Synergistic Therapy for Cervical Cancer by Codelivery of Cisplatin and JQ1 Inhibiting Plk1-Mutant Trp53 Axis.

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 (mPEG113-b-P(Glu10-co-Phe10)-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. In vivo 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 (AUC0-∞): 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.

• Authors: Yinan Wang, Na Shen, Shuchun Li, Haiyang Yu, Yue Wang, Zhilin Liu, Liying Han, Zhaohui Tang
• Journal: Nano letters (Nano Lett) Vol. 21 Issue 6 Pg. 2412-2421 (03 24 2021) ISSN: 1530-6992 [Electronic] United States
• PMID: 33705152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BRD4 protein, human
• Cell Cycle Proteins
• Nuclear Proteins
• Transcription Factors
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Cell Cycle Proteins (genetics)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Female
• Humans
• Nuclear Proteins (genetics)
• Transcription Factors
• Uterine Cervical Neoplasms (drug therapy, genetics)