In vivo Pharmacokinetic and Anticancer Studies of HH-N25, a Selective Inhibitor of Topoisomerase I, and Hormonal Signaling for Treating Breast Cancer

Abstract

Purpose Breast cancer is the most frequently diagnosed cancer globally, and the leading cause of cancer-associated mortality among women. The efficacy of most clinical chemotherapies is often limited by poor pharmacokinetics and the development of drug resistance by tumors. In a continuing effort to explore small molecules as alternative therapies, we herein evaluated the therapeutic potential of HH-N25, a novel nitrogen-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivative. Methods We evaluated the in vivo pharmacokinetic properties and maximum tolerated dose (MTD) of HH-N25 in rats. We also characterized the compound for in vitro and in vivo anticancer activities and its inhibitory effects against DNA topoisomerases and hormonal signaling in breast cancer. Furthermore, we used molecular docking to analyse the ligand–receptor interactions between the compound and the targets. Results The maximum serum concentration (C max ), half-life (t 1/2 beta), mean residence time (MRT), oral clearance (CL/f), and apparent volume of distribution (VD/f) of HH-N25 were 1446.67 ± 312.05 ng/mL, 4.51 ± 0.27 h, 2.56 ± 0.16 h, 8.32 ± 1.45 mL/kg/h, and 1.26 ± 0.15 mL/kg, respectively, after single-dose iv administration at 3 mg/kg body weight. HH-N25 had potent anticancer activity against a panel of human breast cancer cell lines with 50% inhibitory concentrations (IC 50 ) ranging 0.045±0.01~4.21±0.05 µM. The drug also demonstrated marked in vivo anticancer activity at a tolerated dose and prolonged the survival duration of mice without unacceptable toxicities based on body weight changes in human tumor xenograft models. In addition, HH-N25 exhibited a dose-dependent inhibition of topoisomerase I and ligand-mediated activities of progesterone and androgen receptors. Conclusion HH-N25 represents a new molecular entity that selective suppressed TOP1 and hormonal signaling, and shows potent antitumor activities in human breast cancer cells in vitro and in vivo. HH-N25 thus represents a promising anticancer agent that warrants further preclinical and clinical exploration.

Prognostic and Genomic Analysis of Proteasome 20S Subunit Alpha (PSMA) Family Members in Breast Cancer

“…While existing evidence-based treatment strategies use the classical hormonal factors, including the progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor (HER)-2, to stratify BRCA prior to determining the most suitable treatment for patients, plenty of immunohistochemical markers, such as Ki-67, p53, and E-cadherin, are simultaneously employed as predictive tools for those subtypes that still lack druggable molecular targets [ 6 , 7 , 8 , 9 , 10 ]. Over the past few years, studies of the genetic alterations and dysfunction of signal transduction pathways that highly contribute to the advent of numerous predictive biomarkers, including transcriptomic data and messenger (m)RNA levels, have opened up the possibility of having effective therapeutics and have been useful in predicting tumor grades, drug responsiveness, and risks of recurrence of intrinsic subtypes [ 11 , 12 , 13 ].…”

Identification of DPP4/CTNNB1/MET as a Theranostic Signature of Thyroid Cancer and Evaluation of the Therapeutic Potential of Sitagliptin

“…Molecular docking has become an increasingly important tool commonly used to understand drug bimolecular interactions with the target proteins for rational drug design and development [ 62 , 81 , 82 ]. It is useful in estimating binding affinities of the ligand to the proteins and in providing preliminary mechanistic insight into the behavior of a small molecule drug in the binding cavity of target proteins [ 83 , 84 ], as well as elucidating the potential drug-regulated biochemical processes [ 79 , 85 ]. Consequently, we conducted a molecular docking analysis of interactions of DPP4/CTNNB1/MET gene signatures with sitagliptin.…”

Leveraging Bulk and Single-Cell RNA Sequencing Data of NSCLC Tumor Microenvironment and Therapeutic Potential of NLOC-15A, A Novel Multi-Target Small Molecule

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