Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer
<p>Derivatives of right-half RT—DH_18, DH_21, DH_32, DH_35, DH_38, and DH_39. (<b>A</b>) Step-by-step synthesis for right-half RT derivatives (DH_18, DH_21, DH_32, DH_35, DH_38, and DH_39). (<b>B</b>) Structures of DH_18, DH_21, DH_32, DH_35, DH_38, and DH_39.</p> "> Figure 2
<p>Screening for right-half RT derivatives—DH_18, DH_21, DH_32, DH_35, DH_38, and DH_39—on cell viability and apoptosis in lung cancer cells (A549, H23, and H292). (<b>A</b>) Human lung cancer cells were seeded and treated with right-half RT derivatives (0–100 μM) for 24 h. An MTT assay was performed to evaluate IC<sub>50</sub> values for right-half RT derivatives used to treat human lung cancer cells. The IC<sub>50</sub> values were calculated in comparison to the RT parent compound, which acted as a positive control. (<b>B</b>) NSCLC cells were seeded and treated with right-half RT derivatives (0.5 μM) for 24 h. The apoptosis and dead cells were evaluated by co-staining with Hoechst 33342 and PI. The images were captured with a fluorescence microscope, and the percentages for apoptosis and dead cells were calculated. RT served as a positive control. (<b>C</b>) Human dermal papilla cells (DP) and a non-tumorigenic epithelial cell line from human bronchial epithelium cells (BEAS2B) were seeded and treated with DH_32 (0–100 μM) for 24 h. An MTT assay was performed to evaluate IC<sub>50</sub> values for DH_32-treated human dermal papilla cells (DP) and non-tumorigenic epithelial cell line from human bronchial epithelium cells (BEAS2B) cells. The IC<sub>50</sub> values were calculated in comparison to the RT parent compound, which acted as a positive control. Data are presented as mean ± SD (<span class="html-italic">n</span> = 3). Significance is shown as *** <span class="html-italic">p</span> < 0.001 versus untreated control cells.</p> "> Figure 3
<p>DH_32 demonstrated antiproliferative effects, inhibiting colony formation and inducing apoptosis. RT served as the positive control. (<b>A</b>) The proliferative effect of DH_32 on lung cancer cells was evaluated by an MTT assay for 24, 48, and 72 h, analyzed as the relative value to the control group at 0 h. (<b>B</b>) NSCLC cells were seeded and treated with DH_32 (0–100 nM) for 24 h. The colonies were allowed to grow for 7 days and stained with crystal violet to count the number of colony formations. (<b>C</b>) Human lung cancer cells were treated with DH_32 (0–100 nM) for 24 h. The levels of apoptotic-related proteins, including cleaved PARP, Bcl-2, and Bax, were determined by Western blot analysis. The blot was reprobed with β-actin to confirm the equal loading of proteins. Data are presented as mean ± SD (<span class="html-italic">n</span> = 3). Significant is shown as ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001 versus untreated control cells and <sup>###</sup> <span class="html-italic">p</span> < 0.001 versus RT-treated NSCLCs.</p> "> Figure 4
<p>The suppressive effect of DH_32 on the CSC-like phenotype in human lung cancer A549, H23, and H292 cells. Cells were seeded and cultured to form primary spheroids for 7 days. The primary spheroids were trypsinized to form secondary spheroids for 10 days in an ultra-low attachment plate to obtain CSC-rich spheroids. After that, the spheroids were treated with DH_32 (50 nM) for 24 h. The DH_32-treated lung cancer cells were analyzed for the level of stem cell markers CD133, CD44, and transcription factor OCT4. The nucleus of cells was stained with Hoechst33342. (<b>A</b>) The expression level of CD133; (<b>B</b>) the expression level of CD44 and OCT4. The parent compound RT (50 nM) and cisplatin (50 nM) acted as the positive controls. Scale bar = 100 μm.</p> "> Figure 5
<p>Effects of DH_32 on the mRNA and protein levels of stem cell markers (CD133, CD44, and ALDH1A1) and stem cell transcription factors (OCT4, NANOG, and SOX2). (<b>A</b>) Cells were treated with DH_32 (0–100 nM) for 6 h, and the mRNA expression levels of stem cell transcription factors OCT4, NANOG, and SOX2 were determined. The mRNA levels were normalized by housekeeping GAPDH. The relative mRNA expression was calculated by using comparative Ct cycles. (<b>B</b>) The heat map shows the fluorescence intensity of stem cell markers (CD133, CD44, and ALDH1A1) and stem cell transcription factors (OCT4, NANOG, and SOX2) captured by a fluorescence microscope; the fluorescence intensity was determined by Image J software version 1.52a. (<b>C</b>) The protein expression levels of stem cell markers (CD133, CD44, and ALDH1A1) and stem cell transcription factors (OCT4) were determined by Western blot analysis. The blot was reprobed with β-actin to confirm the equal loading of proteins. Data are presented as mean ± SD (<span class="html-italic">n</span> = 3). Significance is shown as * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001 versus untreated control cells.</p> "> Figure 6
<p>DH_32 suppresses CSC properties via β-catenin proteasomal degradation in human lung cancer cells. The cancer cells were treated with various concentrations of DH_32 (0–100 nM) for 24 h. (<b>A</b>) The β-catenin level was measured by immunofluorescence analysis, and the fluorescence intensity was measured by Image J software. (<b>B</b>) The protein expression level of β-catenin was evaluated by Western blot analysis. The blot was reprobed with β-actin to confirm the equal loading of proteins. The blots were quantified by densitometry by Image J software. (<b>C</b>) The effect of DH_32 on the ubiquitin–proteasomal degradation of β-catenin in human lung cancer cells was measured by immunoprecipitation analysis. The human lung cancer cells were treated with DH_32 (50 nM). The cell lysates were prepared and immunoprecipitated with anti-β-catenin. After that, ubiquitinated protein levels were measured by Western blotting by using an anti-ubiquitin antibody. The ubiquitin–β-catenin level was analyzed by densitometry. The parent compound, RT, acted as a positive control. Data are presented as mean ± SD (<span class="html-italic">n</span> = 3). Significant is shown as * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, and *** <span class="html-italic">p</span> < 0.001 versus untreated control cells and <sup>##</sup> <span class="html-italic">p</span> < 0.01 and <sup>###</sup> <span class="html-italic">p</span> < 0.001 versus RT-treated NSCLCs.</p> "> Figure 7
<p>Binding interaction of DH_32 with GSK-3β. (<b>A</b>) The native ligand (PF-04802367) superposition represented by crystal (tan) and flexible conformations (blue) (<b>B</b>) X-ray co-crystal structure of PF-04802367 (reference compound) bound in the ATP-binding site of GSK-3β. The green dashed lines denote hydrogen-bonding interactions. (<b>C</b>) X-ray co-crystal structure of DH_32 bound in the ATP-binding site of GSK-3β. (<b>D</b>) Footprint analysis for DH_32 (red lines) compared to PF-04802367 (reference compound) (blue lines) into the ATP-binding site of GSK-3β.</p> "> Figure 8
<p>Binding interaction of DH_32 with β-catenin (<b>A</b>) The native ligand (R9Q) superposition represented by crystal (tan) and flexible conformations (blue) (<b>B</b>) X-ray co-crystal structure of R9Q (reference compound) bound in the binding site of β-catenin. The green dashed lines denote hydrogen-bonding interactions. (<b>C</b>) X-ray co-crystal structure of DH_32 bound in the binding site of β-catenin. (<b>D</b>) Footprint analysis for DH_32 (red lines) compared to the R9Q (reference compound) (blue lines) into the binding site of β-catenin.</p> "> Figure 9
<p>Summarized figure for the effect of direction interactions of the right-half RT analog, DH_32, with targeted β-catenin in lung cancer cells. This study revealed that DH_32 has the ability to reduce stem cell markers (CD133, CD44, and ALDH1A1) and stem cell transcription factors (OCT4, NANOG, and SOX2) in lung cancer cells. Moreover, the inhibitory impacts on the CSC characteristics and stem cell transcription factors achieved by DH_32 are mediated through the proteasomal degradation of β-catenin.</p> "> Scheme 1
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-9-methoxy-8,11-dimethyl-7,10-dioxo-3-(pyridin-2-ylmethyl)-1,2,3,4,5,6,7,10-octahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>4a</b>: DH_18).</p> "> Scheme 2
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-9-methoxy-8,11-dimethyl-7,10-dioxo-3-(pyridin-3-ylmethyl)-1,2,3,4,5,6,7,10-octahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>4b</b>: DH_21).</p> "> Scheme 3
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-9-methoxy-8,11-dimethyl-3-(naphthalen-2-ylmethyl)-7,10-dioxo-1,2,3,4,5,6,7,10-octahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>4c</b>: DH_32).</p> "> Scheme 4
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5S)-10-(benzyloxy)-9-methoxy-8,11-dimethyl-3-(prop-2-yn-1-yl)-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>2d</b>).</p> "> Scheme 5
<p>Synthesis of (1R,4R,5S)-10-hydroxy-9-methoxy-8,11-dimethyl-3-(prop-2-yn-1-yl)-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>3d</b>).</p> "> Scheme 6
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-9-methoxy-8,11-dimethyl-7,10-dioxo-3-(prop-2-yn-1-yl)-1,2,3,4,5,6,7,10-octahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>4d</b>: DH_35).</p> "> Scheme 7
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-10-(benzyloxy)-3-(2-hydroxyethyl)-9-methoxy-8,11-dimethyl-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>2e</b>).</p> "> Scheme 8
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-10-hydroxy-3-(2-hydroxyethyl)-9-methoxy-8,11-dimethyl-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>3e</b>).</p> "> Scheme 9
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-3-(2-hydroxyethyl)-9-methoxy-8,11-dimethyl-7,10-dioxo-1,2,3,4,5,6,7,10-octahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>4e</b>: DH_38).</p> "> Scheme 10
<p>Synthesis of (1<span class="html-italic">R</span>,4<span class="html-italic">R</span>,5<span class="html-italic">S</span>)-3-(2-{1,3-dioxoisoindolin-2-yl} ethyl)-9-methoxy-8,11-dimethyl-7,10-dioxo-1,2,3,4,5,6,7,10-octahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile (<b>4f</b>: DH_39).</p> ">
Abstract
:1. Introduction
2. Results
2.1. Synthesis of Right-Half RT Derivative DH_32
2.2. Assessing Cytotoxicity through an MTT Assay When Screening for Right-Half RT Analogs
2.3. DH_32 Inhibits Proliferation, Decreases Colony Formation, and Affects Apoptosis-Related Proteins
2.4. Inhibitory Effect of DH_32 on CSCs in Various Lung Cancer Cell Lines
2.5. DH_32 Suppression of CSC-like Phenotypes in Lung Cancer Cells
2.6. DH_32 Destabilizes β-Catenin and Facilitates Proteasomal Degradation
2.7. Analysis of Compound DH_32 Interactions with the GSK-3β Protein
2.8. Binding Interaction of DH_32 with β-Catenin
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Reagents and Antibodies
4.3. Synthesis of Right-Half RT Analogs
4.4. Preparation of Stock Solution for RT Derivatives
4.5. Cell Viability Assay
4.6. Nuclear Staining Assay
4.7. Proliferation Assay
4.8. Colony Formation Assay
4.9. Three-Dimensional (3D) CSC Spheroid Formation
4.10. Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR)
4.11. Immunofluorescence
4.12. Western Blot Analysis
4.13. Immunoprecipitation
4.14. Molecular Docking
4.15. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compounds | Grid Score (kcal/mol) | VDW Energy (kcal/mol) | ES Energy (kcal/mol) |
---|---|---|---|
DH_32 | −38.421 | −37.933 | −0.489 |
PF-04802367 (reference compound) | −49.199 | −46.755 | −2.444 |
Compounds | Grid Score (kcal/mol) | VDW Energy (kcal/mol) | ES Energy (kcal/mol) |
---|---|---|---|
DH_32 | −35.559 | −35.623 | 0.064 |
R9Q (reference compound) | −29.044 | −27.517 | −1.527 |
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Ei, Z.Z.; Racha, S.; Yokoya, M.; Hotta, D.; Zou, H.; Chanvorachote, P. Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer. Mar. Drugs 2023, 21, 627. https://doi.org/10.3390/md21120627
Ei ZZ, Racha S, Yokoya M, Hotta D, Zou H, Chanvorachote P. Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer. Marine Drugs. 2023; 21(12):627. https://doi.org/10.3390/md21120627
Chicago/Turabian StyleEi, Zin Zin, Satapat Racha, Masashi Yokoya, Daiki Hotta, Hongbin Zou, and Pithi Chanvorachote. 2023. "Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer" Marine Drugs 21, no. 12: 627. https://doi.org/10.3390/md21120627