cancer-targeting
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Anti-apoptotic mechanisms contribute to the development of cancer and the resistance of cancer cells to antitumor therapies. This review focuses on the progress towards clinical application of therapies that directly modulate the apoptosis pathways. RECENT FINDINGS: A growing understanding of the mechanisms that control apoptosis has generated a number of strategies for modulating apoptotic pathways, including activation of death receptors and neutralization of anti-apoptotic proteins. Striking antitumor efficacy has been achieved in preclinical cancer models. To date, early-phase testing has not yet established the clinical utility of these strategies. SUMMARY: There is every reason to be optimistic that the wealth of knowledge about the molecular controls of apoptosis will eventually be translated into new clinical therapies for cancer. It is likely that the optimum utility of these pro-apoptotic therapies will be in combination with other treatment modalities, and careful patient selection will be necessary.
- MeSH
- apoptóza MeSH
- biologické modely MeSH
- lidé MeSH
- nádorový supresorový protein p53 antagonisté a inhibitory MeSH
- nádory metabolismus terapie MeSH
- proteiny regulující apoptózu antagonisté a inhibitory MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory MeSH
- receptory domény smrti antagonisté a inhibitory MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
The majority of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) affect normal expression of the genes, including oncogenes and tumour suppressive genes, which make them a new class of targets for drug development in cancer. Although microRNAs (miRNAs) are the most studied regulatory ncRNAs to date, and miRNA-targeted therapeutics have already reached clinical development, including the mimics of the tumour suppressive miRNAs miR-34 and miR-16, which reached phase I clinical trials for the treatment of liver cancer and mesothelioma, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognised. Here, we describe obstacles and advances in the development of ncRNA therapeutics and provide the comprehensive overview of the ncRNA chemistry and delivery technologies. Furthermore, we summarise recent knowledge on the biological functions of miRNAs and their involvement in carcinogenesis, and discuss the strategies of their therapeutic manipulation in cancer. We review also the emerging insights into the role of lncRNAs and their potential as targets for novel treatment paradigms. Finally, we provide the up-to-date summary of clinical trials involving miRNAs and future directions in the development of ncRNA therapeutics.
- MeSH
- cílená molekulární terapie metody trendy MeSH
- lidé MeSH
- mikro RNA genetika MeSH
- modely genetické MeSH
- nádory farmakoterapie genetika MeSH
- nekódující RNA genetika MeSH
- protinádorové látky terapeutické užití MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- RNA dlouhá nekódující genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Microtubule-targeting agents (MTAs) constitute a diverse group of chemical compounds that bind to microtubules and affect their properties and function. Disruption of microtubules induces various cellular responses often leading to cell cycle arrest or cell death, the most common effect of MTAs. MTAs have found a plethora of practical applications in weed control, as fungicides and antiparasitics, and particularly in cancer treatment. Here we summarize the current knowledge of MTAs, the mechanisms of action and their role in cancer treatment. We further outline the potential use of MTAs in anti-metastatic therapy based on inhibition of cancer cell migration and invasiveness. The two main problems associated with cancer therapy by MTAs are high systemic toxicity and development of resistance. Toxic side effects of MTAs can be, at least partly, eliminated by conjugation of the drugs with various carriers. Moreover, some of the novel MTAs overcome the resistance mediated by both multidrug resistance transporters as well as overexpression of specific β-tubulin types. In anti-metastatic therapy, MTAs should be combined with other drugs to target all modes of cancer cell invasion.
- MeSH
- lidé MeSH
- mikrotubuly účinky léků MeSH
- nádory farmakoterapie MeSH
- protinádorové látky farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
MicroRNAs (miRNAs) are short, 18-25-nucleotide long, non-coding single-stranded RNAs, which are capable to regulate gene expression on post-transcriptional level through binding to their target protein-encoding mRNAs. miRNAs regulate individual components of multiple oncogenic pathways. One of them is epidermal growth factor receptor (EGFR) signalling pathway that regulates cell proliferation, differentiation, migration, angiogenesis and apoptosis. All these processes are deregulated in colorectal cancer (CRC). Moreover, EGFR has been validated as the therapeutic target in CRC, and monoclonal antibodies cetuximab and panitumumab are used in the therapy of patients with metastatic CRC. Because of the extensive involvement of miRNAs in the regulation of EGFR signalling, it seems they could also serve as promising predictive biomarkers to anti-EGFR therapy. In this review, we summarize current knowledge about miRNAs targeting EGFR signalling pathway, their functioning in CRC pathogenesis and potential usage as biomarkers.
- MeSH
- erbB receptory genetika metabolismus MeSH
- kolorektální nádory genetika metabolismus MeSH
- lidé MeSH
- mikro RNA genetika MeSH
- nádorové biomarkery genetika MeSH
- proteinkinasy genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- RNA interference MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Mitochondria-targeting peptides represent an emergent tool for cancer inhibition. Here supramolecular assemblies of novel amphiphilic cell-penetrating peptides for targeting cancer cell mitochondria are reported. The employed strategy aims at amplifying the apoptotic stimuli by weakening the mitochondrial VDAC1 (voltage-dependent anion channel-1)-hexokinase-II (HK-II) interaction. Peptide engineering is performed with the N-terminus of the HK-II protein, which binds to VDAC1. First, a designed positively charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV). Second, a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV in order to enhance the intracellular delivery of the HK-II scaffold. The self-assembly properties of these two synthetic peptides are investigated by synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron (cryo-TEM) imaging, which evidence the formation of nanoassemblies of ellipsoid-like shapes. Circular dichroism (CD) spectroscopy demonstrates the induction of partial α-helical structures in the amphiphilic peptides. Confocal microscopy reveals the specific mitochondrial location of Pal-pHK-pKV assemblies in human non-small cell lung cancer (NSCLC) A549 cells. The cytotoxicity and apoptotic studies indicate the enhanced bioactivity of Pal-pHK-pKV self-assembled reservoirs, which cause massive A549 cell death with regard to pHK-pKV. Of significance, Pal-pHK-pKV treatment of non-cancerous NCM460 cells resulted in substantially lower cytotoxicity. The results demonstrate the potential of self-assembled lipo-peptide (HK-II-derived) conjugates as a promising strategy in cancer therapy.
- MeSH
- buněčná smrt účinky léků MeSH
- buňky A549 MeSH
- hexokinasa metabolismus MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- lipidy chemie MeSH
- lipopeptidy chemická syntéza terapeutické užití MeSH
- mitochondrie metabolismus MeSH
- nádory plic farmakoterapie patologie MeSH
- napětím ovládaný aniontový kanál 1 metabolismus MeSH
- penetrační peptidy chemická syntéza metabolismus MeSH
- povrchově aktivní látky metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Tyrozinkinázové inhibitory EGFR se staly základní léčbou nemocných s pokročilým nemalobuněčným karcinomem plic s mutacemi EGFR, vyznačující se vysokou četností léčebných odpovědí a prodloužením doby do progrese nemoci ve srovnání s klasickou léčbou platinovým dubletem. U většiny nemocných dochází zhruba do 12 měsíců od zahájení léčby k vzniku sekundární rezistence a progresi nemoci. Nejčastějším mechanismem této rezistence je mutace T790M. Inhibitory EGFR 3. generace jsou cílené proti této mutaci. Z doposud testovaných inhibitorů 3. generace se do klinické praxe doposud dostal pouze osimertinib. V článku budou shrnuta data o účinku tyrozinkinázových inhibitorů 3. generace v léčbě nemocných s nemalobuněčným karcinomem plic.
EGFR tyrosinkinase inhibitors became a cornerstone of therapy patients with advanced non-small cell lung cancer harbouring mutations in the EGFR kinase domain. EGFR TKI therapy is characterized by high response rate and prolonged progression free survival when compared with standard platinum-based chemotherapy dublets. Despite this, vast majority of patients develope during first 12 months of therapy resistence to TKI and tumor progression. The most common mechanism of this resistence is a secondary T790M mutation. EGFR TKI of third generation are deginged to overcome this type of resistence. Osimertinib became only one of these 3rd generation tyrosinkinase inhibitors adopted for clinical use. This paper will summarize data about 3rd generation EGFR TKI in the treatment of patients with non-small cell lung cancer.
- Klíčová slova
- mutace T790M, osimertinib, rociletinib, studie AURA3, studie FLAURA, naquotinib,
- MeSH
- chemorezistence * MeSH
- cílená molekulární terapie MeSH
- erbB receptory antagonisté a inhibitory genetika MeSH
- inhibitory proteinkinas * farmakologie klasifikace škodlivé účinky terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- mutace MeSH
- mutační analýza DNA metody MeSH
- nemalobuněčný karcinom plic * farmakoterapie genetika komplikace patologie MeSH
- piperaziny MeSH
- přežití bez známek nemoci MeSH
- protinádorové látky terapeutické užití MeSH
- signální transdukce MeSH
- tyrosinkinasy * antagonisté a inhibitory MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
