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Tytuł:
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Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo .
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Autorzy:
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Song XQ; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Liu RP; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Wang SQ; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Li Z; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Ma ZY; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Zhang R; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Xie CZ; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Qiao X; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Xu JY; Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
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Źródło:
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Journal of medicinal chemistry [J Med Chem] 2020 Jun 11; Vol. 63 (11), pp. 6096-6106. Date of Electronic Publication: 2020 May 22.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
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MeSH Terms:
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Antineoplastic Agents/*chemistry
Platinum/*chemistry
Prodrugs/*chemistry
Receptor, Melatonin, MT1/*metabolism
Receptors, Estrogen/*metabolism
Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Binding Sites ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; Humans ; Immune System/drug effects ; Immune System/metabolism ; Mice ; Mice, Nude ; Molecular Docking Simulation ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Neoplasms/drug therapy ; Neoplasms/pathology ; Prodrugs/pharmacology ; Prodrugs/therapeutic use ; Protein Structure, Tertiary ; Receptor, Melatonin, MT1/chemistry ; Receptors, Estrogen/chemistry
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Substance Nomenclature:
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0 (Antineoplastic Agents)
0 (NF-kappa B)
0 (Prodrugs)
0 (Receptor, Melatonin, MT1)
0 (Receptors, Estrogen)
49DFR088MY (Platinum)
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Entry Date(s):
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Date Created: 20200514 Date Completed: 20201112 Latest Revision: 20201112
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Update Code:
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20240105
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DOI:
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10.1021/acs.jmedchem.0c00343
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PMID:
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32401032
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Multitargeted therapy could rectify various oncogenic pathways to block tumorigenesis and progression. The combination of endocrine-, immune-, and chemotherapy might exert a highly synergistic effect against certain tumors. Herein, a series of smart Pt(IV) prodrugs 3 - 6 , named Melatplatin, were rationally designed not only to multitarget DNA, MT1, and estrogen receptor (ER) but also to activate immune response. Melatplatin, conjugating first-line chemotherapeutic Pt drugs with human endogenous melatonin (MT), significantly enhanced drug efficacy especially in ER high-expression (ER + ) cells, among which 3 presented the most potent cytotoxicity toward ER + MCF-7 with nanomolar IC 50 values 100-fold lower than cisplatin. Melatplatin could bind well to melatonin receptor (MT1) according to molecular docking. Besides, 3 evidently increased intracellular accumulation and DNA damage, upregulated γH2AX and P53, and silenced NF-κB to induce massive apoptosis. Most strikingly, 3 effectively inhibited tumor growth and attenuated systemic toxicity compared to cisplatin in vivo , promoting lymphocyte proliferation in spleen to achieve immune modulation.
