BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies. METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations. RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2. CONCLUSION: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.
- MeSH
- ABC transportér z rodiny G, člen 2 * metabolismus antagonisté a inhibitory MeSH
- apoptóza účinky léků MeSH
- bortezomib * farmakologie MeSH
- inhibitory HIV-proteasy * farmakologie MeSH
- inhibitory proteasomu farmakologie MeSH
- lidé MeSH
- Lopinavir * farmakologie MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny antagonisté a inhibitory metabolismus MeSH
- nelfinavir * farmakologie MeSH
- oligopeptidy * farmakologie MeSH
- P-glykoproteiny metabolismus MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie MeSH
- signální dráha UPR * účinky léků MeSH
- stres endoplazmatického retikula účinky léků MeSH
- synergismus léků * MeSH
- triple-negativní karcinom prsu * farmakoterapie patologie MeSH
- XBP1 metabolismus genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. Despite radical surgery and radiotherapy supported by chemotherapy, the disease still remains incurable with an extremely low median survival rate of 12-15 months from the time of initial diagnosis. The main cause of treatment failure is considered to be the presence of cells that are resistant to the treatment. MicroRNAs (miRNAs) as regulators of gene expression are involved in the tumor pathogenesis, including GBM. MiR-338 is a brain-specific miRNA which has been described to target pathways involved in proliferation and differentiation. In our study, miR-338-3p and miR-338-5p were differentially expressed in GBM tissue in comparison to non-tumor brain tissue. Overexpression of miR-338-3p with miRNA mimic did not show any changes in proliferation rates in GBM cell lines (A172, T98G, U87MG). On the other hand, pre-miR-338-5p notably decreased proliferation and caused cell cycle arrest. Since radiation is currently the main treatment modality in GBM, we combined overexpression of pre-miR-338-5p with radiation, which led to significantly decreased cell proliferation, increased cell cycle arrest, and apoptosis in comparison to irradiation-only cells. To better elucidate the mechanism of action, we performed gene expression profiling analysis that revealed targets of miR-338-5p being Ndfip1, Rheb, and ppp2R5a. These genes have been described to be involved in DNA damage response, proliferation, and cell cycle regulation. To our knowledge, this is the first study to describe the role of miR-338-5p in GBM and its potential to improve the sensitivity of GBM to radiation.
- MeSH
- buněčné dělení účinky léků účinky záření MeSH
- glioblastom genetika patologie MeSH
- kontrolní body buněčného cyklu účinky léků účinky záření MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové proteiny biosyntéza genetika MeSH
- mikro RNA genetika MeSH
- monomerní proteiny vázající GTP biosyntéza genetika MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny biosyntéza genetika MeSH
- nádory mozku genetika patologie MeSH
- neuropeptidy biosyntéza genetika MeSH
- poškození DNA genetika MeSH
- proteinfosfatasa 2 biosyntéza genetika MeSH
- regulace genové exprese u nádorů genetika MeSH
- RNA nádorová genetika MeSH
- stanovení celkové genové exprese MeSH
- tolerance záření genetika MeSH
- transportní proteiny biosyntéza genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
High-grade gliomas (HGGs) are malignant primary brain tumors of glial cell origin. Despite optimal course of treatment, including maximal surgical resection followed by adjuvant chemo- and/or radiotherapy, the prognosis still remains poor. The main reason is the commonly occurring chemo- and radioresistance of these tumors. In recent years, several signaling pathways, especially PI3K/AKT and ATM/CHK2/p53, have been linked to the resistance of gliomas. Moreover, additional studies have shown that these pathways are significantly regulated by microRNAs (miRNAs), short endogenous RNA molecules that modulate gene expression and control many biological processes including apoptosis, proliferation, cell cycle, invasivity, and angiogenesis. MiRNAs are not only highly deregulated in gliomas, their expression signatures have also been shown to predict prognosis and therapy response. Therefore, they present promising biomarkers and therapeutic targets that might overcome the resistance to treatment and improve prognosis of glioma patients. In this review, we summarize the current knowledge of the functional role of miRNAs in gliomas resistance to chemo- and radiotherapy.
- MeSH
- apoptóza MeSH
- chemorezistence genetika MeSH
- DNA vazebné proteiny metabolismus MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- gliom * farmakoterapie genetika radioterapie MeSH
- invazivní růst nádoru MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- nádorové supresorové proteiny metabolismus MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory mozku farmakoterapie genetika radioterapie MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- proteiny buněčného cyklu metabolismus MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- tolerance záření genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
