jm0c00343_si_006.pdb (6.59 kB)
Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo
dataset
posted on 2020-05-22, 20:30 authored by Xue-Qing Song, Rui-Ping Liu, Shu-Qing Wang, Zhe Li, Zhong-Ying Ma, Ran Zhang, Cheng-Zhi Xie, Xin Qiao, Jing-Yuan XuMultitargeted 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.
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cisplatinfirst-line chemotherapeutic Pt drugsAnticancer Melatplatin Prodrugsestrogen receptorintracellular accumulationoncogenic pathwaysImmune Responsemultitarget DNAtumor growthLow Toxicityblock tumorigenesisVivo Multitargeted therapydrug efficacynanomolar IC 50 values 100-DNA damageMT 1-ERMCF -7upregulated γ H 2AXER high-expressionNF -κBlymphocyte proliferationmelatonin receptorHigh Effect
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