In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification
Abstract
:1. Introduction
2. Materials and Methods
2.1. Plant Material and Extraction Process
2.2. In Vitro Cytotoxic Activity
2.2.1. Cell Culture and MTT Cytotoxic Assay
2.2.2. Annexin V/PI Staifning and Cell Cycle Analysis
2.2.3. RT-PCR for the Apoptosis-Related Genes
2.3. In Vivo Experiment (Xenograft Model)
2.3.1. Animals
2.3.2. Study Design
2.3.3. Biochemical Investigation and Histopathological Examination
2.4. LC/Triple-TOF-MS/MS Metabolomic Analysis
2.5. Molecular Docking Simulations of the Metabolites Detected by LC/Triple-TOF-MS/MS Analysis
2.6. HPLC-DAD Analysis
2.6.1. Standard Compounds
2.6.2. Apparatus and Operating Conditions
2.6.3. Sample Preparation
2.6.4. Calibration Graphs and Calculations
3. Results and Discussion
3.1. In Vitro Cytotoxic Activity of the Ethanolic Crude Extract of A. judaica L.
3.1.1. The Cytotoxic Activity of A. judaica L. Extract against A549 Cells Using MTT Assay
3.1.2. Effect of Crude Extract of A. judaica L. on Apoptosis Induction in A549 Cells Using Flow Cytometry
3.1.3. Effect of Crude Extract of A. judaica L. on mRNA Gene Expression of Apoptosis-related Genes
3.2. In Vivo Study (Xenograft Model)
3.2.1. Effect of A. judaica Crude Extract on Tumor Mass Growth Xenografts
3.2.2. Biochemical Investigation and Histopathological Examination of Liver Tissues
3.3. LC/Triple-TOF-MS/MS Metabolomic Analysis of Ethanolic Crude Extract of Artemisia judaica L.
3.4. Molecular Docking Simulations
3.5. Identification and Quantification of Flavonoids by Using HPLC Analysis
3.5.1. Qualitative Identification
3.5.2. Quantitative Estimation
Linearity
System Precision
Method Precision
Limits of Detection and Quantification
Analytical Solution Stability
Sample Analysis
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Forward | Reverse |
---|---|---|
P53 | 5′-CCCCTCCTGGCCCCTGTCATCTTC-3′ | 5′-GCAGCGCCTCACAACCTCCGTCAT-3′ |
BAX | 5′-GTTTCATCCAGGATCGAGCAG-3′ | 5′-CATCTTCTTCCAGATGGTGA-3′ |
CASP-3 | 5′-TGGCCCTGAAATACGAAGTC-3′ | 5′-GGCAGTAGTCGACTCTGAAG-3′ |
CASP-8 | 5′-AATGTTGGAGGAAAGCAAT-3′ | 5′-CATAGTCGTTGATTATCTTCAGC-3′ |
CASP-9 | 5′-CGAACTAACAGGCAAGCAGC-3′ | 5′-ACCTCACCAAATCCTCCAGAAC-3′ |
BCL2 | 5′-CCTGTGGATGACTGAGTACC-3′ | 5′-GAGACAGCCAGGAGAAATCA-3′ |
β-actin | 5′-GTGACATCCACACCCAGAGG-3′ | 5′-ACAGGATGTCAAAACTGCCC-3′ |
Sample | IC50 (μg/mL) * | |||
---|---|---|---|---|
Prostate PC-3 | Breast MDA-MB-231 | Ovarian A2780 | Lung A549 | |
A. judaica L. crude extract | 59.8 ± 3.25 | 98.6 ± 4.65 | NA | 14.2 ± 0.84 |
Doxorubicin | 9.36 ± 1.52 | 7.26 ± 0.98 | 2.36 ± 0.65 | 9.98 ± 0.97 |
Polarity Mode | MZmine ID | Ret. Time (min) | Measured m/z | Calculated m/z | Mass Error (ppm) | Adduct | Molecular Formula | MS/MS Spectrum | Deduced Compound | Ref | |
---|---|---|---|---|---|---|---|---|---|---|---|
Coumarins and their glycosides | |||||||||||
1 | Negative | 801 | 4.07 | 339.0659 | 339.0716 | −16.81 | [M − H]− | C15H16O9 | 339.1 > 177 | Esculin | [48] |
2 | Positive | 1717 | 7.45 | 193.0517 | 193.0501 | 8.29 | [M + H]+ | C10H8O4 | 193 > 178 > 133 > 122 | Scopoletin | [49] |
Flavonoids and their glycosides | |||||||||||
3 | Negative | 1480 | 6.59 | 431.0977 | 431.0978 | −0.23 | [M − H]− | C21H20O10 | 431.1 > 311.1 | Vitexin | [50] |
4 | Positive | 1434 | 6.73 | 611.1583 | 611.1612 | −4.75 | [M + H]+ | C27H30O16 | 611.1 > 303.1 | Rutin | [51] |
5 | Negative | 1631 | 6.92 | 447.0922 | 447.0927 | −1.12 | [M − H]− | C21H20O11 | 447.1 > 327.1 | Orientin | [50] |
6 | Positive | 1566 | 7.13 | 303.0507 | 303.0505 | 0.66 | [M + H]+ | C15H10O7 | 303 > 257 > 229 > 183 > 165 > 153 > 137 | Quercetin | [52] |
7 | Positive | 1579 | 7.16 | 287.0554 | 287.0556 | −0.7 | [M + H]+ | C15H10O6 | 287 > 269 > 241 > 213 >149 >137 | Fisetin | [53] |
8 | Negative | 1793 | 7.42 | 577.1612 | 577.1557 | 9.53 | [M − H]− | C27H30O14 | 577.1 > 269.1 | Rhoifolin | [54] |
9 | Positive | 1869 | 7.76 | 287.0525 | 287.0536 | −3.83 | [M + H]+ | C15H10O6 | 287.2 > 231 > 165.1 > 121.0 | Kaempferol | [53] |
10 | Negative | 2065 | 8.59 | 285.0405 | 285.0399 | 2.10 | [M − H]− | C15H10O6 | 285.2 > 133.0 | Luteolin | [55] |
11 | Negative | 2068 | 8.65 | 315.0505 | 315.0505 | zero | [M − H]− | C16H12O7 | 315.1 > 300.1 | Isorhamnetin | [56] |
12 | Negative | 2171 | 9.23 | 271.0601 | 271.0606 | −1.84 | [M − H]− | C15H12O5 | 271 > 177 > 151 | Naringenin | [49] |
13 | Negative | 2324 | 10.08 | 269.0453 | 269.0450 | 1.12 | [M − H]− | C15H10O5 | 269.2 > 116.8 | Apigenin | [55] |
14 | Positive | 2739 | 10.34 | 301.0680 | 301.0701 | −6.98 | [M + H]+ | C16H12O6 | 301.1 > 286 > 258.0 | Diosmetin | [57] |
15 | Positive | 3059 | 11.52 | 285.0761 | 285.0763 | −0.7 | [M + H]+ | C16H12O5 | 285.0 > 267.9 > 242.1 | Acacetin | [58] |
Phenolic acids | |||||||||||
16 | Negative | 590 | 1.62 | 163.0394 | 163.0395 | −0.61 | [M − H]− | C9H8O4 | 163 > 119 | p-Coumaric acid | [59] |
17 | Negative | 725 | 2.43 | 193.0514 | 193.0501 | 6.73 | [M − H]− | C10H10O4 | 193 > 178> 149 > 134 | Ferulic acid | [59] |
18 | Negative | 751 | 3.30 | 137.0222 | 137.0231 | −6.6 | [M − H]− | C7H6O3 | 137 > 93 > 65 | p-Hydroxy benzoic acid | [60] |
19 | Negative | 991 | 4.97 | 153.0166 | 153.0178 | −7.8 | [M − H]− | C7H6O4 | 153 > 109 | Protocatechuic acid | [60] |
20 | Negative | 1163 | 5.55 | 179.0336 | 179.0344 | −4.47 | [M − H]− | C9H8O4 | 179 > 135 > 134 | Caffeic acid | [60] |
Sterols | |||||||||||
21 | Positive | 5376 | 21.9 | 380.3320 | 380.3343 | −6.05 | [M + H − H20]+ | C28H44O | 380 > 69 | Ergosterol | [61] |
22 | Negative | 3245 | 22.84 | 455.3567 | 455.3525 | 9.22 | [M − H]− | C30H48O3 | 455 | Betulinic acid | [62] |
23 | Positive | 5641 | 23.74 | 413.3615 | 413.3633 | −4.35 | [M + H]+ | C29H48O | 413 > 395.3 > 81.1 | Stigmasterol | [63] |
Terpenes | |||||||||||
24 | Negative | 1071 | 5.29 | 163.0754 | 163.0759 | −3.07 | [M − H]− | C10H12O2 | 163 > 146 > 119 | Hinokitiol/β-thujaplicin | [64] |
25 | Positive | 2327 | 8.83 | 121.1004 | 121.1017 | −10.73 | [M + H]+ | C9H12 | 121 > 119 > 105 > 91 > 77 | Mesitylene | [65] |
26 | Positive | 3393 | 12.85 | 165.0897 | 165.0916 | −11.5 | [M + H]+ | C10H12O2 | 165 > 149 > 103 | Eugenol | [66] |
27 | Negative | 3245 | 22.84 | 455.3567 | 455.3525 | 9.22 | [M − H]− | C30H48O3 | 455 | Ursolic acid | [67] |
Terpenoid bitter principles | |||||||||||
28 | Positive | 5246 | 21.18 | 283.1499 | 283.1545 | −16.25 | [M + H]+ | C15H22O5 | 283 > 265 > 247 > 237 > 209 | Artemisinin | [68] |
Other classes | |||||||||||
29 | Positive | 64 | 1.22 | 123.0553 | 123.0558 | −4.06 | [M + H]+ | C6H6N2O | 123 > 80 | Nicotinamide | [69] |
30 | Positive | 3829 | 15.21 | 286.1450 | 286.1443 | 2.45 | [M + H]+ | C17H19NO3 | 286.1 > 201 > 171 > 143 > 135 | Piperine | [70] |
No. | Detected Metabolite | Type of Study | Mechanism of Action | Ref. |
---|---|---|---|---|
1 | Vitexin | -Animal study with acute lung injury | Vitexin upregulated nuclear factor erythroid-2-related factor2 (Nrf2) and activated heme oxygenase (HO)-1. | [81] |
2 | Rutin | -Human lung cancer cell line, A549 | Rutin downregulated the expression of anti-apoptotic gene (Bcl-2) and decreased the levels of tumor necrosis factor (TNF-α). | [97] |
3 | Quercetin | -Human lung cancer cell line, A549 -Xenograft animal model | Quercetin downregulated the expression of anti-apoptotic gene (Bcl-2) and upregulated the expression of the proapoptotic gene (Bax). | [98] |
4 | Fisetin | -Human lung cancer cell line, A549 | Fisetin induced cell cycle arrest at G2 phase and upregulated the expression of the apoptosis-regulating gene (Caspases 3 and 9). | [99] |
5 | Kaempeferol | -Human lung cancer cell line, A549 | Kaempeferol upregulated the expression of proapoptotic gene (Bax) and downregulated the expression of anti-apoptotic genes (Bcl-2 and Bcl-xL). | [100] |
6 | Luteolin | -Human lung cancer cell line, A549 | Luteolin suppressed migration and invasion of lung cancer cells. | [101] |
7 | Isorhamnetin | -Human lung cancer cell line, A549 -Animal model with Lewis lung cancer cells | Isorhamnetin upregulated the expression of proapoptotic genes (Bax, P53 and Caspase-3) and downregulated the expression of anti-apoptotic genes (Bcl-2, cyclinD1). | [102] |
8 | Naringenin | -Human lung cancer cell line, A549 | Naringenin suppressed migration of lung cancer cells, upregulated the expression of proapoptotic genes (Bax and Caspase-3) and downregulated the expression of matrixmetallo proteinases (MMP-2 and MMP-9). | [103] |
9 | Apigenin | -Human lung cancer cell line, A549 | Apigenin suppressed migration of lung cancer cells and downregulated the expression of MMP-9. | [104] |
10 | Diosmetin | -Human lung cancer cell lines, A549, H1299, H460, SPC-A1, H441, H1650 and Calu-3. -Xenograft animal model | Diosmetin induced apoptosis and enhanced the efficacy of paclitaxel, a chemotherapeutic agent. | [105] |
11 | Acacetin | -Human lung cancer cell line, A549 | Acacetin suppressed migration of lung cancer cells and downregulated the expression of MMP-2 and 9. | [106] |
12 | Ferulic acid | -Human lung cancer cell line, H1299 | Ferulic acid suppressed migration of lung cancer cells and downregulated the expression of MMP-2 and 9. | [107] |
13 | p-Hydroxy benzoic acid | -Human lung cancer cell line, A549 | p-Hydroxy benzoic acid upregulated the expression of proapoptotic gene (Caspase-1) and interleukines (IL1β, and IL18). | [108] |
14 | Protocatechuic acid | -Human lung cancer cell lines, A549, H3255, and Calu-6 | Protocatechuic acid upregulated the expression of proapoptotic genes (Bax and Caspase-3) and downregulated the expression of anti-apoptotic genes (Bcl-2) and matrixmetallo proteinases. | [109] |
15 | Caffeic acid | -Human lung cancer cell line, H1299 -Xenograft animal model | Caffeic acid enhanced the efficacy of paclitaxel and upregulated the expression of Caspases-3 and 9. | [110] |
16 | Ergosterol | -Human lung cancer cell line, A549 | Ergosterol suppressed the proliferation of lung cancer cells. | [111] |
17 | Eugenol | -Human lung cancer cell line, A549 -Human embryonic lung fibroblast, MRC-5 | Eugenol suppressed migration of lung cancer cells and downregulated the expression of MMP-2. | [112] |
18 | Hinokitiol | -Human lung cancer cell line, A549 | Hinokitiol suppressed migration of lung cancer cells, downregulated the expression of MMP-2 and upregulated the expression of proapoptotic genes (Bax, P53 and Caspase-3). | [113] |
19 | Ursolic acid | -Human lung cancer cell line, A549 | Ursolic acid suppressed migration of lung cancer cells and downregulated miR-21 that is correlated with a tumor growth. | [114] |
20 | Piperine | -Human fibrosarcoma cell, HT-1080 -B16F10 melanoma animal model | Piperine suppressed metastasise and migration of lung cancer cells. | [115] |
Co-Crystallized Ligands (Key Interactions) | Ligand-Receptor Interactions towards CDK-2 (PD’a4l) * | Ligand-Receptor Interactions towards EGFR (PDB = 1M17) # |
---|---|---|
2 HB with Leu 83 + 1 Arene-Cation Interaction with Lys 89 | 1 HB with Met 769 | |
Metabolite 1 | 1 HB with Lys 89 | 1 HB with 769 |
Metabolite 2 | - | - |
Metabolite 3 | 1 HB with Lys 89 | - |
Metabolite 4 | 1 HB with Lys 89 | - |
Metabolite 5 | 1 HB with Lys 89 + 1 arene-cation interaction with Lys 89 | 1 HB with 769 |
Metabolite 6 | 1 HB with Leu 83 | 1 HB with 769 |
Metabolite 7 | 1 HB with Lys 89 + 1 arene-cation interaction with Lys 89 | 1 HB with 769 |
Metabolite 8 | 1 arene-cation interaction with Lys 89 | - |
Metabolite 9 | 1 HB with Leu 83 + 1 arene-cation interaction with Lys 89 | - |
Metabolite 10 | 1 HB with Leu 83 | 1 HB with 769 |
Metabolite 11 | 1 HB with Leu 83 | - |
Metabolite 12 | 1 HB with Lys 89 | 1 HB with 769 |
Metabolite 13 | - | - |
Metabolite 14 | 2 HB with Leu 83 and Lys 89 | 1 HB with Met 769 |
Metabolite 15 | 1 arene-cation interaction with Lys 89 | - |
Metabolite 16 | - | - |
Metabolite 17 | - | - |
Metabolite 18 | - | - |
Metabolite 19 | - | |
Metabolite 20 | 1 arene-cation interaction with Lys 89 | 1 HB with 769 |
Metabolite 21 | ||
Metabolite 22 | 1 HB with Lys 89 | - |
Metabolite 23 | 1 HB with Leu 83 | |
Metabolite 24 | - | - |
Metabolite 25 | - | - |
Metabolite 26 | - | - |
Metabolite 27 | 1 HB with Leu 83 + 1 arene-cation interaction with Lys 89 | 1 HB with Met 769 |
Metabolite 28 | - | - |
Metabolite 29 | - | - |
Metabolite 30 | 1 HB with Leu 83 | - |
Validation Parameters | Rutin | Quercetin | Kaempferol | Apigenin |
---|---|---|---|---|
Regression equation | y = 13,199x − 787,148 | y = 15,764.37x − 40,216.27 | y = 71,227x − 46,571 | y = 8938.8x + 357,854 |
Correlation coefficient (R2) | 0.997 | 0.999 | 0.998 | 0.993 |
Linearity range (µg/mL) | 10–200 | 5–100 | 10–150 | 5–100 |
Limit of detection (µg/mL) | 0.7 | 0.5 | 0.4 | 0.5 |
Limit of quantification (µg/mL) | 2.5 | 1.61 | 1.4 | 1.53 |
System precision (%RSD) | 3.16 | 2.25 | 1.59 | 2.26 |
Method precision (%RSD) | 1.93 | 2.78 | 2.19 | 1.31 |
Concentration (mg/gm) | 6 ±0.019 | 0.413 ± 0.00007 | 0.3603 ± 0.0033 | 3.9 ± 0.007 |
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Goda, M.S.; Nafie, M.S.; Awad, B.M.; Abdel-Kader, M.S.; Ibrahim, A.K.; Badr, J.M.; Eltamany, E.E. In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification. Antioxidants 2022, 11, 17. https://doi.org/10.3390/antiox11010017
Goda MS, Nafie MS, Awad BM, Abdel-Kader MS, Ibrahim AK, Badr JM, Eltamany EE. In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification. Antioxidants. 2022; 11(1):17. https://doi.org/10.3390/antiox11010017
Chicago/Turabian StyleGoda, Marwa S., Mohamed S. Nafie, Basma M. Awad, Maged S. Abdel-Kader, Amany K. Ibrahim, Jihan M. Badr, and Enas E. Eltamany. 2022. "In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification" Antioxidants 11, no. 1: 17. https://doi.org/10.3390/antiox11010017
APA StyleGoda, M. S., Nafie, M. S., Awad, B. M., Abdel-Kader, M. S., Ibrahim, A. K., Badr, J. M., & Eltamany, E. E. (2022). In Vitro and In Vivo Studies of Anti-Lung Cancer Activity of Artemesia judaica L. Crude Extract Combined with LC-MS/MS Metabolic Profiling, Docking Simulation and HPLC-DAD Quantification. Antioxidants, 11(1), 17. https://doi.org/10.3390/antiox11010017