Omanische Heilpflanze im Fokus der Phytochemie IPB-Wissenschaftler und Partner aus Dhofar haben jüngst die omanische Heilpflanze Terminalia dhofarica unter die phytochemische Lupe genommen. Die Pflanze ist reich an…
Geschmack ist vorhersagbar: Mit FlavorMiner. FlavorMiner heißt das Tool, das IPB-Chemiker und Partner aus Kolumbien jüngst entwickelt haben. Das Programm kann, basierend auf maschinellem Lernen (KI), anhand der…
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)6OHMater. Sci. Eng. C-Mater. Biol. Appl.100315-322(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 modelExp. Cell Res.380159-170(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 TriangleAnticancer Res.395403-5415(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.