Methionine γ-Lyase-Daidzein in Combination with S-Propyl-L-cysteine Sulfoxide as a Targeted Prodrug Enzyme System for Malignant Solid Tumor Xenografts
Abstract
:1. Introduction
2. Results
2.1. Steady-State Kinetic Parameters of the β-Elimination Reaction Catalyzed by the Enzyme and Characterization of the Conjugated C115H MGL-Dz
2.2. C115H MGL-Dz Cytotoxicity on Different Cancer Cells Viability in the Presence of Propiin In Vitro
2.3. Cytotoxicity Effect of Dipropyl Thiosulfinate on Various Cancer Cells Viability
2.4. SW620 and HT29 Xenografts Showed Different Responses to the Pharmacological Pair In Situ
2.5. The Pharmacological Pair Inhibits Growth of Pancreatic Adenocarcinoma Panc1 and MIA-PaCa2 Xenografts
2.6. The Pharmacological Pair Enhances the Suppression of Prostate Cancer 22Rv1 Xenograft Growth
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. Preparation of C115H MGL and Enzymes Assays
4.3. Steady-State Kinetics
4.4. Preparation of C115H MGL/Propiin Mixture and Quantitative Determination of Dipropyl Thiosulfinate
4.5. Synthesis of C115H MGL-Dz
4.6. Cell Lines and Cytotoxicity Evaluation
4.6.1. The Cytotoxicity of the C115H MGL-Dz in the Presence of Propiin
4.6.2. The Cytotoxicity of Dipropyl Thiosulfinate Generated by the Pharmacological Pair C115H MGL/Propiin
4.7. Animals and Evaluation of Antitumor Activity
4.8. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Substrate | C115H MGL * | C115H MGL-Dz | ||||
---|---|---|---|---|---|---|
kcat, s−1 | Km, mM | kcat/Km, (M−1 s−1) | kcat, s−1 | Km, mM | kcat/Km, (M−1 s−1) | |
S-Met-L-Cys | 29.6 | 7.8 | 3.8 × 103 | 20.8 ± 2.0 | 7.1 ± 0.52 | 2.9 × 103 |
Alliin | 26.8 | 1.0 | 2.6 × 104 | 17.9 ± 1.4 | 0.6 ± 0.07 | 2.5 × 104 |
Methiin | 6.1 | 1.1 | 5.5 × 103 | 1.6 ± 0.2 | 0.3 ± 0.05 | 4.6 × 103 |
Propiin | 28 | 1.6 | 1.7 × 104 | 16.9 ± 1.8 | 1.0 ± 0.14 | 1.6 × 104 |
Tissue Sources | Cell Lines | C115H MGL-Dz |
---|---|---|
IC50 (µM) | ||
Colon cancer | HT29 | 6.9 ± 0.4 |
COLO205 | ND | |
SW620 * | ND | |
Pancreatic cancer | Panc1 | 3.8 ± 0.1 |
MIA-PaCa-2 | 6.4 ± 0.5 | |
Prostate adenocarcinoma | 22Rv1 | 5.4 ± 0.2 |
DU-145 | 17.4 ± 0.9 | |
PC3 | 16.9 ± 0.5 |
Tissue Sources | Cell Lines | Dipropyl Thiosulfinate |
---|---|---|
IC50 (µM) | ||
Colon cancer | HT-29 | 43.1 ± 3.4 |
COLO205 | 48.6 ± 4.3 | |
HCT116 | 43.4 ± 4.3 | |
SW620 * | 19.2 ± 0.9 | |
Pancreatic cancer | Panc1 | 18.6 ± 0.5 |
MIA-PaCa-2 | 62.6 ± 1.8 | |
Prostate adenocarcinoma | 22Rv1 | 66.3 ± 2.6 |
DU-145 | 60.9 ± 0.6 | |
PC3 | 51.2 ± 3.0 |
HT-29 | SW 620 | |||||||
---|---|---|---|---|---|---|---|---|
Specimen | Initial Tumor Volume, mm3 | Final Tumor Volume, mm3 | TGI, % | Body Weight, g | Initial Tumor Volume, mm3 | Final Tumor Volume, mm3 | TGI, % | Body Weight, g |
Control | 104 ± 44 | 571 ± 114 | - | 22.2 ± 1 | 82 ± 13 | 219 ± 27 | - | 25.8 ± 0.4 |
C115H MGL-Dz + propiin | 102 ± 20 | 275 ± 48 | 52 (p = 0.04) | 21.4 ± 1 | 82 ± 12 | 170.9 ± 9 | 22 (p = 0.12) | 22.1 ± 0.4 |
C115H MGL-Dz + PBS | 98 ± 26 | 361 ± 69 | 37 (p = 0.1) | 22.7 ± 1 | 85 ± 11 | 185 ± 12 | 15 (p = 0.258) | 24.8 ± 1.9 |
C115H MGL + propiin | 100 ± 22 | 320 ± 69 | 44 (p = 0.09) | 21.1 ± 1 | 83 ± 9.3 | 167 ± 36 | 24 (p = 0.155) | 24.6 ± 1.0 |
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Abo Qoura, L.; Morozova, E.; Kulikova, V.; Karshieva, S.; Sokolova, D.; Koval, V.; Revtovich, S.; Demidkina, T.; Pokrovsky, V.S. Methionine γ-Lyase-Daidzein in Combination with S-Propyl-L-cysteine Sulfoxide as a Targeted Prodrug Enzyme System for Malignant Solid Tumor Xenografts. Int. J. Mol. Sci. 2022, 23, 12048. https://doi.org/10.3390/ijms231912048
Abo Qoura L, Morozova E, Kulikova V, Karshieva S, Sokolova D, Koval V, Revtovich S, Demidkina T, Pokrovsky VS. Methionine γ-Lyase-Daidzein in Combination with S-Propyl-L-cysteine Sulfoxide as a Targeted Prodrug Enzyme System for Malignant Solid Tumor Xenografts. International Journal of Molecular Sciences. 2022; 23(19):12048. https://doi.org/10.3390/ijms231912048
Chicago/Turabian StyleAbo Qoura, Louay, Elena Morozova, Vitalia Kulikova, Saida Karshieva, Darina Sokolova, Vasiliy Koval, Svetlana Revtovich, Tatyana Demidkina, and Vadim S. Pokrovsky. 2022. "Methionine γ-Lyase-Daidzein in Combination with S-Propyl-L-cysteine Sulfoxide as a Targeted Prodrug Enzyme System for Malignant Solid Tumor Xenografts" International Journal of Molecular Sciences 23, no. 19: 12048. https://doi.org/10.3390/ijms231912048