A Novel Inhibitor of Poly(ADP- R ibose) Polymerase-1 Inhibits Proliferation of a BRCA-Deficient Breast Cancer Cell Line via the DNA D amage- A ctivated cGAS-STING Pathway
- Chem Res Toxicol. 2024 Apr 15;37(4):561-570. doi: 10.1021/acs.chemrestox.3c00343.
- 1. Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
- 2. School of Public Health, Qingdao University, Qingdao 266071, China.
- 3. Department of Molecular Craniofacial Embryology and Oral Histology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo 113-8510, Japan.
- 4. Department of Oral, Plastic and Aesthetic Surgery, Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, China.
- 5. Department of Radiotherapy, Yizhou Tumor Hospital, Zhuozhou 072750, China.
- 6. Department of Radiotherapy, University of Tsukuba Hospital, Tsukuba 305-8576, Japan.
- 7. Department of Pharmacy, Qingdao University of Science and Technology, Qingdao 266041, China.
Loss-of-function mutations in the Breast Cancer Susceptibility Gene (BRCA1 and BRCA2) are often detected in patients with breast Cancer. Poly(ADP-ribose) polymerase-1 (PARP1) plays a key role in the repair of DNA strand breaks, and PARP inhibitors have been shown to induce highly selective killing of BRCA1/2-deficient tumor cells, a mechanism termed synthetic lethality. In our previous study, a novel PARP1 inhibitor─(E)-2-(2,3-dibromo-4,5-dimethoxybenzylidene)-N-(4-fluorophenyl) hydrazine-1-carbothioamide (4F-DDC)─was synthesized, which significantly inhibited PARP1 activity with an IC50 value of 82 ± 9 nM. The current study aimed to explore the mechanism(s) underlying the antitumor activity of 4F-DDC under in vivo and in vitro conditions. 4F-DDC was found to selectively inhibit the proliferation of BRCA mutant cells, with highly potent effects on HCC-1937 (BRCA1-/-) cells. Furthermore, 4F-DDC was found to induce Apoptosis and G2/M cell cycle arrest in HCC-1937 cells. Interestingly, immunofluorescence and Western blot results showed that 4F-DDC induced DNA double strand breaks and further activated the cGAS-STING pathway in HCC-1937 cells. In vivo analysis results revealed that 4F-DDC inhibited the growth of HCC-1937-derived tumor xenografts, possibly via the induction of DNA damage and activation of the cGAS-STING pathway. In summary, the current study provides a new perspective on the antitumor mechanism of PARP inhibitors and showcases the therapeutic potential of 4F-DDC in the treatment of breast Cancer.