the disintegration of cancer cell spheroids. The effect of statins on gene expression was significantly less pronounced in stem cells compared to pancreatic cancer cells. In conclusion, the low efficacy of statins on non-tumor and stem cells at concentrations sufficient for cancer cells growth inhibition, support their applicability in chemoadjuvant tumor therapy.

• Klíčová slova
• 3-Hydroxy-3-methylglutaryl coenzyme A inhibitors, Cell spheroids, Microarray analysis, Pancreatic cancer cells, Statins, Stem cells,
• MeSH
• buněčné sféroidy účinky léků   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mezenchymální kmenové buňky * účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní * farmakoterapie   patologie   metabolismus   MeSH
• statiny * farmakologie   MeSH
• viabilita buněk * účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• statiny * MeSH

Many cancer therapies aim to trigger apoptosis in cancer cells. Nevertheless, the presence of oncogenic alterations in these cells and distorted composition of tumour microenvironment largely limit the clinical efficacy of this type of therapy. Luckily, scientific consensus describes about 10 different cell death subroutines with different regulatory pathways and cancer cells are probably not able to avoid all of cell death types at once. Therefore, a focused and individualised therapy is needed to address the specific advantages and disadvantages of individual tumours. Although much is known about apoptosis, therapeutic opportunities of other cell death pathways are often neglected. Molecular heterogeneity of head and neck squamous cell carcinomas (HNSCC) causing unpredictability of the clinical response represents a grave challenge for oncologists and seems to be a critical component of treatment response. The large proportion of this clinical heterogeneity probably lies in alterations of cell death pathways. How exactly cells die is very important because the predominant type of cell death can have multiple impacts on the therapeutic response as cell death itself acts as a second messenger. In this review, we discuss the different types of programmed cell death (PCD), their connection with HNSCC pathogenesis and possible therapeutic windows that result from specific sensitivity to some form of PCD in some clinically relevant subgroups of HNSCC.

• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• chemorezistence MeSH
• dlaždicobuněčné karcinomy hlavy a krku farmakoterapie   genetika   metabolismus   patologie   MeSH
• ferroptóza účinky léků   MeSH
• genetická heterogenita MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory hlavy a krku farmakoterapie   genetika   metabolismus   patologie   MeSH
• nekroptóza účinky léků   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyroptóza účinky léků   MeSH
• regulovaná buněčná smrt účinky léků   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové látky MeSH

Statins, besides being powerful cholesterol-lowering drugs, also exert potent anti-proliferative activities. However, their anti-cancer efficacy differs among the individual statins. Thus, the aim of this study was to identify the biological pathways affected by individual statins in an in vitro model of human pancreatic cancer. The study was performed on a human pancreatic cancer cell line MiaPaCa-2, exposed to all commercially available statins (12 μM, 24 h exposure). DNA microarray analysis was used to determine changes in the gene expression of treated cells. Intracellular concentrations of individual statins were measured by UPLC (ultra performance liquid chromatography)-HRMS (high resolution mass spectrometer). Large differences in the gene transcription profiles of pancreatic cancer cells exposed to various statins were observed; cerivastatin, pitavastatin, and simvastatin being the most efficient modulators of expression of genes involved namely in the mevalonate pathway, cell cycle regulation, DNA replication, apoptosis and cytoskeleton signaling. Marked differences in the intracellular concentrations of individual statins in pancreatic cancer cells were found (>11 times lower concentration of rosuvastatin compared to lovastatin), which may contribute to inter-individual variability in their anti-cancer effects. In conclusion, individual statins exert different gene expression modulating effects in treated pancreatic cancer cells. These effects may be partially caused by large differences in their bioavailability. We report large differences in gene transcription profiles of pancreatic cancer cells exposed to various statins. These data correlate to some extent with the intracellular concentrations of statins, and may explain the inter-individual variability in the anti-cancer effects of statins.

• MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní genetika   metabolismus   patologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• stanovení celkové genové exprese MeSH
• statiny farmakologie   MeSH
• transkriptom účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• statiny MeSH

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

• Klíčová slova
• Cancer biology, Cancer prevention, Cancer therapy, Tumor microenvironment,
• MeSH
• cílená molekulární terapie MeSH
• karcinogeneze účinky léků   genetika   MeSH
• lidé MeSH
• nádorové mikroprostředí účinky léků   genetika   MeSH
• nádory farmakoterapie   genetika   prevence a kontrola   MeSH
• patologická angiogeneze farmakoterapie   genetika   prevence a kontrola   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky terapeutické užití   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• protinádorové látky MeSH