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Publikation

Predarska, I.; Saoud, M.; Drača, D.; Morgan, I.; Komazec, T.; Eichhorn, T.; Mihajlović, E.; Dunđerović, D.; Mijatović, S.; Maksimović-Ivanić, D.; Hey-Hawkins, E.; Kaluđerović, G. N.; Mesoporous silica nanoparticles enhance the anticancer efficacy of platinum(IV)-phenolate conjugates in breast cancer cell lines Nanomaterials 12, 3767, (2022) DOI: 10.3390/nano12213767

The main reasons for the limited clinical efficacy of the platinum(II)-based agent cisplatin include drug resistance and significant side effects. Due to their better stability, as well as the possibility to introduce biologically active ligands in their axial positions constructing multifunctional prodrugs, creating platinum(IV) complexes is a tempting strategy for addressing these limitations. Another strategy for developing chemotherapeutics with lower toxicity relies on the ability of nanoparticles to accumulate in greater quantities in tumor tissues through passive targeting. To combine the two approaches, three platinum(IV) conjugates based on a cisplatin scaffold containing in the axial positions derivatives of caffeic and ferulic acid were prepared and loaded into SBA-15 to produce the corresponding mesoporous silica nanoparticles (MSNs). The free platinum(IV) conjugates demonstrated higher or comparable activity with respect to cisplatin against different human breast cancer cell lines, while upon immobilization, superior antiproliferative activity with markedly increased cytotoxicity (more than 1000-fold lower IC50 values) compared to cisplatin was observed. Mechanistic investigations with the most potent conjugate, cisplatin-diacetyl caffeate (1), and the corresponding MSNs (SBA-15|1) in a 4T1 mouse breast cancer cell line showed that these compounds induce apoptotic cell death causing strong caspase activation. In vivo, in BALB/c mice, 1 and SBA-15|1 inhibited the tumor growth while decreasing the necrotic area and lowering the mitotic rate.
Publikation

Krajnović, T.; Pantelić, N. ?.; Wolf, K.; Eichhorn, T.; Maksimović-Ivanić, D.; Mijatović, S.; Wessjohann, L. A.; Kaluđerović, G. N.; Anticancer potential of Xanthohumol and Isoxanthohumol loaded into SBA-15 mesoporous silica particles against B16F10 melanoma cells Materials 15, 5028, (2022) DOI: 10.3390/ma15145028

Xanthohumol (XN) and isoxanthohumol (IXN), prenylated flavonoids from Humulus lupulus, have been shown to possess antitumor/cancerprotective, antioxidant, antiinflammatory, and antiangiogenic properties. In this study, mesoporous silica (SBA-15) was loaded with different amounts of xanthohumol and isoxanthohumol and characterized by standard analytical methods. The anticancer potential of XN and IXN loaded into SBA-15 has been evaluated against malignant mouse melanoma B16F10 cells. When these cells were treated with SBA-15 containing xanthohumol, an increase of the activity correlated with a higher immobilization rate of XN was observed. Considering the amount of XN loaded into SBA-15 (calculated from TGA), an improved antitumor potential of XN was observed (IC50 = 10.8 ± 0.4 and 11.8 ± 0.5 µM for SBA-15|XN2 and SBA-15|XN3, respectively; vs. IC50 = 18.5 ± 1.5 µM for free XN). The main mechanism against tumor cells of immobilized XN includes inhibition of proliferation and autophagic cell death. The MC50 values for SBA-15 loaded with isoxanthohumol were over 300 µg/mL in all cases investigated.
Publikation

Drača, D.; Edeler, D.; Saoud, M.; Dojčinović, B.; Dunđerović, D.; Đmura, G.; Maksimović-Ivanić, D.; Mijatović, S.; Kaluđerović, G. N.; Antitumor potential of cisplatin loaded into SBA-15 mesoporous silica nanoparticles against B16F1 melanoma cells: in vitro and in vivo studies J. Inorg. Biochem. 217, 111383, (2021) DOI: 10.1016/j.jinorgbio.2021.111383

CP (cisplatin) and mesoporous silica SBA-15 (Santa Barbara amorphous 15) loaded with CP (→SBA-15|CP) were tested in vitro and in vivo against low metastatic mouse melanoma B16F1 cell line. SBA-15 only, as drug carrier, is found to be not active, while CP and SBA-15|CP revealed high cytotoxicity in lower μM range. The activity of SBA-15|CP was found similar to the activity of CP alone. Both CP and SBA-15|CP induced inhibition of cell proliferation (carboxyfluorescein succinimidyl ester - CFSE assay) along with G2/M arrest (4′,6-diamidino-2-phenylindole - DAPI assay). Apoptosis (Annexin V/ propidium iodide - PI assay), through caspase activation (apostat assay) and nitric oxide (NO) production (diacetate(4-amino-5-methylamino-2′,7′-difluorofluorescein-diacetat) - DAF FM assay), was identified as main mode of cell death. However, slight elevated autophagy (acridine orange - AO assay) was detected in treated B16F1 cells. CP and SBA-15|CP did not affect production of ROS (reactive oxygen species) in B16F1 cells. Both SBA-15|CP and CP induced in B16F1 G2 arrest and subsequent senescence. SBA-15|CP, but not CP, blocked the growth of melanoma in C57BL/6 mice. Moreover, hepato- and nephrotoxicity in SBA-15|CP treated animals were diminished in comparison to CP confirming multiply improved antitumor potential of immobilized CP. Outstandingly, SBA-15 boosted in vivo activity and diminished side effects of CP.
Publikation

Krajnović, T.; Drača, D.; Kaluđerović, G. N.; Dunđerović, D.; Mirkov, I.; Wessjohann, L. A.; Maksimović-Ivanić, D.; Mijatović, S.; The hop-derived prenylflavonoid isoxanthohumol inhibits the formation of lung metastasis in B16-F10 murine melanoma model Food Chem. Toxicol. 129, 257-268, (2019) DOI: 10.1016/j.fct.2019.04.046

Isoxanthohumol (IXN), a prenylflavonoid from hops and beer, gained increasing attention as a potential chemopreventive agent. In the present study, IXN antimetastatic potential in vitro against the highly invasive melanoma cell line B16-F10 and in vivo in a murine metastatic model was investigated. Melanoma cell viability was diminished in a dose-dependent manner following the treatment with IXN. This decrease was a consequence of autophagy and caspase-dependent apoptosis. Additionally, the dividing potential of highly proliferative melanoma cells was dramatically affected by this isoflavanone, which was in correlation with an abrogated cell colony forming potential, indicating changes in their metastatic features. Concordantly, IXN promoted strong suppression of the processes that define metastasis– cell adhesion, invasion, and migration. Further investigation at the molecular level revealed that the abolished metastatic potential of a melanoma subclone was due to disrupted integrin signaling. Importantly, these results were reaffirmed in vivo where IXN inhibited the development of lung metastatic foci in tumor-challenged animals. The results of the present study may highlight the beneficial effects of IXN on melanoma as the most aggressive type of skin cancer and will hopefully shed a light on the possible use of this prenylflavonoid in the treatment of metastatic malignancies.
Publikation

Edeler, D.; Drača, D.; Petković, V.; Natalio, F.; Maksimović-Ivanić, D.; Mijatović, S.; Schmidt, H.; Kaluđerović, G. N.; Impact of the mesoporous silica SBA-15 functionalization on the mode of action of Ph3Sn(CH2)6OH Mater. Sci. Eng. C-Mater. Biol. Appl. 100, 315-322, (2019) DOI: 10.1016/j.msec.2019.03.010

Herein appropriateness of nonfunctionalized mesoporous silica nanoparticles SBA-15 and functionalized with (3-chloropropyl)triethoxysilane (→ SBA-15~Cl) and (3-aminopropyl)triethoxysilane (→ SBA-15~NH2) on delivery of physically adsorbed Ph3Sn(CH2)6OH (Sn6) is evaluated. Fluorescent nanomaterial, bearing isatoic moiety, loaded with Sn6 (→ SBA-15~NF|Sn6) was used for cellular uptake study. The fluorescent nanomaterial is efficiently acquired and distributed into the cytoplasm of the cells even after 2 h of cultivation. According to the attained data, all SBA-15 materials loaded with Sn6 diminished cellular viability in dose dependent manner while carriers alone (SBA-15, SBA-15~Cl, SBA-15~NH2) did not show cytotoxicity against B16 cells. According to the MC50 values structural modification of SBA-15 did not improve the efficacy of tested drug. While progressive apoptosis was detected upon the treatment with SBA-15|Sn6, exposure of cells to SBA-15~NH2|Sn6 revealed extinguished apoptosis in time, accompanied with lower caspase activity. This effect is probably due to triggered autophagic process under the treatment with the SBA-15~NH2|Sn6, thus opposed to apoptosis. Presented results suggested that functionalization of SBA-15 was not beneficial for the efficacy of loaded drug, thus, all of them are almost equally efficient considering loaded Sn6 content. Importantly, functionalization of SBA-15 does have an influence on the mode of action and differentiation inducing properties.
Publikation

Drača, D.; Mijatović, S.; Krajnović, T.; Pristov, J. B.; Đukić, T.; Kaluđerović, G. N.; Wessjohann, L. A.; Maksimović-Ivanić, D.; The synthetic tubulysin derivative, tubugi-1, improves the innate immune response by macrophage polarization in addition to its direct cytotoxic effects in a murine melanoma model Exp. Cell Res. 380, 159-170, (2019) DOI: 10.1016/j.yexcr.2019.04.028

Synthetic tubugis are equally potent but more stable than their natural forms. Their anticancer potential was estimated on a solid melanoma in vitro and in vivo. Tubugi-1 induced the apoptosis in B16 cells accompanied with strong intracellular production of reactive species, subsequently imposing glutathione and thiol group depletion. Paradoxically, membrane lipids were excluded from the cascade of intracellular oxidation, according to malondialdehyde decrease. Although morphologically apoptosis was typical, externalization of phosphatidylserine (PS) as an early apoptotic event was not detected. Even their exposition is pivotal for apoptotic cell eradication, primary macrophages successfully eliminated PS-deficient tubugi-1 induced apoptotic cells. The tumor volume in animals exposed to the drug in therapeutic mode was reduced in comparison to control as well as to paclitaxel-treated animals. Importantly, macrophages isolated from tubugi-1 treated animals possessed conserved phagocytic activity and were functionally and phenotypically recognized as M1. The cytotoxic effect of tubugi-1 is accomplished through its ability to polarize the macrophages toward M1, probably by PS independent apoptotic cell engulfment. The unique potential of tubugi-1 to prime the innate immune response through the induction of a specific pattern of tumor cell apoptosis can be of extraordinary importance from fundamental and applicable aspects.
Publikation

Drača, D.; Mijatović, S.; Krajnović, T.; Kaluđerović, G. N.; Wessjohann, L. A.; Maksimović-Ivanić, D.; Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle Anticancer Res. 39, 5403-5415, (2019) DOI: 10.21873/anticanres.13734

Background/Aim: Tubugi-1 is a more stable and accessible synthetic counterpart of natural tubulysins. This study aimed to evaluate its cytotoxic potential against anaplastic human melanoma cells. Materials and Methods: The viability of A-375 cells was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assay. The type of cell death and proliferative rate were investigated using flow cytometry and fluorescent microscopy, while the molecular background was evaluated by western blot. Results: Tubugi-1 reduced the viability of A-375 cells, inducing massive micronucleation, followed by augmented expression of inhibitor of nuclear factor-κB and caspase-2, typical of a mitotic catastrophe. Disturbed proliferation and G2M block with prominent caspase activity, weakened the expression of B-cell lymphoma 2 and B-cell lymphoma 2-associated X transient up-regulation, coexisted with intensive autophagy. Specific inhibition of autophagy by chloroquine resulted in conversion from mitotic catastrophe to rapid apoptosis. Conclusion: Multilevel anticancer action of tubugi-1 is extended by co-application of an autophagy inhibitor, giving a new dimension in further preclinical advancement of this potential agent.
Publikation

Edeler, D.; Arlt, S.; Petković, V.; Ludwig, G.; Drača, D.; Maksimović-Ivanić, D.; Mijatović, S.; Kaluđerović, G. N.; Delivery of [Ru(η6-p-cymene)Cl2{Ph2P(CH2)3SPh-κP}] using unfunctionalized and mercapto functionalized SBA-15 mesoporous silica: Preparation, characterization and in vitro study J. Inorg. Biochem. 180, 155-162, (2018) DOI: 10.1016/j.jinorgbio.2017.12.011

SBA-15 (Santa Barbara Amorphous 15) mesoporous silica and its functionalized form (with 3-mercaptopropyltriethoxysilane) SBA-15~SH were used as carriers for [Ru(η6-p-cymene)Cl2{Ph2P(CH2)3SPh-κP}] complex, denoted as [Ru]. Prepared mesoporous silica nanomaterials were characterized by traditional methods. Materials without [Ru] complex did not show any cytotoxic activity against melanoma B16 and B16-F10 cell lines. On the contrary, materials containing [Ru] such as SBA-15|[Ru] and SBA-15~SH|[Ru], exhibited very high activity against tested tumor cell lines, moreover with similar inhibitory potential. According to the loaded amount of the [Ru] in SBA-15|[Ru] and SBA-15~SH|[Ru] the IC50 values are 1–2μM depending on the test used, thus in comparison to [Ru] alone the activity of nanomaterials containing [Ru] are elevated 3–6 times in vitro. However, the mechanism of apoptosis induction differs for these two mesoporous silica. Unlike reference [Ru] compound and SBA-15~SH|[Ru], SBA-15|[Ru] induces high caspase activation. Discrepancy in mechanism of drugs action at intracellular level points towards an influence of functionalization as well as availability of the drug. Moreover, both SBA-15|[Ru] and SBA-15~SH|[Ru] similarly to [Ru] are declining autophagy in B16 cell line.
Publikation

Mijatović, S.; Bramanti, A.; Nicoletti, F.; Fagone, P.; Kaluđerović, G. N.; Maksimović-Ivanić, D.; Naturally occurring compounds in differentiation based therapy of cancer Biotechnol. Adv. 36, 1622-1632, (2018) DOI: 10.1016/j.biotechadv.2018.04.001

Differentiation of cancer cells entails the reversion of phenotype from malignant to the original. The conversion to cell type characteristic for another tissue is named transdifferentiation. Differentiation/transdifferentiation of malignant cells in high grade tumor mass could serve as a nonaggressive approach that potentially limits tumor progression and augments chemosensitivity. While this therapeutic strategy is already being used for treatment of hematological cancers, its feasibility for solid malignancies is still debated. We will presently discuss the natural compounds that show these properties, with focus on anthraquinones from Aloe vera, Senna, Rheum sp. and hop derived prenylflavonoids.
Publikation

Krajnović, T.; Maksimović-Ivanić, D.; Mijatović, S.; Drača, D.; Wolf, K.; Edeler, D.; Wessjohann, L.; Kaluđerović, G. N.; Drug Delivery System for Emodin Based on Mesoporous Silica SBA-15 Nanomaterials 8, 322, (2018) DOI: 10.3390/nano8050322

In this study mesoporous silica SBA-15 was evaluated as a vehicle for the transport of cytotoxic natural product emodin (EO). SBA-15 was loaded with different quantities of EO (SBA-15|EO1–SBA-15|EO5: 8–36%) and characterized by traditional methods. Several parameters (stabilities) and the in vitro behavior on tumor cell lines (melanoma A375, B16 and B16F10) were investigated. SBA-15 suppresses EO release in extremely acidic milieu, pointing out that EO will not be discharged in the stomach. Furthermore, SBA-15 protects EO from photodecomposition. In vitro studies showed a dose dependent decrease of cellular viability which is directly correlated with an increasing amount of EO in SBA-15 for up to 27% of EO, while a constant activity for 32% and 36% of EO in SBA-15 was observed. Additionally, SBA-15 loaded with EO (SBA-15|EO3) does not disturb viability of peritoneal macrophages. SBA-15|EO3 causes inhibition of tumor cell proliferation and triggers apoptosis, connected with caspase activation, upregulation of Bax, as well as Bcl-2 and Bim downregulation along with amplification of poly-(ADP-ribose)-polymerase (PARP) cleavage fragment. Thus, the mesoporous SBA-15 is a promising carrier of the water-insoluble drug emodin.
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