Chemometric and Transcriptomic Profiling, Microtubule Disruption and Cell Death Induction by Secalonic Acid in Tumor Cells

Özenver, Nadire; Dawood, Mona; Fleischer, Edmond; Klinger, Anette; Efferth, Thomas

doi:10.3390/molecules25143224

Cited by 7 publications

(7 citation statements)

References 50 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fluorescence imaging was performed by using 470 nm excitation and 525 nm emission for GFP and 447 nm emission for DAPI of EVOS digital inverted microscope (Life Technologies). Each experiment was done at least thrice and representative images were selected [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

Özenver

Abdelfatah

Klinger³

et al. 2020

Invest New Drugs

Self Cite

View full text Add to dashboard Cite

SummaryMultiple myeloma (MM) is a devastating disease with low survival rates worldwide. The mean lifetime of patients may be extendable with new drug alternatives. Aurora A kinase (AURKA) is crucial in oncogenesis, because its overexpression or amplification may incline the development of various types of cancer, including MM. Therefore, inhibitors of AURKA are innovative and promising targets. Natural compounds always represented a valuable resource for anticancer drug development. In the present study, based on virtual drug screening of more than 48,000 natural compounds, the antibiotic deschloro-chlorotricin (DCCT) has been identified to bind to AURKA with even higher binding affinity (free bindung energy: −12.25 kcal/mol) than the known AURKA inhibitor, alisertib (free binding energy: −11.25 kcal/mol). The in silico studies have been verified in vitro by using microscale thermophoresis. DCCT inhibited MM cell lines (KMS-11, L-363, RPMI-8226, MOLP-8, OPM-2, NCI-H929) with IC50 values in a range from 0.01 to 0.12 μM. Furthermore, DCCT downregulated AURKA protein expression, induced G2/M cell cycle arrest and disturbed the cellular microtubule network as determined by Western blotting, flow cytometry, and fluorescence microscopy. Thus, DCCT may be a promising lead structure for further derivatization and the development of specific AURKA inhibitors in MM therapy.

show abstract

Section: Methodsmentioning

confidence: 99%

Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

Özenver

Abdelfatah

Klinger³

et al. 2020

Invest New Drugs

Self Cite

View full text Add to dashboard Cite

show abstract

“…A new biological evaluation of secalonic acid F (82) resulted in the identification of a potential target, MARCH1, for the treatment of hepatocellular carcinoma, in which the downregulation suppressed the migration and invasion of HepG2 and Hep3B cancer cells [234]. Finally, the most recent study obtained by Özenver and co-workers demonstrated the potency and selective toxicity of 82 against leukemia and multiple myeloma cells with regard to normal cells mediated through apoptosis and necrosis, as well as tubulin disassembly [235].…”

Section: Miscellaneous Compoundsmentioning

confidence: 99%

Anticancer Activities of Marine-Derived Phenolic Compounds and Their Derivatives

et al. 2022

View full text Add to dashboard Cite

Since the middle of the last century, marine organisms have been identified as producers of chemically and biologically diverse secondary metabolites which have exerted various biological activities including anticancer, anti-inflammatory, antioxidant, antimicrobial, antifouling and others. This review primarily focuses on the marine phenolic compounds and their derivatives with potent anticancer activity, isolated and/or modified in the last decade. Reports on the elucidation of their structures as well as biosynthetic studies and total synthesis are also covered. Presented phenolic compounds inhibited cancer cells proliferation or migration, at sub-micromolar or nanomolar concentrations (lamellarins D (37), M (38), K (39), aspergiolide B (41), fradimycin B (62), makulavamine J (66), mayamycin (69), N-acetyl-N-demethylmayamycin (70) or norhierridin B (75)). In addition, they exhibited anticancer properties by a diverse biological mechanism including induction of apoptosis or inhibition of cell migration and invasive potential. Finally, phlorotannins 1–7 and bromophenols 12–29 represent the most researched phenolic compounds, of which the former are recognized as protective agents against UVB or gamma radiation-induced skin damages. Finally, phenolic metabolites were assorted into six main classes: phlorotannins, bromophenols, flavonoids, coumarins, terpenophenolics, quinones and hydroquinones. The derivatives that could not be attributed to any of the above-mentioned classes were grouped in a separate class named miscellaneous compounds.

show abstract

“…DAPI was detected at 470 nm excitation and 447 nm emission. Images were analyzed using Fiji ImageJ software (National Institutes of Health, Bethesda, MD, USA) [61].…”

Section: Fluorescence Microscopy Of P-h3(ser10)mentioning

confidence: 99%

“…Hoechst stain was detected at 470 nm excitation and 447 nm emission. Images were analyzed using Fiji ImageJ software [61].…”

Section: Fluorescence Microscopy Of the Microtubule Cytoskeletonmentioning

confidence: 99%

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G2M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib’s ability to prevent mitotic exit. However, cells accumulated in the sub-G0G1 fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.

show abstract

Chemometric and Transcriptomic Profiling, Microtubule Disruption and Cell Death Induction by Secalonic Acid in Tumor Cells

Cited by 7 publications

References 50 publications

Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

Identification and characterization of deschloro-chlorothricin obtained from a large natural product library targeting aurora A kinase in multiple myeloma

Anticancer Activities of Marine-Derived Phenolic Compounds and Their Derivatives

Repurposing of the ALK Inhibitor Crizotinib for Acute Leukemia and Multiple Myeloma Cells

Contact Info

Product

Resources

About