Synergistic Therapy for Cervical Cancer by Codelivery of Cisplatin and JQ1 Inhibiting Plk1-Mutant Trp53 Axis.
basic_science · Level V
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- Record sourced from PubMed, PMID 33705152.
- Also identified by DOI 10.1021/acs.nanolett.0c04402.
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Abstract
JQ1, a specific inhibitor of bromodomain-containing protein 4 (BRD4), could have great potential in the treatment of cervical cancer. However, its clinical application is limited by its short plasma half-life and limited antitumor efficacy. In this work, cisplatin (CDDP) was first utilized as the stabilizer and cooperator in the nanosystem (mPEG<sub>113</sub>-<i>b</i>-P(Glu<sub>10</sub>-<i>co</i>-Phe<sub>10</sub>)-CDDP/JQ1, called PGP-CDDP/JQ1) to break through the efficiency limitation of JQ1. The PGP-CDDP/JQ1 had a combination index (CI) of 0.21, exerting a strong cytotoxic synergistic effect. <i>In vivo</i> experiments revealed that PGP-CDDP/JQ1 had a significantly higher tumor inhibition effect (tumor inhibition rate: 85% vs 14%) and plasma stability of JQ1 (area under the curve (AUC<sub>0-∞</sub>): 335.97 vs 16.88 μg × h/mL) than free JQ1. The mechanism underling the synergism of JQ1 with CDDP in PGP-CDDP/JQ1 was uncovered to be inhibiting Plk1-mutant Trp53 axis. Thus, this study provides an optional method for improving the clinical application of JQ1 in cervical cancer.
Medical subject headings
- Antineoplastic Agents
- Uterine Cervical Neoplasms