Targeting HR Repair as a Synthetic Lethal Approach to Increase DNA Damage Sensitivity by a RAD52 Inhibitor in BRCA2-Deficient Cancer Cells

Abstract

BRCA mutation, one of the most common types of mutations in breast and ovarian cancer, has been suggested to be synthetically lethal with depletion of RAD52. Pharmacologically inhibiting RAD52 specifically eradicates BRCA-deficient cancer cells. In this study, we demonstrated that curcumin, a plant polyphenol, sensitizes BRCA2-deficient cells to CPT-11 by impairing RAD52 recombinase in MCF7 cells. More specifically, in MCF7-siBRCA2 cells, curcumin reduced homologous recombination, resulting in tumor growth suppression. Furthermore, a BRCA2-deficient cell line, Capan1, became resistant to CPT-11 when BRCA2 was reintroduced. In vivo, xenograft model studies showed that curcumin combined with CPT-11 reduced the growth of BRCA2-knockout MCF7 tumors but not MCF7 tumors. In conclusion, our data indicate that curcumin, which has RAD52 inhibitor activity, is a promising candidate for sensitizing BRCA2-deficient cells to DNA damage-based cancer therapies.

Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review

“…The molecular targets of the active metabolite of irinotecan, SN-38, are Top1-DNA covalent reaction intermediates that are reversibly stabilized by SN-38 and result in DNA strand breaks [Figure 5] [28] . DNA damage by irinotecan has been documented in regards to an increase in DNA damage by the inhibition of proteins, such as Rad51 and Rad52, which are involved in DNA repair.…”

“…DNA damage by irinotecan has been documented in regards to an increase in DNA damage by the inhibition of proteins, such as Rad51 and Rad52, which are involved in DNA repair. Curcumin was reported to target homologous recombination through the inhibition of Rad52, resulting in the sensitization of irinotecan-inducing DNA damage [ 29 ] . Flavopiridol, a cyclin-dependent kinase inhibitor, was shown to be beneficial to patients with advanced solid tumors that expressed wild-type p53 treated with irinotecan through the suppression of Rad51 [ 30 ] .…”

Protective Effect of Curcuma Extract in an Ex Vivo Model of Retinal Degeneration via Antioxidant Activity and Targeting the SUMOylation

“…Hendriks et al [ 55 ] demonstrated that curcumin was able to prevent the SUMOylation of histone H3. Also, more recently, it was shown to block the SUMOylation of RAD52, a protein important for DNA double-strand break repair [ 56 ]. Being SUMOylation activated and influenced by oxidative stress [ 13 ], these results, together with our previous findings, indicate that Curcuma could act as a SUMOylation inhibitor with both direct inhibiting protein SUMOylation and indirect inhibiting oxidative stress mechanisms.…”

Psorachromene induces apoptosis and suppresses tumor growth in NSCLC cells harboring EGFR L858R/T790M/C797S

“…The docking analysis of EGFR L858R/T790M/C797S (PDB ID: 6LUB) and of the EGFR wild‐type apo structure (PDB ID: 5FED) with psorachromene was performed using BIOVIA Discovery Studio software, version 19.1.0.18287, as described previously (Tseng et al, 2021).…”