BTH-8, a novel poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor, causes DNA double-strand breaks and exhibits anticancer activities in vitro and in vivo

• Published in: International journal of biological macromolecules Vol. 150; pp. 238 - 245
• Main Authors: Guo, Chuanlong, Zhang, Fan, Wu, Xiaochen, Yu, Xuemin, Wu, Xianggen, Shi, Dayong, Wang, Lijun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2020
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Binding Sites; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; DNA Breaks, Double-Stranded - drug effects; DNA double-strand breaks; Dose-Response Relationship, Drug; Female; G2 Phase Cell Cycle Checkpoints - drug effects; HCC-1937; Humans; In vivo; Mice; Models, Molecular; Molecular Conformation; Molecular Structure; PARP-1 inhibitor; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly(ADP-ribose) Polymerase Inhibitors - chemistry; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Protein Binding; Structure-Activity Relationship; Xenograft Model Antitumor Assays; In vivo; PARP-1 inhibitor; DNA double-strand breaks; HCC-1937; Apoptosis
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2020.02.069

Poly (ADP-ribose) polymerase (PARP) is a family of enzymes that play an important role in DNA repair. We designed 2-(2,3,6-tribromo-4,5-dimethoxybenzylidene) hydrazinecarbothioamide (BTH-8) as a novel human PARP (PARP-1) inhibitor with anticancer activities in vitro and in vivo. With an IC50 value of 79.79 ± 2.16 nM, BTH-8 caused DNA double-strand breaks, increased the foci quantitation of γ-H2AX and inhibited poly(ADP-ribose) (PAR) formation. BTH-8 could bind to PARP-1 with the target affinity [KD (equilibrium dissociation constant) value] of 1.372 μM. BTH-8 can inhibit the proliferation of a variety of tumor cells, especially BRCA-deficient cells (HCC-1937 and Capan-1). Further investigation showed that BTH-8 effectively induced a significant amount of G2/M cell cycle arrest and cell apoptosis in HCC-1937 cells. BTH-8 also exhibited antitumor activity in vivo, which was achieved by the inhibition of PARP-1. In sum, our study indicates that BTH-8 might be a novel suitable PARP-1 inhibitor to treat human breast cancer.