Článek se soustředí na farmakoterapii farmakorezistentní schizofrenie. Nejprve je uvedena definice farmakorezistentní schizofrenie a způsoby vyloučení pseudorezistence. Detailněji jsou rozebrány možnosti léčby, tj. změna stávající léčby, augmentace a kombinace antipsychotik. Na závěr je krátce zmíněna perspektivní léčba.
The paper is focused on pharmacotherapy of treatment-resistant schizophrenia and exclusion of pseudoresistance. The treatment options including switch, augmentation and combination of antipsychotics are described. Finally, perspective substances are briefly mentioned.
- MeSH
- antipsychotika MeSH
- klozapin terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- léková rezistence * MeSH
- lidé MeSH
- refrakterní schizofrenie * farmakoterapie MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Coriolus versicolor (CV), known in traditional Chinese medicine for over 2000 years, is currently used in China and Japan to reduce chemotherapy or radiotherapy side effects in cancer patients. Despite extensive research, its effects still need improvement. This study aimed to determine if combining CV extract with LY294002, an inhibitor of the phosphatidylinositol-3-kinase (PI3K) signalling pathway, enhances cancer cell treatment, potentially leading to a novel therapeutic approach. Three human cancer cell lines (MCF-7, HeLa, and A549) were treated with CV extract alone or combined with LY294002. Cell viability was assessed using MTT assays. Then, HeLa and MCF-7 cells most sensitive to the co-treatment were used to evaluate colony formation, apoptosis, cell cycle, cell migration and invasion, and phospho-PI3K expression. The results demonstrated that LY294002 enhanced the CV extract's anti-tumour effects by reducing cell viability and colony formation. The combined treatment with CV extract and LY294002 more effectively induced G0/G1 cell cycle arrest, promoted apoptosis, reduced cell invasion and migration, and inhibited phospho-PI3K expression compared to each agent alone. This study highlights the potent cytotoxic enhancement between CV extract and LY294002 on cancer cells, primarily by inhibiting phospho-PI3K expression. These findings suggest promising avenues for developing novel combination therapies targeting cancer.
- MeSH
- apoptóza * účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- buňky A549 MeSH
- chromony * farmakologie MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- HeLa buňky MeSH
- inhibitory fosfoinositid-3-kinasy * farmakologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- morfoliny * farmakologie MeSH
- nádorové buněčné linie MeSH
- pohyb buněk * účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky farmakologie MeSH
- rostlinné extrakty farmakologie chemie MeSH
- signální transdukce účinky léků MeSH
- synergismus léků MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a CHK1 inhibitor (MK-8776, CHK1i) produced a synergistic effect, reducing cell viability and inducing marked oxidative stress and DNA damage, particularly in the HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX and caspase-3/7 activity. Both HCC cell lines exhibited heightened sensitivity to the combined treatment. The effect of drugs on the expression of proliferation markers in an olaparib-resistant patient-derived xenograft (PDX) model of ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by a drop in proliferation marker Ki-67 levels in response to PARPi combined with CHK1i. No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles.
- MeSH
- apoptóza účinky léků MeSH
- buňky Hep G2 MeSH
- checkpoint kinasa 1 metabolismus antagonisté a inhibitory MeSH
- ftalaziny * farmakologie MeSH
- hepatocelulární karcinom * farmakoterapie patologie metabolismus MeSH
- játra účinky léků patologie metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory jater * farmakoterapie patologie metabolismus MeSH
- nádory vaječníků * farmakoterapie patologie metabolismus MeSH
- PARP inhibitory farmakologie terapeutické užití MeSH
- piperaziny * farmakologie MeSH
- poškození DNA účinky léků MeSH
- proliferace buněk účinky léků MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie terapeutické užití škodlivé účinky MeSH
- pyrazoly farmakologie MeSH
- pyrimidiny MeSH
- synergismus léků * MeSH
- viabilita buněk účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Platinum(IV) compounds possess distinct properties that set them apart from platinum(II) compounds. Often designed as prodrugs, they are reduced within cancer cells to their active platinum(II) form, enabling their cytotoxic effects. Their versatility also lies in their ability to be functionalized and conjugated with bioactive molecules to enhance cancer cell targeting. This report introduces new prodrugs that combine antitumor cisplatin with axially coordinated eugenol, leveraging their synergistic action to target cancer stem cells. A third bioactive ligand, 4-phenylbutyrate or octanoate, was added to further enhance biological activity, creating 'triple action' prodrugs. These new platinum(IV) prodrugs offer a novel approach to cancer therapy by improving targeting, increasing efficacy, overcoming drug resistance, and reducing tumor invasiveness while sparing healthy tissue.
- MeSH
- cisplatina * farmakologie MeSH
- eugenol * farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky * účinky léků patologie MeSH
- nádory tračníku * farmakoterapie patologie MeSH
- prekurzory léčiv * farmakologie chemie MeSH
- protinádorové látky * farmakologie chemie MeSH
- synergismus léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The emergence of biofilm-induced drug tolerance poses a critical challenge to public healthcare management. Pseudomonas aeruginosa, a gram-negative opportunistic bacterium, is involved in various biofilm-associated infections in human hosts. Towards this direction, in the present study, a combinatorial approach has been explored as it is a demonstrably effective strategy for managing microbial infections. Thus, P. aeruginosa has been treated with cuminaldehyde (a naturally occurring phytochemical) and gentamicin (an aminoglycoside antibiotic) in connection to the effective management of the biofilm challenges. It was also observed that the test molecules could show increased antimicrobial activity against P. aeruginosa. A fractional inhibitory concentration index (FICI) of 0.65 suggested an additive interaction between cuminaldehyde and gentamicin. Besides, a series of experiments such as crystal violet assay, estimation of extracellular polymeric substance (EPS), and microscopic images indicated that an enhanced antibiofilm activity was obtained when the selected compounds were applied together on P. aeruginosa. Furthermore, the combination of the selected compounds was found to reduce the secretion of virulence factors from P. aeruginosa. Taken together, this study suggested that the combinatorial application of cuminaldehyde and gentamicin could be considered an effective approach towards the control of biofilm-linked infections caused by P. aeruginosa.
- MeSH
- antibakteriální látky * farmakologie MeSH
- benzaldehydy * farmakologie MeSH
- biofilmy * účinky léků MeSH
- cymeny farmakologie MeSH
- faktory virulence MeSH
- gentamiciny * farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- Pseudomonas aeruginosa * účinky léků fyziologie MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The current global scenario presents us with a growing increase in infections caused by fungi, referred to by specialists in the field as a "silent epidemic", aggravated by the limited pharmacological arsenal and increasing resistance to this therapy. For this reason, drug repositioning and therapeutic compound combinations are promising strategies to mitigate this serious problem. In this context, this study investigates the antifungal activity of the non-toxic, low-cost and widely available cationic polyelectrolyte Poly(diallyldimethylammonium chloride) (PDDA), in combination with different antifungal drugs: systemic (amphotericin B, AMB), topical (clioquinol, CLIO) and oral (nitroxoline, NTX). For each combination, different drug:PDDA ratios were tested and, through the broth microdilution technique, the minimum inhibitory concentration (MIC) of these drugs in the different ratios against clinically important Candida species strains was determined. Overall, PDDA combinations with the studied drugs demonstrated a significant increase in drug activity against most strains, reaching MIC reductions of up to 512 fold for the fluconazole resistant Candida krusei (Pichia kudriavzevii). In particular, the AMB-PDDA combination 1:99 was highly effective against AMB-resistant strains, demonstrating the excellent profile of PDDA as an adjuvant/association in novel antifungal formulations with outdated conventional drugs.
- MeSH
- amfotericin B farmakologie MeSH
- antifungální látky * farmakologie MeSH
- Candida * účinky léků MeSH
- fungální léková rezistence MeSH
- kandidóza mikrobiologie farmakoterapie MeSH
- kvartérní amoniové sloučeniny * farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- Pichia MeSH
- polyelektrolyty farmakologie MeSH
- polyethyleny farmakologie chemie MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem closely linked to dietary habits, particularly high fructose consumption. This study investigates the combined effects of fructose and common food preservatives (sodium benzoate, sodium nitrite, and potassium sorbate) on the development and progression of MASLD. Methods: We utilized a human microbiota-associated mouse model, administering 10% fructose with or without preservatives for 11 weeks. Liver histology, hepatic gene expression (microarray analysis), biochemical markers, cytokine profiles, intestinal permeability, and gut microbiome composition (16S rRNA and Internal Transcribed Spacer (ITS) sequencing) were evaluated. Results: Fructose and potassium sorbate synergistically induced liver pathology characterized by increased steatosis, inflammation and fibrosis. These histological changes were associated with elevated liver function markers and altered lipid profiles. The treatments also induced significant changes in both the bacterial and fungal communities and disrupted intestinal barrier function, leading to increased pro-inflammatory responses in the mesenteric lymph nodes. Liver gene expression analysis revealed a wide range of transcriptional changes induced by fructose and modulated by the preservative. Key genes involved in lipid metabolism, oxidative stress, and inflammatory responses were affected. Conclusions: Our findings highlight the complex interactions between dietary components, gut microbiota, and host metabolism in the development of MASLD. The study identifies potential risks associated with the combined consumption of fructose and preservatives, particularly potassium sorbate. Our data reveal new mechanisms that are involved in the development of MASLD and open up a new avenue for the prevention and treatment of MASLD through dietary interventions and the modulation of the microbiome.
- MeSH
- exprese genu účinky léků MeSH
- fruktosa * škodlivé účinky MeSH
- játra * metabolismus účinky léků MeSH
- kyselina sorbová farmakologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- potravinářské konzervační látky * farmakologie škodlivé účinky MeSH
- střevní mikroflóra * účinky léků MeSH
- synergismus léků MeSH
- ztučnělá játra MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I1⁄2 and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.
- MeSH
- duktální karcinom slinivky břišní * farmakoterapie patologie metabolismus MeSH
- inhibitory proteinkinas * farmakologie MeSH
- lidé MeSH
- MAP kinasový signální systém * účinky léků MeSH
- nádorové buněčné linie MeSH
- nádory slinivky břišní * patologie farmakoterapie metabolismus MeSH
- protoonkogenní proteiny p21(ras) metabolismus genetika MeSH
- raf kinasy metabolismus antagonisté a inhibitory MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.
- MeSH
- apoptóza účinky léků MeSH
- benzothiazoly MeSH
- bicyklické sloučeniny heterocyklické * farmakologie terapeutické užití MeSH
- chemorezistence * MeSH
- isochinoliny MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protein bcl-X * metabolismus antagonisté a inhibitory MeSH
- protein BCL2L11 * metabolismus genetika MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus antagonisté a inhibitory MeSH
- sulfonamidy * farmakologie terapeutické užití MeSH
- synergismus léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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
