Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells
<p>Phosphine agents decrease cell proliferation. (<b>a</b>) Cell viability studies with P1 (red), P2 (purple), and CDDP (grey) used as a positive control in GC AGS cells (left side) and in healthy HPDE cells (right side) after 48 h of treatment. The cells were treated with increasing concentrations of either agent (0–25 µM). The percentage of viable cells was quantified by an MTS assay. The data represent the mean values obtained in three experiments performed in quadruplicate. (<b>b</b>) A Colony Forming Unit (CFU) assay was used to determine cell clonogenicity. The AGS cells were treated with CDDP (20 µM), P1 (10 and 20 µM), or P2 (5 and 10 µM), and the colonies that formed were stained with crystal violet and quantified 10 days later. (<b>c</b>) The AGS cells were pre-treated with CDDP (20 µM), P1 (20 µM), and P2 (10 µM) for 3 h. Then, the cells were counted and seeded (see the <a href="#sec4-ijms-25-07739" class="html-sec">Section 4</a>), and the colonies were then stained with crystal violet and quantified 10 days later. In both CFU assays, statistical significance was evaluated by one-way ANOVA with a Dunnett post-test (ns = not significant, * <span class="html-italic">p</span> < 0.05) compared to the untreated cells (C: control). N = 3. (<b>d</b>) The AGS cells were treated with increasing concentrations of P1 and P2 (10, 20, and 30 µM). Twenty-four hours after the treatments, the cells were fixed and stained with propidium iodide. The graphs show the cell cycle profile after the treatments (left panel) and the percentage of cells in each phase (right panel). Apoptosis was quantified as the percentage of cells with DNA content < 2N. Statistical significance was evaluated by one-way ANOVA followed by a Dunnett post-test (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, **** <span class="html-italic">p</span> < 0.0001) compared to the untreated cells (C: control). N = 3.</p> "> Figure 2
<p>P1 and P2 generate ROS and cause DNA damage. (<b>a</b>) The detection of ROS in AGS cells after treatment with H<sub>2</sub>O<sub>2</sub> (positive control, 200 µM), CDDP (10 µM), P1 (20 µM), and P2 (10 µM) by confocal microscopy using DHE and MitoSox as O<sub>2</sub><sup>•−</sup> Red fluorescence indicator in cytosol and mitochondria, respectively. The cells were treated with the compounds for 1 h followed by 30 min of incubation with the probes. Representative images of each condition were taken (H<sub>2</sub>O<sub>2</sub> and CDDP are included in <a href="#app1-ijms-25-07739" class="html-app">Figure S3b</a>) in fluorescence (upper panel) and brightfield (lower panel) conditions. The scale bar represents 20 μm. Fluorescence intensity (per cell) was quantified and depicted in the graph. Statistical significance was evaluated by one-way ANOVA followed by a Dunnett post-test (ns = not significant, **** <span class="html-italic">p</span> < 0.0001) compared to the untreated cells (C: control). N = 3. (<b>b</b>) The ratio of GSH/GSSG determined with a commercial colorimetric kit (see the <a href="#sec4-ijms-25-07739" class="html-sec">Section 4</a>). The AGS cells were treated with the IC<sub>50</sub> concentration of the compounds and were collected after 24 h to perform the assay. N = 3. Statistical significance was evaluated with Student’s 2-tailed <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01) compared to the untreated cells (control). (<b>c</b>) The AGS cells were treated with CDDP (20 µM), P1 (20 µM), and P2 (10 µM) for 3 h. γ-H<sub>2</sub>AX foci (green fluorescence) were detected by immunofluorescence using DAPI to stain nuclear DNA (blue fluorescence). Representative images of each condition were taken (Scale bar: 20 µm). The graph represents the number of foci per nuclei for each condition. Statistical significance was evaluated by one-way ANOVA followed by a Dunnett post-test, **** <span class="html-italic">p</span> < 0.0001) compared to the untreated cells (C: control). N = 3.</p> "> Figure 3
<p>P1 and P2 target mitochondria and induce intrinsic apoptosis. (<b>a</b>) Phosphine agents produce mitochondrial dysfunction in AGS GC cells. Mean fold-change ± SD of the ratio of the ΔΨm probe CMX-ROS (Red) versus the Mitochondrial Mass probe MitoGreen (Green) as a measurement to evaluate mitochondrial functionality in AGS cells treated for 2 h with CDDP (10 µM), P1 (20 µM), and P2 (10 µM). Representative images for each condition were taken (CDDP was used as a positive control). The scale bar represents 20 μm. Fluorescence intensity (per cell) was quantified and depicted in the graph. * <span class="html-italic">p</span> < 0.05, *** <span class="html-italic">p</span> < 0.001, as determined by one-way ANOVA followed by a Dunnett post-test, compared to the control, set as 1.0. N = 3. (<b>b</b>) Western blot analysis of mitochondrial apoptosis: MCL1 and BAK (left panel), and BIM (right panel). Representative Western blots in AGS cells after treatment with IC<sub>50</sub> concentration of CDDP, P1, or P2 at different times (3, 6, and 24 h). GAPDH was used as an endogenous loading control. The graphs show the mean ± SD densitometric analyses of each protein normalized with GAPDH from three independent experiments by using ImageJ (area under the peak method), control cells (C, white bars), CDDP (grey), P1 (red), and P2 (purple). Statistical significance was evaluated with Student’s 2-tailed <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001) compared to the untreated cells (C: control), set as 1.0.</p> "> Figure 4
<p>P2 produces ER stress. (<b>a</b>) RNA was isolated from the AGS cells stimulated with a 24 h treatment of the complexes. HSPA5, ERN1, XBP1, EIF2AK3, ATF4, DDIT3, and ATF6 were quantified by RT-qPCR. Target gene expression was normalized to GAPDH. All experiments were performed three times per triplicate with IC<sub>50</sub> concentrations of each compound used in all the assays. Statistical significance was evaluated by Student’s 2-tailed <span class="html-italic">t</span>-test (ns: not significant * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001) compared to untreated cells (C), set as 1.0. (<b>b</b>) Western blot analysis of reticulum stress proteins: GRP78, p-eIF2α, CHOP, XBP1 * inespecific bands), and ATF6. GAPDH or α-Tubulin was used as endogenous loading controls. The graphs show the mean ± SD densitometric analyses of each protein normalized with GAPDH from three independent experiments by using ImageJ (area under the peak method), control cells (C, white bars), CDDP (grey), P1 (red), and P2 (purple). Statistical significance was evaluated by Student’s 2-tailed <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001) compared to the untreated cells (C: control), set as 1.0.</p> "> Figure 5
<p>(<b>a</b>,<b>b</b>) P1 and P2 impair autophagy. Western blot analysis of autophagy: p62 and LC3, and Nrf2. Representative Western blots in AGS cells after the treatment with IC<sub>50</sub> concentration of CDDP, P1, or P2 at different time points (3, 6, and 24 h). GAPDH was used as an endogenous loading control. The graphs show the mean ± SD densitometric analyses of each protein normalized with GAPDH from three independent experiments by using ImageJ (area under the peak method), control cells (C, white bars), CDDP (grey), P1 (red), and P2 (purple). Statistical significance was evaluated with Student’s 2-tailed <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01) compared to the untreated cells (C: control), set as 1.0.</p> "> Figure 6
<p>Hypothetical model of P1 and P2 mechanism of action. Created using biorender.com <a href="https://www.biorender.com/" target="_blank">https://www.biorender.com/</a> (accessed on 28 June 2024).</p> ">
Abstract
:1. Introduction
2. Results
2.1. Phospine-Based Agents P1 and P2 Decrease Cell Proliferation
2.2. P1 and P2 Generate ROS and Produce DNA Damage
2.3. P1 and P2 Target Mitochondria and Induce Apoptosis
2.4. P1 and P2 Produce ER Stress and Block Autophagy
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Chemicals
4.3. Cell Viability
4.4. Clonogenic Assay
4.5. Wound Healing (Cell Migration) Assay
4.6. Cellular Uptake and Distribution by ICP-MS
4.7. Cell Cycle Profile Analysis
4.8. ROS Detection by Confocal Microscopy
4.9. Ratio GSH/GSSG
4.10. Immunofluorescence Assay
4.11. Mitochondrial Membrane Potential
4.12. Western Blotting
4.13. RT-qPCR
4.14. Statistics and Reproducibility
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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AGS | MKN45 | PANC1 | AC16 | HPDE | |
---|---|---|---|---|---|
CDDP | 24.95 ± 2.78 (0.1) | 7.22 ± 0.72 (0.2) | 9.71 ± 1.21 (0.2) | 6.51 ± 1.87 | 1.58 ± 0.89 |
P1 | 9.12 ± 0.59 (>2.7) | 20.91 ± 1.73 (>1.2) | 10.57 ± 2.43 (>2.4) | 19.91 ± 2.89 | >25 |
P2 | 5.66 ± 0.41 (3.9) | 10.15 ± 0.13 (2.2) | 9.74 ± 0.50 (2.3) | 7.57 ± 1.64 | 22.09 ± 0.53 |
Pt (ng·mL−1) | ||
---|---|---|
Nucleus | Cytoplasm | |
Control | <0.05 | <0.05 |
P1 | 0.54 ± 0.24 | 0.87 ± 0.18 |
P2 | 1.35 ± 0.07 | 2.25 ± 0.64 |
Primer | Sequence |
---|---|
HSPA5 | F: TGCCCAACGCCAAGCAACC R: AATAGCAGCTGCCGTAGGCTCG |
ERN1 | F: ATCTTGGGCGAACAGAATACACC R: CACCGGAGCTCTCGGGTTTTG |
XBP1 | F: GCTTCTGTCGGGGCAGC R: ACTCTGTTTTTCAGTTTCCTCCTCA |
EIF2AK3 | F: GGGAGCAGGGAAGAAAAGGTCA R: ACACCAAGGAACCGGATCCCAC |
ATF4 | F: GGGCTCCTCCGAATGGCTGG R: CGGAGAAGGCATCCTCCTTGC |
DDIT3 | F: ACCTCCTGGAAATGAAGAGGAAGAA R: GGGCTCTGGGAGGTGCTTGT |
ATF6 | F: AACCTGCACCCACTAAAGGCCA R: TCCCCCAGCAACAGCAAGGAC |
GAPDH | F: GAGAGACCCTCACTGCTG R: GATGGTACATGACAAGGTGG |
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Melones-Herrero, J.; Delgado-Aliseda, P.; Figueiras, S.; Velázquez-Gutiérrez, J.; Quiroga, A.G.; Calés, C.; Sánchez-Pérez, I. Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells. Int. J. Mol. Sci. 2024, 25, 7739. https://doi.org/10.3390/ijms25147739
Melones-Herrero J, Delgado-Aliseda P, Figueiras S, Velázquez-Gutiérrez J, Quiroga AG, Calés C, Sánchez-Pérez I. Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells. International Journal of Molecular Sciences. 2024; 25(14):7739. https://doi.org/10.3390/ijms25147739
Chicago/Turabian StyleMelones-Herrero, Jorge, Patricia Delgado-Aliseda, Sofía Figueiras, Javier Velázquez-Gutiérrez, Adoración Gomez Quiroga, Carmela Calés, and Isabel Sánchez-Pérez. 2024. "Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells" International Journal of Molecular Sciences 25, no. 14: 7739. https://doi.org/10.3390/ijms25147739