Topical 2′-Hydroxyflavanone for Cutaneous Melanoma
Abstract
:1. Introduction
2. Results
2.1. 2HF Inhibited the Growth/Survival of Melanoma Cell Lines in Vitro
2.2. 2HF-Induced Apoptosis in Melanoma Cell Lines in Vitro
2.3. 2HF Depletes Rlip and PARP1 and Influences the Cytotoxic Effects of PARP1 Inhibitor AZD 2461
2.4. 2HF Inhibits Endocytosis as Effectively as Depletion of Rlip
2.5. 2HF Treatment Inhibits Melanoma Signaling in Vitro
2.6. 2HF and Sunitinib Co-Treatment on Mouse and Human Melanoma Cells in Vitro
2.7. 2HF is Poorly Orally Absorbed and Rapidly Metabolized after Oral or IV Dosing
2.8. Topical 2HF Inhibited the Growth of Implants of B16-F0 and B16-F10 Melanoma
2.9. 2HF Regulates Cancer Signaling in Tumors Induced by B16-F0 and B16-F10 Melanoma Cells
2.10. 2HF Was Absorbed Systemically but Did Not Exhibit any Significant Systemic Toxicity
3. Discussion
4. Materials and Methods
4.1. Reagents and Cell Lines
4.2. Ethics Statement
4.3. IC50 of 2HF on Melanoma Cell Line
4.4. Effect of Sunitinib on 2HF-Mediated B16-F0, B16-F10, and SK-MEL-24 Cell Death
4.5. Effect of 2HF on Key Signaling and Apoptotic Proteins Responsible for Melanoma Cell Growth/Death
4.6. Detection of 2HF-Induced Apoptosis in Mouse and Human Melanoma Cells by DNA Fragmentation
4.7. Detection of 2HF-Induced Apoptosis in Mouse and Human Melanoma Cells by TUNEL Assay
4.8. Effect of RLIP76 Depletion on EGF Binding and Internalization
4.9. Animal Studies
4.10. Assessment of Angiogenesis, Proliferation, and Apoptosis
4.11. LC-MS/MS Analysis of 2HF in Serum
4.12. Single Dose Pharmacokinetic Study of 2HF
4.13. Effect of 2HF on Blood Chemistry of B16-F0 Melanoma-Bearing C57B Mice
4.14. Statistical Analysis
5. Conclusions
Supplementary Materials
Supplementary File 1Author Contributions
Funding
Conflicts of Interest
Appendix A
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Parameter | B16-F0 | B16-F10 | SK-MEL-24 |
---|---|---|---|
2HF IC50 | 38.59 ± 1.61 µM | 41.95 ± 1.83 µM | 44.92 ± 1.67 µM |
PARP1i IC50 | 16.52 ± 4.86 µM | 29.88 ± 28.53 µM | 55.00 ± 23.90 µM |
PARP1i IC50 with 20µM 2HF | 10.31 ± 1.41 µM | 12.86 ± 2.72 µM | 43.02 ± 16.21 µM |
Intact PARP1 | ++ | + | ++++ |
Cleaved PARP1 C-terminus | + | ++ | +++ |
Cleaved PARP1 N-terminus | +++ | ++ | ++ |
BRCA1 detection by WB | + | - | - |
BRCA2 detection by WB | - | - | + |
Parameter | Vehicle (PLO Gel) | 2HF + PLO Gel Treated (Topically Each Day) |
---|---|---|
CBC | ||
RBC (×106/µL) | 8.6 ± 0.3 | 8.7 ± 0.2 |
WBC (×103/µL) | 9.0 ± 0.7 | 9.4 ± 0.7 |
Platelets (×103/µL) | 746.0 ± 48 | 689.0 ± 54 |
Hemoglobin (g/dL) | 13.6 ± 0.3 | 13.7 ± 0.4 |
Hematocrit (%) | 42.4 ± 0.8 | 41.8 ± 1.1 |
Plasma/Serum | ||
Glucose (mg/dL) | 176.0 ± 12.4 | 179.0 ± 15.7 |
Creatinine (mg/dL) | 0.17 ± 0.0 | 0.19 ± 0.0 |
Albumin (g/dL) | 2.3 ± 0.1 | 2.8 ± 0.1 |
ALT(units/L) | 105.0 ± 8.7 | 84.0 ± 5.4 * |
AST(units/L) | 414.0 ± 14.2 | 311.0 ± 12.0 * |
ALP(units/L) | 75.7 ± 4.6 | 108.4 ± 7.2 * |
LDH(units/L) | 6126.0 ± 274.0 | 2150.0 ± 123.0 * |
Triglycerides(mg/dL) | 166.0 ± 9.7 | 111.0 ± 7.3 * |
Cholesterol (mg/dL) | 98.0 ± 5.5 | 83.0 ± 2.4 |
n = 3 mice in each group * p < 0.05 |
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Bose, C.; Singh, S.P.; Igid, H.; Green, W.C.; Singhal, S.S.; Lee, J.; Palade, P.T.; Rajan, A.; Ball, S.; Tonk, V.; et al. Topical 2′-Hydroxyflavanone for Cutaneous Melanoma. Cancers 2019, 11, 1556. https://doi.org/10.3390/cancers11101556
Bose C, Singh SP, Igid H, Green WC, Singhal SS, Lee J, Palade PT, Rajan A, Ball S, Tonk V, et al. Topical 2′-Hydroxyflavanone for Cutaneous Melanoma. Cancers. 2019; 11(10):1556. https://doi.org/10.3390/cancers11101556
Chicago/Turabian StyleBose, Chhanda, Sharda P. Singh, Henry Igid, William C. Green, Sharad S. Singhal, Jihyun Lee, Philip T. Palade, Aditya Rajan, Somedeb Ball, Vijay Tonk, and et al. 2019. "Topical 2′-Hydroxyflavanone for Cutaneous Melanoma" Cancers 11, no. 10: 1556. https://doi.org/10.3390/cancers11101556
APA StyleBose, C., Singh, S. P., Igid, H., Green, W. C., Singhal, S. S., Lee, J., Palade, P. T., Rajan, A., Ball, S., Tonk, V., Hindle, A., Tarbox, M., & Awasthi, S. (2019). Topical 2′-Hydroxyflavanone for Cutaneous Melanoma. Cancers, 11(10), 1556. https://doi.org/10.3390/cancers11101556