Tiliacora triandra Leaf Powder Ethanolic Extract in Combination with Cisplatin or Gemcitabine Synergistically Inhibits the Growth of Cholangiocarcinoma Cells In Vitro and in Nude Mouse Xenograft Models
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Cell Lines and Culture Conditions
2.3. Preparation of T. triandra Leaf Powder Ethanolic Extract (TLPE)
2.4. Preparation of Phenolic Extract for the Analysis of Phenolic Acids
2.5. Phenolic Acid Compositions of TLPE
2.6. Total Phenolic Contents of TLPE
2.7. Antiproliferative Activity Assay
2.8. Hemolytic Activity
2.9. Determination of Drug Interaction
2.10. Apoptosis Analysis by Flow Cytometry
2.11. Cell Cycle Analysis by Flow Cytometry
2.12. Western Blot Analysis
2.13. Antitumor Activity in Nude Mouse Xenograft Model
2.14. Histopathology
2.15. Statistical Analysis
3. Results
3.1. Phenolic Contents and Phenolic Acid Compositions of TLPE
3.2. Antiproliferative Effects of the Single Agent Treatment of Cis, Gem, and TLPE
3.3. Hemolytic Toxicity of Cis, Gem, and TLPE by Hemolytic Assay
3.4. Combination Index and Dose Reduction Index of Cis or Gem and TLPE in Combination Treatments
3.5. Antiproliferative Effects of the Synergistic Combination Treatments of TLPE and Cis or Gem against CCA Cell Lines
3.6. Effect of the Combination Treatment of TLPE and Cis or Gem on Cell Cycle Progression and Apoptosis Induction
3.7. Effect of the Combination Treatment of TLPE and Cis or Gem on Apoptosis-Related Proteins and ERK Signaling
3.8. Antitumor Effect of Cis, Gem, and TLPE on CCA Xenograft Mice
3.9. In Vivo Toxicological Evaluation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sample | Phenolic Acids (mg/g of Dry Extract) a | |||||
---|---|---|---|---|---|---|
p-Hydroxybenzoic Acid | Vanillic Acid | Syringic Acid | p-Coumaric Acid | Ferulic Acid | Sinapinic Acid | |
TLPE | 4.07 ± 0.64 | 2.49 ± 0.58 | 4.40 ± 1.96 | 6.65 ± 3.31 | 5.98 ± 1.34 | 9.98 ± 2.25 |
CCA Cells | Drug Combination | Exposure Time | CI | DRI | |||||
---|---|---|---|---|---|---|---|---|---|
Cis | Gem | TLPE | |||||||
IC50 of TLPE (µg/mL) | IC20 of Cis (µM) | IC20 of Gem (µM) | |||||||
Alone | Combination | ||||||||
KKU-M213B | 204.18 ± 3.47 | 54.88 ± 10.34 | 23.44 ± 0.30 | - | 24 h | 0.68 ± 0.07 | 3.11 | - | 3.79 |
26.06 ± 1.79 | 16.42 ± 1.05 | 5.26 ± 0.07 | - | 48 h | 0.98 ± 0.02 | 4.63 | - | 1.59 | |
25.59 ± 2.21 | 29.37 ± 7.97 | 3.93 ± 1.27 | - | 72 h | 2.00 ± 0.52 | 2.72 | - | 1.15 | |
KKU-100 | 674.76 ± 6.21 | 261.60 ± 11.78 | 23.17 ± 1.43 | - | 24 h | 0.86 ± 0.04 | 2.11 | - | 2.58 |
91.18 ± 7.51 | 22.66 ± 5.00 | 3.78 ± 1.36 | - | 48 h | 0.56 ± 0.08 | 4.05 | - | 3.48 | |
37.53 ± 5.26 | 17.92 ± 2.73 | 1.09 ± 0.19 | - | 72 h | 1.04 ± 0.08 | 2.69 | - | 2.14 | |
KKU-M213B | 26.06 ± 1.79 | 5.26 ± 4.97 | - | 10.83 ± 1.97 | 48 h | 0.84 ± 0.23 | 1.86 | 8.65 | |
25.59 ± 2.21 | 19.61 ± 2.89 | - | 4.31 ± 0.48 | 72 h | 1.75 ± 0.27 | 1.70 | 1.25 | ||
KKU-100 | 91.18 ± 7.51 | 32.95 ± 0.02 | - | 0.12 ± 0.02 | 48 h | 1.06 ± 0.06 | 1.97 | 2.77 | |
37.53 ± 5.26 | 2.14 ± 0.77 | - | 0.10 ± 0.02 | 72 h | 0.63 ± 0.09 | 1.87 | 2.77 |
Group | Initial Body Weight (g) | Final Body Weight (g) | % BWC | Organ Index (g/100 g Body Weight) | ||
---|---|---|---|---|---|---|
Liver | Kidney | Spleen | ||||
Vehicle control | 22.53 ± 0.91 | 23.60 ± 0.53 | 4.83 | 7.66 ± 0.22 | 0.97 ± 0.05 | 0.64 ± 0.13 |
Cis | 22.72 ± 1.26 | 18.31 ± 2.21 | −19.59 | 7.09 ± 0.59 | 0.84 ± 0.03 a | 0.32 ± 0.05 a |
Gem | 22.26 ± 0.96 | 23.12 ± 0.94 | 3.85 | 6.94 ± 0.22 a | 0.95 ± 0.04 | 1.74 ± 0.32 a |
TLPE | 22.07 ± 0.60 | 22.71 ± 0.63 | 2.92 | 8.39 ± 0.89 a | 1.01 ± 0.03 | 0.70 ± 0.11 |
TLPE + Cis | 23.13 ± 0.76 | 19.65 ± 2.66 | −15.21 | 7.99 ± 0.25 | 0.91 ± 0.02 a,b,d | 0.42 ± 0.16 |
TLPE + Gem | 22.94 ± 1.27 | 23.13 ± 1.18 | 0.83 | 7.45 ± 0.34 | 0.94 ± 0.04 | 2.39 ± 0.25 a,c,d |
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Samankul, A.; Senawong, G.; Utaiwat, S.; Prompipak, J.; Woranam, K.; Phaosiri, C.; Sripa, B.; Senawong, T. Tiliacora triandra Leaf Powder Ethanolic Extract in Combination with Cisplatin or Gemcitabine Synergistically Inhibits the Growth of Cholangiocarcinoma Cells In Vitro and in Nude Mouse Xenograft Models. Medicina 2023, 59, 1269. https://doi.org/10.3390/medicina59071269
Samankul A, Senawong G, Utaiwat S, Prompipak J, Woranam K, Phaosiri C, Sripa B, Senawong T. Tiliacora triandra Leaf Powder Ethanolic Extract in Combination with Cisplatin or Gemcitabine Synergistically Inhibits the Growth of Cholangiocarcinoma Cells In Vitro and in Nude Mouse Xenograft Models. Medicina. 2023; 59(7):1269. https://doi.org/10.3390/medicina59071269
Chicago/Turabian StyleSamankul, Arunta, Gulsiri Senawong, Suppawit Utaiwat, Jeerati Prompipak, Khanutsanan Woranam, Chanokbhorn Phaosiri, Banchob Sripa, and Thanaset Senawong. 2023. "Tiliacora triandra Leaf Powder Ethanolic Extract in Combination with Cisplatin or Gemcitabine Synergistically Inhibits the Growth of Cholangiocarcinoma Cells In Vitro and in Nude Mouse Xenograft Models" Medicina 59, no. 7: 1269. https://doi.org/10.3390/medicina59071269