Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo.
J Med Chem
; 63(11): 6096-6106, 2020 06 11.
Article
en En
| MEDLINE
| ID: mdl-32401032
ABSTRACT
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 IC50 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Platino (Metal)
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Profármacos
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Receptores de Estrógenos
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Receptor de Melatonina MT1
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Antineoplásicos
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
China