Natural product β-thujaplicin inhibits homologous recombination repair and sensitizes cancer cells to radiation therapy

Abstract

Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR)-mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients’ responses to radiation therapy, a mainstay of treatment for many human cancers. In this study, in order to systematically identify natural products with an inhibitory effect on HR repair, we developed a high-throughput image-based HR repair screening assay and screened a chemical library containing natural products. Among the most interesting of the candidate compounds identified from the screen was β-thujaplicin, a bioactive compound isolated from the heart wood of plants in the Cupressaceae family, can significantly inhibit HR repair. We further demonstrated that β-thujaplicin inhibits HR repair by reducing the recruitment of a key HR repair protein, Rad51, to DNA double-strand breaks. More importantly, our results showed that β-thujaplicin can radiosensitize cancer cells. Additionally, β-thujaplicin sensitizes cancer cells to PARP inhibitor in different cancer cell lines. Collectively, our findings for the first time identify natural compound β-thujaplicin, which has a good biosafety profile, as a novel HR repair inhibitor with great potential to be translated into clinical applications as a sensitizer to DNA-damage-inducing treatment such as radiation and PARP inhibitor. In addition, our study provides proof of the principle that our robust high-throughput functional HR repair assay can be used for a large-scale screening system to identify novel natural products that regulate DNA repair and cellular responses to DNA damage-inducing treatments such as radiation therapy.

Natural Compounds That Target DNA Repair Pathways and Their Therapeutic Potential to Counteract Cancer Cells

“…Capsaicin, the main bioactive compound found in chili peppers of the Capsicum genus, downregulates the ERCC1 protein in lung cancer cells by promoting its proteasomal degradation, thereby enhancing the cytotoxic effects of the EGFR inhibitor erlotinib (111,112). b-Thujaplicin, a natural monoterpenoid found in the wood of trees in the Cupressaceae family, sensitized osteosarcoma cells to damage caused by ionizing radiation, as it inhibits the formation of RAD51 foci and keeps RPA phosphorylated (113). Retiegeric acid B potentiates the effects of cisplatin on hormone-refractory prostate cancer cells by affecting nucleotide excision repair, particularly ERCC1, TFB5, and RPA1 proteins, and mismatch repair, presumably MSH2 and MSH6 proteins (114).…”

Screening a redox library identifies the anti-tumor drug Hinokitiol for treating intrahepatic cholangiocarcinoma

“…It has been reported that Hinokitiol inhibits epidermal growth factorinduced cell migration and signaling pathways in human cervical adenocarcinoma [38]. Zhang et al [39] found that Hinokitiol can increase the sensitivity of cancer cells to radiotherapy by inhibiting homologous recombination and repair of cancer cells. Recent reports have found that Hinokitiol can induce autophagy signal transduction by downregulating the AKT/mTOR pathway, thereby inhibiting tumor growth [40,41].…”

Chalcomoracin inhibits cell proliferation and increases sensitivity to radiotherapy in human non-small cell lung cancer cells via inducing endoplasmic reticulum stress-mediated paraptosis

“…Studies have revealed that natural products can sensitize cancer cells to radiation therapy [ 23 , 24 ]. The mechanisms by which the natural components synergize with IR to facilitate cancer cell killing are usually by enhancing apoptosis, affecting the cell cycle, and/or attenuating angiogenesis [ 25 – 29 ].…”