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1.
J Inorg Biochem ; 257: 112614, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38781850

ABSTRACT

Ruthenium complexes containing triphenylphosphine diamide ligands were prepared, characterized, and tested for their biological activity against various cancer cell lines and the malaria parasite, Plasmodium falciparum. The effect of M (mono-substituted) and B (bis-substituted) complexes on the human cervical carcinoma (HeLa) cell line was investigated using the MTT assay. Five (B2, B3, B5, B6, and B13) of the 24 synthesized ruthenium complexes showed significant effects with IC50 values ranging between 0.3 and 2.3 µM. Evaluation of the potential biomolecular targets of B2 and B13 by fluorescence spectroscopy revealed relevant interactions with BSA and only a weak affinity for ctDNA. Complexes M2, B2, M13 and B13 were selected for further biological characterization. Their effect on the viability of two ovarian cancer cell lines was compared to normal cell lines, denoting their selectivity. Upon treatment of four different drug-resistant gynaecological cancer cell lines, differing in their multidrug-resistant phenotypes, the efficacy of the bis-substituted complexes was shown to be greater than their mono-substituted counterparts. The non-MDR cells are sensitive to all the tested complexes, compared to MDR cells which are less sensitive. Upon investigation of complexes M2, M13, B2, and B13 against sensitive and multidrug-resistant parasite strains of P. falciparum, the bis-substituted complexes were again shown to be the most potent, with submicromolar activity against both strains. Furthermore, the resistance indexes for the complexes were approximately equal to 1, which is at least 5-fold lower than chloroquine diphosphate, suggesting the ability of these complexes to retain their activity in resistant forms of the parasite.

2.
Int J Mol Sci ; 25(9)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38732083

ABSTRACT

Three new phenanthridine peptide derivatives (19, 22, and 23) were synthesized to explore their potential as spectrophotometric probes for DNA and RNA. UV/Vis and circular dichroism (CD) spectra, mass spectroscopy, and computational analysis confirmed the presence of intramolecular interactions in all three compounds. Computational analysis revealed that compounds alternate between bent and open conformations, highlighting the latter's crucial influence on successful polynucleotide recognition. Substituting one glycine with lysine in two regioisomers (22, 23) resulted in stronger binding interactions with DNA and RNA than for a compound containing two glycines (19), thus emphasizing the importance of lysine. The regioisomer with lysine closer to the phenanthridine ring (23) exhibited a dual and selective fluorimetric response with non-alternating AT and ATT polynucleotides and induction of triplex formation from the AT duplex. The best binding constant (K) with a value of 2.5 × 107 M-1 was obtained for the interaction with AT and ATT polynucleotides. Furthermore, apart from distinguishing between different types of ds-DNA and ds-RNA, the same compound could recognize GC-rich DNA through distinct induced CD signals.


Subject(s)
Circular Dichroism , DNA , Lysine , Peptides , Phenanthridines , Phenanthridines/chemistry , Lysine/chemistry , Peptides/chemistry , DNA/chemistry , DNA/metabolism , RNA/chemistry , Nucleic Acid Conformation
3.
J Med Chem ; 67(8): 6081-6098, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38401050

ABSTRACT

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.


Subject(s)
2,2'-Dipyridyl , Antineoplastic Agents , Phosphines , Silver , Humans , Phosphines/chemistry , Phosphines/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Silver/chemistry , Silver/pharmacology , 2,2'-Dipyridyl/chemistry , 2,2'-Dipyridyl/pharmacology , Cell Line, Tumor , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Apoptosis/drug effects , Crystallography, X-Ray , Ligands , Cell Death/drug effects , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Drug Resistance, Neoplasm/drug effects
4.
Int Urol Nephrol ; 56(3): 1007-1017, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37891379

ABSTRACT

Most solid metastatic cancers are resistant to chemotherapy. However, metastatic testicular germ cell tumors (TGCT) are cured in over 80% of patients using cisplatin-based combination therapy. Published data suggest that TGCTs are sensitive to cisplatin due to limited DNA repair and presumably also to a propensity to undergo apoptosis. To further investigate this aspect, cisplatin-induced activation of apoptotic pathways was investigated in cisplatin-sensitive testis tumor cells (TTC) and compared to cisplatin-resistant bladder cancer cells. Apoptosis induction was investigated using flow cytometry, caspase activation and PARP-1 cleavage. Immunoblotting and RT-PCR were applied to investigate pro- and anti-apoptotic proteins. Transfections were performed to target p53- and Fas/FasL-mediated apoptotic signaling. Immunoblotting experiments revealed p53 to be induced in TTC, but not bladder cancer cells following cisplatin. Higher levels of pro-apoptotic Bax and Noxa were observed in TTC, anti-apoptotic Bcl-2 was solely expressed in bladder cancer cells. Cisplatin led to translocation of Bax to the mitochondrial membrane in TTC, resulting in cytochrome C release. Cisplatin increased the expression of FasR mRNA and FasL protein in all tumor cell lines. Targeting the apoptotic pathway via siRNA-mediated knockdown of p53 and FAS reduced death receptor-mediated apoptosis and increased cisplatin resistance in TTC, indicating the involvement of FAS-mediated apoptosis in the cisplatin TTC response. In conclusion, both the death receptor and the mitochondrial apoptotic pathway become strongly activated in TTC following cisplatin treatment, explaining, together with attenuated DNA repair, their unique sensitivity toward platinum-based anticancer drugs.


Subject(s)
Antineoplastic Agents , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Urinary Bladder Neoplasms , Male , Humans , Cisplatin/pharmacology , Cisplatin/therapeutic use , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/metabolism , Testicular Neoplasms/drug therapy , Testicular Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis , Urinary Bladder Neoplasms/drug therapy , Cell Line, Tumor , Receptors, Death Domain/metabolism
5.
Biochim Biophys Acta Rev Cancer ; 1879(1): 189052, 2024 01.
Article in English | MEDLINE | ID: mdl-38097143

ABSTRACT

High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive type of epithelial ovarian cancer, with high recurrence rate and chemoresistance being the main issues in its clinical management. HGSOC is specifically challenging due to the metastatic dissemination via spheroids in the ascitic fluid. The HGSOC spheroids represent the invasive and chemoresistant cellular fraction, which is impossible to investigate in conventional two-dimensional (2D) monolayer cell cultures lacking critical cell-to-cell and cell-extracellular matrix interactions. Three-dimensional (3D) HGSOC cultures, where cells aggregate and exhibit relevant interactions, offer a promising in vitro model of peritoneal metastasis and multicellular drug resistance. This review summarizes recent studies of HGSOC in 3D culture conditions and highlights the role of multicellular HGSOC spheroids and ascitic environment in HGSOC metastasis and chemoresistance.


Subject(s)
Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Drug Resistance, Neoplasm , Carcinoma, Ovarian Epithelial/drug therapy
6.
Acta Pharm ; 73(4): 601-616, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-38147483

ABSTRACT

Olive leaves as a main byproduct of olive oil and fruit industry are a valuable source of phytochemicals such as polyphenols, with multiple biomedical effects. Apart from leaves, olive branches and stems make up a significant amount of olive waste. It is well known that the drying process and long-term storage affect the stability and concentration of polyphenols present in raw materials. For that matter, two different means of storing olive waste, at room temperature and +4 °C, were compared by determining the content of the polyphenol oleuropein (OLE) in olive leaf, branch, and stem extracts (LE, BE, and SE) by HPLC-DAD method. Total phenols (TPC), o-diphenols (o-DPC), and total flavonoids (TFC) content in extracts were assessed by UV-Vis measurements. LE prepared from leaves stored at +4 °C had the highest OLE content, 30.7 mg g-1 of dry extract (DE). SE from stems stored at +4 °C was the richest in TPC and TFC (193 mg GAE/g DE and 82.9 mg CE/g DE, respectively), due to the higher purity of the extract. The biological activity of extracts was determined on cervical cancer (HeLa), melanoma (A375), metastatic melanoma (A375M) tumor cell lines, and on spontaneously immortalized cell line of keratinocytes (HaCaT), using the MTT assay. The data show that all extracts had a similar dose-dependent effect on cell viability in HeLa cells, while the effect of LE on melanoma A375 and A375M, and HaCaT cells was cell-line dependent.


Subject(s)
Melanoma , Olea , Uterine Cervical Neoplasms , Female , Humans , Melanoma/drug therapy , HeLa Cells , Iridoids/pharmacology , Iridoids/chemistry , Polyphenols/pharmacology , Olea/chemistry , Antioxidants/analysis , Plant Leaves/chemistry , Plant Extracts/chemistry
7.
Cell Mol Life Sci ; 80(10): 294, 2023 Sep 17.
Article in English | MEDLINE | ID: mdl-37718345

ABSTRACT

Resistance to platinum- and taxane-based chemotherapy represents a major obstacle to long-term survival in ovarian cancer (OC) patients. Here, we studied the interplay between acquired carboplatin (CBP) resistance using two OC cell models, MES-OV CBP and SK-OV-3 CBP, and non-P-glycoprotein-mediated cross-resistance to paclitaxel (TAX) observed only in MES-OV CBP cells. Decreased platination, mesenchymal-like phenotype, and increased expression of α- and γ-tubulin were observed in both drug-resistant variants compared with parental cells. Both variants revealed increased protein expression of class III ß-tubulin (TUBB3) but differences in TUBB3 branching and nuclear morphology. Transient silencing of TUBB3 sensitized MES-OV CBP cells to TAX, and surprisingly also to CBP. This phenomenon was not observed in the SK-OV-3 CBP variant, probably due to the compensation by other ß-tubulin isotypes. Reduced TUBB3 levels in MES-OV CBP cells affected DNA repair protein trafficking and increased whole-cell platination level. Furthermore, TUBB3 depletion augmented therapeutic efficiency in additional OC cells, showing vice versa drug-resistant pattern, lacking ß-tubulin isotype compensation visible at the level of total ß-tubulin (TUBB) in vitro and ex vivo. In summary, the level of TUBB in OC should be considered together with TUBB3 in therapy response prediction.


Subject(s)
Ovarian Neoplasms , Tubulin , Humans , Female , Carboplatin/pharmacology , Carboplatin/therapeutic use , Up-Regulation , Tubulin/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Transcriptional Activation
8.
Dalton Trans ; 52(33): 11698-11704, 2023 Aug 22.
Article in English | MEDLINE | ID: mdl-37555301

ABSTRACT

Two novel pyrene triphenylphosphine ruthenium conjugates act as fluorescent turn-on beacons for serum albumin, being non-fluorescent in aqueous media but exhibiting strong emission upon binding to BSA. The selective cytotoxicity of the compounds against tumour cells is enhanced upon irradiation by UV-light, paving the way for application in photodynamic therapy under two-photon excitation.


Subject(s)
Ruthenium , Serum Albumin, Bovine , Serum Albumin, Bovine/chemistry , Ruthenium/chemistry , Serum Albumin , Spectrometry, Fluorescence , Pyrenes
9.
Biomed Pharmacother ; 166: 115349, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37634476

ABSTRACT

BACKGROUND: DNA methylation, histone modifications, and miRNAs affect ovarian cancer (OC) progression and therapy response. PURPOSE: Identification of epigenetically downregulated miRNAs in drug-resistant OC cell lines with a possible role in drug resistance and/or drug-induced mesenchymal-like phenotype. METHODS: MiRNA profiling was performed on parental and carboplatin-resistant OC cells, MES-OV and MES-OV CBP. RT-qPCR validation, epigenetic modulation and other CBP-resistant OC cell lines were used to select miRNAs of interest. The integration of miRNA-predicted target genes and differentially expressed genes (DEGs), pathway and functional analysis were used for forecasting their biological role. Data mining was performed to determine their possible prognostic and predictive values. RESULTS: MiRNA profiling revealed 48 downregulated miRNAs in OC cells whose drug sensitivity and metastatic potential were impacted by epigenetic modulators. Of the fourteen selected, nine were validated as changed, and seven of these restored their expression upon treatment with epigenetic inhibitors. Only three had similar expression patterns in other OC cell lines. MiRNA-mRNA integrative analysis resulted in 56 target DEGs. Pathway analysis revealed that these genes are involved in cell adhesion, migration, and invasion. The functional analysis confirmed the role of miR-103a-3p, miR-17-5p and miR-107 in cell invasion, while data mining showed their prognostic and predictive values. Only miR-103a-3p was epigenetically regulated at the constitutive level. CONCLUSION: High throughput miRNA and cDNA profiling coupled with pathway analysis and data mining delivered evidence for miRNAs which can be epigenetically regulated in drug-resistant, mesenchymal-like OC cells as possible markers to combat therapy-induced short overall survival and tumor metastatic potential.


Subject(s)
Ovarian Neoplasms , Female , Humans , Carboplatin/pharmacology , Prognosis , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Phenotype
10.
Biomolecules ; 13(1)2023 01 07.
Article in English | MEDLINE | ID: mdl-36671513

ABSTRACT

The binding interactions of six ligands, neutral and monocationic asymmetric monomethine cyanine dyes comprising benzoselenazolyl moiety with duplex DNA and RNA and G-quadruplex structures were evaluated using fluorescence, UV/Vis (thermal melting) and circular dichroism (CD) spectroscopy. The main objective was to assess the impact of different substituents (methyl vs. sulfopropyl vs. thiopropyl/thioethyl) on the nitrogen atom of the benzothiazolyl chromophore on various nucleic acid structures. The monomethine cyanine dyes with methyl substituents showed a 100-fold selectivity for G-quadruplex versus duplex DNA. Study results indicate that cyanines bind with G-quadruplex via end π-π stacking interactions and possible additional interactions with nucleobases/phosphate backbone of grooves or loop bases. Cyanine with thioethyl substituent distinguishes duplex DNA and RNA and G-quadruplex structures by distinctly varying ICD signals. Furthermore, cell viability assay reveals the submicromolar activity of cyanines with methyl substituents against all tested human cancer cell lines. Confocal microscopy analysis shows preferential accumulation of cyanines with sulfopropyl and thioethyl substituents in mitochondria and indicates localization of cyanines with methyl in nucleus, particularly nucleolus. This confirms the potential of examined cyanines as theranostic agents, possessing both fluorescent properties and cell viability inhibitory effect.


Subject(s)
G-Quadruplexes , Selenium , Humans , Precision Medicine , DNA/chemistry , Circular Dichroism , Fluorescent Dyes/pharmacology , Fluorescent Dyes/chemistry , RNA
11.
Br J Cancer ; 128(7): 1344-1359, 2023 03.
Article in English | MEDLINE | ID: mdl-36717670

ABSTRACT

BACKGROUND: In ovarian cancer (OC) therapy, even initially responsive patients develop drug resistance. METHODS: Here, we present an OC cell model composed of variants with differing degrees of acquired resistance to carboplatin (CBP), cross-resistance to paclitaxel, and CBP-induced metastatic properties (migration and invasion). Transcriptome data were analysed by two approaches identifying differentially expressed genes and CBP sensitivity-correlating genes. The impact of selected genes and signalling pathways on drug resistance and metastatic potential, along with their clinical relevance, was examined by in vitro and in silico approaches. RESULTS: TMEM200A and PRKAR1B were recognised as potentially involved in both phenomena, also having high predictive and prognostic values for OC patients. CBP-resistant MES-OV CBP8 cells were more sensitive to PI3K/Akt/mTOR pathway inhibitors Rapamycin, Wortmannin, SB216763, and transcription inhibitor Triptolide compared with parental MES-OV cells. When combined with CBP, Rapamycin decreased the sensitivity of parental cells while Triptolide sensitised drug-resistant cells to CBP. Four PI3K/Akt/mTOR inhibitors reduced migration in both cell lines. CONCLUSIONS: A newly established research model and two distinct transcriptome analysis approaches identified novel candidate genes enrolled in CBP resistance development and/or CBP-induced EMT and implied that one-gene targeting could be a better approach than signalling pathway inhibition for influencing both phenomena.


Subject(s)
Ovarian Neoplasms , Proto-Oncogene Proteins c-akt , Humans , Female , Carboplatin/pharmacology , Carboplatin/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Drug Resistance, Neoplasm/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Sirolimus , Gene Expression Profiling , Cell Line, Tumor
12.
Dalton Trans ; 51(44): 17008-17021, 2022 Nov 15.
Article in English | MEDLINE | ID: mdl-36301147

ABSTRACT

Seven bis(2-picolyl)amine (bpa) and five iminodiacetamide (imda) ligands were prepared with different modifications in their side chain structure. The coordination properties of the ligands (L) were influenced by changes in the aliphatic linker length (C1, C2, or C3), amide group isomers and type of chiral terminal group. Complexation with Cu(II) afforded two polymorphs of a ML complex which features tetradentate coordination of a ligand with C2 linkers, while crystal structures of three trans-fac ML2 complexes with Cu(II) and Ni(II) show tridentate coordination of ligands with a C3 linker. The stoichiometry and stereochemistry of Zn(II) and Cu(II) complexes was further studied in solution by NMR and UV-Vis spectroscopy. DFT calculations gave an insight into the relative stability of isomers, as well as potential hydrogen bonding between two ligands in a ML2 complex. Furthermore, ML complexes of Cu(II) exhibited DNA cleavage activity.


Subject(s)
Amines , Coordination Complexes , Ligands , Amines/chemistry , Molecular Structure , Crystallography, X-Ray , Zinc/chemistry , Copper/chemistry , Coordination Complexes/chemistry
13.
Bioorg Chem ; 127: 105999, 2022 10.
Article in English | MEDLINE | ID: mdl-35809513

ABSTRACT

New monomethine, unsymmetrical styryl dyes consisting of benzothiazole and N-methylpiperazine or N-phenylpiperazine scaffolds were synthesized, and their binding affinities for different ds-polynucleotides and G-quadruplex were studied. Substitution of piperazine unit with methyl or phenyl group strongly influenced their binding modes, binding affinities, spectroscopic responses and antiproliferative activities. Compounds with N-methylpiperazine substituents showed a significant preference for AT-DNA polynucleotides and demonstrated AT-minor groove binding, which manifested in strong fluorescence increase, significant double helix stabilization, and positive induced circular dichroism spectra. These compounds formed complexes with G-quadruplex by π-π stacking interactions of dye with the top or bottom G-tetrad. Bulkier compounds with N-phenylpiperazine function are probably bound to ds-polynucleotide by partial intercalation between base pairs. On the other hand, they showed stronger stabilization of G-quadruplex compared to methyl-substituted compounds. Fluorimetric titrations pointed to possible mixed stoichiometry's: 1:1 complex with π-π stacking interactions of dye on the top or bottom G-tetrad and 1:2 complex with dye positioned between two G-quadruplex molecules. Bulkier dyes with N-phenylpiperazine fragments demonstrated micromolar and submicromolar antiproliferative activity that was especially pronounced for leukaemia and lymphoma. Flow cytometric assay shows dose- and time-dependent increase in SubG0/G1 phase. Furthermore, the compounds enter the cells readily and accumulate in the mitochondrial space, co-localize with the standard mitochondrial markers.


Subject(s)
Coloring Agents , G-Quadruplexes , DNA/chemistry , Ligands , Piperazines/pharmacology , Polynucleotides , Precision Medicine
14.
Cancer Lett ; 520: 361-373, 2021 11 01.
Article in English | MEDLINE | ID: mdl-34389435

ABSTRACT

The anthracycline derivative doxorubicin (Doxo) induces DNA double-strand breaks (DSBs) by inhibition of DNA topoisomerase type II. Defective mismatch repair (MMR) contributes to Doxo resistance and has been reported for colon and mammary carcinomas. Here, we investigated the outcome of pharmacological inhibition of various DNA repair-related mechanisms on Doxo-induced cytotoxicity employing MMR-deficient HCT-116 colon carcinoma cells. Out of different inhibitors tested (i.e. HDACi, PARPi, MRE11i, RAD52i, RAD51i), we identified the RAD51-inhibitor B02 as the most powerful compound to synergistically increase Doxo-induced cytotoxicity. B02-mediated synergism rests on pleiotropic mechanisms, including pronounced G2/M arrest, damage to mitochondria and caspase-driven apoptosis. Of note, B02 also promotes the cytotoxicity of oxaliplatin and 5-fluoruracil (5-FU) in HCT-116 cells and, furthermore, also increases Doxo-induced cytotoxicity in MMR-proficient colon and mammary carcinoma cells. Summarizing, pharmacological inhibition of RAD51 is suggested to synergistically increase the cytotoxic efficacy of various types of conventional anticancer drugs in different tumor entities. Hence, pre-clinical in vivo studies are preferable to determine the therapeutic window of B02 in a clinically oriented therapeutic regimen.


Subject(s)
Colonic Neoplasms/drug therapy , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/genetics , Rad51 Recombinase/genetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Caspases/genetics , Cell Proliferation/drug effects , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , DNA Damage/drug effects , DNA Mismatch Repair/drug effects , DNA Mismatch Repair/genetics , Doxorubicin/adverse effects , Drug Synergism , Fluorouracil/pharmacology , HCT116 Cells , Humans , Mitochondria/drug effects , Mitochondria/genetics , Oxaliplatin/pharmacology , Rad51 Recombinase/antagonists & inhibitors
15.
Arch Toxicol ; 95(7): 2279-2297, 2021 07.
Article in English | MEDLINE | ID: mdl-34003341

ABSTRACT

Over the last decade, important clinical benefits have been achieved in cancer patients by using drug-targeting strategies. Nevertheless, drug resistance is still a major problem in most cancer therapies. Epithelial-mesenchymal plasticity (EMP) and tumour microenvironment have been described as limiting factors for effective treatment in many cancer types. Moreover, epithelial-to-mesenchymal transition (EMT) has also been associated with therapy resistance in many different preclinical models, although limited evidence has been obtained from clinical studies and clinical samples. In this review, we particularly deepen into the mechanisms of which intermediate epithelial/mesenchymal (E/M) states and its interconnection to microenvironment influence therapy resistance. We also describe how the use of bioinformatics and pharmacogenomics will help to figure out the biological impact of the EMT on drug resistance and to develop novel pharmacological approaches in the future.


Subject(s)
Epithelial-Mesenchymal Transition , Neoplasms , Drug Resistance, Neoplasm , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Tumor Microenvironment
16.
Arh Hig Rada Toksikol ; 72(4): 326-332, 2021 Dec 30.
Article in English | MEDLINE | ID: mdl-34985836

ABSTRACT

Non-planar di-ortho-substituted PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl), one of the most abundant PCB congeners in the environment and in biological and human tissues, has been identified as potential endocrine disruptor affecting the reproductive and endocrine systems in rodents, wildlife, and humans. The aim of this study was to gain a deeper insight into its mode/mechanism of action in Chinese hamster ovary K1 cells (CHO-K1). PCB 153 (10-100 µmol/L) inhibited CHO-K1 cell proliferation, which was confirmed with four bioassays (Trypan Blue, Neutral Red, Kenacid Blue, and MTT), of which the MTT assay proved the most sensitive. PCB 153 also induced ROS formation in a dose-dependent manner. Apoptosis was seen after 6 h of exposure to PCB 153 doses ≥50 µmol/L, while prolonged exposure resulted in the activation of the necrotic pathway. PCB 153-induced disturbances in normal cell cycle progression were time-dependent, with the most significant effects occurring after 72 h.


Subject(s)
Endocrine Disruptors , Polychlorinated Biphenyls , Animals , CHO Cells , Cricetinae , Cricetulus , Endocrine Disruptors/toxicity , Polychlorinated Biphenyls/toxicity
17.
Drug Resist Updat ; 53: 100715, 2020 12.
Article in English | MEDLINE | ID: mdl-32679188

ABSTRACT

It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) are crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurtures tumor-initiating/cancer stem-like cells (CSCs), induces both EMT and MDR leading to tumor relapses. Pro-thrombotic microenvironment created by inflammatory cytokines and chemokines from TAMs, MDSCs and CAFs is also involved in EMT and MDR. MDSCs are the most common mediators of immunosuppression and are also involved in resistance to targeted therapies, e.g. BRAF inhibitors and oncolytic viruses-based therapies. Expansion of both cancer and stroma cells causes hypoxia by hypoxia-inducible transcription factors (e.g. HIF-1α) resulting in drug resistance. TME factors induce the expression of transcriptional EMT factors, MDR and metabolic adaptation of cancer cells. Promoters of several ATP-binding cassette (ABC) transporter genes contain binding sites for canonical EMT transcription factors, e.g. ZEB, TWIST and SNAIL. Changes in glycolysis, oxidative phosphorylation and autophagy during EMT also promote MDR. Conclusively, EMT signaling simultaneously increases MDR. Owing to the multifactorial nature of MDR, targeting one mechanism seems to be non-sufficient to overcome resistance. Targeting inflammatory processes by immune modulatory compounds such as mTOR inhibitors, demethylating agents, low-dosed histone deacetylase inhibitors may decrease MDR. Targeting EMT and metabolic adaptation by small molecular inhibitors might also reverse MDR. In this review, we summarize evidence for TME components as causative factors of EMT and anticancer drug resistance.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer-Associated Fibroblasts/drug effects , Cancer-Associated Fibroblasts/immunology , Cancer-Associated Fibroblasts/metabolism , Cell Line, Tumor , DNA Demethylation/drug effects , Disease Models, Animal , Drug Resistance, Multiple/immunology , Drug Resistance, Neoplasm/immunology , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/immunology , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Neoplasms/immunology , Neoplasms/pathology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Tumor-Associated Macrophages/drug effects , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism
18.
Antioxidants (Basel) ; 9(5)2020 May 24.
Article in English | MEDLINE | ID: mdl-32456297

ABSTRACT

The roles of phenolics from olive oils as effective anticancer agents have been documented in various in vitro studies of different cancer cells lines, but the relationship between the phenolic profile of olive oil and its biological activity needs more elucidation. In this study, we analysed phenolic profiles of extra virgin olive oils (EVOOs) from different autochthonous cultivars from Croatia (Oblica, Bjelica, Buza, Zizolera) and investigated the biological effect of EVOO phenolic extracts (EVOO-PEs) on human cervical (HeLa) and human colon (SW48) cancer cell lines alone and in combination with cisplatin (cDDP), carboplatin (CBP), 5-fluorouracil (5-FU) and irinotecan. The quantitative evaluation of olive oil polyphenols was performed by HPLC-DAD and spectrophotometric analysis. The biological effect of EVOO-PEs alone and in combination with anticancer drugs was measured by MTT assay. Analysed EVOO-PEs differ in phenolic profile and inhibited HeLa and SW48 cells in a dose-dependent manner. Further, it is shown that EVOO-PEs (Oblica-Sea, Buza and Zizolera), in combination with anticancer drugs, increase the metabolic activity of HeLa and SW48 cells and have a protective role. These data imply careful consummation of olive oil during chemotherapy of cancer patients.

19.
Drug Resist Updat ; 46: 100645, 2019 09.
Article in English | MEDLINE | ID: mdl-31585396

ABSTRACT

Curative cancer therapy remains a major challenge particularly in cancers displaying multidrug resistance (MDR). The MDR phenotype is characterized by cross-resistance to a wide array of anticancer drugs harboring distinct structures and mechanisms of action. The multiple factors involved in mediating MDR may include host factors, tumor factors as well as tumor-host interactions. Among the host factors are genetic variants and drug-drug interactions. The plethora of tumor factors involves decreased drug uptake primarily via impaired influx transporters, increased drug efflux predominantly due to the overexpression of MDR efflux transporters of the ATP-binding cassette superfamily or due to drug efflux mediated by extracellular vesicles (EVs) or drug-loaded lysosomes undergoing exocytosis, deregulation of cell death mechanisms (i.e. anti-apoptotic modalities), enhanced DNA damage repair, epigenetic alterations and/or deregulation of microRNAs. The intratumor heterogeneity and dynamics, along with cancer stem cell plasticity, are important tumor factors. Among the tumor-host interactions are the role of the tumor microenvironment, selective pressure of various stressor conditions and agents, acidic pH and the intracellular transfer of traits mediated by EVs. The involvement of these diverse factors in MDR, highlights the need for precision medicine and real-time personalized treatments of individual cancer patients. In this review, written by a group of researchers from COST Action STRATAGEM "New diagnostic and therapeutic tools against multidrug resistant tumors", we aim to bring together these multidisciplinary and interdisciplinary features of MDR cancers. Importantly, it is becoming increasingly clear that deciphering the molecular mechanisms underlying anticancer drug resistance, will pave the way towards the development of novel precision medicine treatment modalities that are able to surmount distinct and well-defined mechanisms of anticancer drug resistance.


Subject(s)
Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , Neoplasms/genetics , Antineoplastic Agents/therapeutic use , Biological Transport/drug effects , Biological Transport/genetics , Drug Interactions/genetics , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , Neoplasms/drug therapy , Neoplastic Stem Cells/drug effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics
20.
Arch Toxicol ; 93(8): 2265-2277, 2019 08.
Article in English | MEDLINE | ID: mdl-31289894

ABSTRACT

A common strategy to overcome acquired chemotherapy resistance is the combination of a specific anticancer drug (e.g., topoisomerase I inhibitor irinotecan) together with a putative sensitizer. The purpose of this study was to analyze the cytostatic/cytotoxic response of colorectal carcinoma (CRC) cells to irinotecan, depending on the mismatch repair (MMR) and p53 status and to examine the impact of BV6, a bivalent antagonist of inhibitors of apoptosis c-IAP1/c-IAP2, alone or combined with irinotecan. Therefore, several MSH2- or MSH6-deficient cell lines were complemented for MMR deficiency, or MSH6 was knocked out/down in MMR-proficient cells. Upon irinotecan, MMR-deficient/p53-mutated lines repaired DNA double-strand breaks by homologous recombination less efficiently than MMR-proficient/p53-mutated lines and underwent elevated caspase-9-dependent apoptosis. Opposite, BV6-mediated sensitization was achieved only in MMR-proficient/p53-mutated cells. In those cells, c-IAP1 and c-IAP2 were effectively degraded by BV6, caspase-8 was fully activated, and both canonical and non-canonical NF-κB signaling were triggered. The results were confirmed ex vivo in tumor organoids from CRC patients. Therefore, the particular MMR+/p53mt signature, often found in non-metastasizing (stage II) CRC might be used as a prognostic factor for an adjuvant therapy using low-dose irinotecan combined with a bivalent IAP antagonist.


Subject(s)
Colorectal Neoplasms/drug therapy , DNA Mismatch Repair/genetics , Irinotecan/pharmacology , Oligopeptides/pharmacology , Tumor Suppressor Protein p53/genetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Baculoviral IAP Repeat-Containing 3 Protein/antagonists & inhibitors , Baculoviral IAP Repeat-Containing 3 Protein/metabolism , Caspase 8/metabolism , Cell Death/drug effects , Cell Line, Tumor , Colorectal Neoplasms/genetics , DNA Mismatch Repair/drug effects , DNA-Binding Proteins/genetics , Humans , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Inhibitor of Apoptosis Proteins/metabolism , Irinotecan/administration & dosage , MutS Homolog 2 Protein/genetics , Oligopeptides/administration & dosage , Thiolester Hydrolases/metabolism , Topoisomerase I Inhibitors/pharmacology , Tumor Suppressor Protein p53/metabolism
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