Enhancement of cisplatin cytotoxicity by Retigeric acid B involves blocking DNA repair and activating DR5 in prostate cancer cells

Abstract

Retigeric acid B (RAB), a natural compound isolated from lichen, has been demonstrated to inhibit cell growth and promote apoptosis in prostate cancer (PCa) cells. The present study evaluated the function of RAB combined with clinical chemotherapeutic drugs in PCa cell lines by MTT assay, reverse transcription quantitative polymerase chain reaction and western blot analysis, and identified that RAB at low doses produced significant synergistic cytotoxicity in combination with cisplatin (CDDP); however, no marked synergism between RAB and the other chemotherapeutics was observed. Additional studies revealed that RAB exerted an inhibitory effect on DNA damage repair pathways, including the nucleotide excision repair and mismatch repair pathways, which are involved in the sensitivity to CDDP-based chemotherapy, as suggested by the significantly downregulated expression of certain associated repair proteins. Notably, Excision repair cross-complementing 1, a critical gene in the nucleotide excision repair pathway, exhibited the most significant decrease. When combined with CDDP, RAB-mediated impairment of DNA repair resulted in prolonged DNA damage, as demonstrated by the long-lasting appearance of phosphorylation of histone H2AX at Ser139, which potentially enhanced the chemosensitivity to CDDP. Concurrently, the proapoptotic protein death receptor 5 (DR5) was activated by RAB, which also enhanced the chemotherapeutic response of CDDP. Knockdown of DR5 partially blocked RAB-CDDP synergism, suggesting the crucial involvement of DR5 in this event. The results of the present study identified that RAB functioned synergistically with CDDP to increase the efficacy of CDDP by inhibiting DNA damage repair and activating DR5, suggesting the mechanistic basis for the antitumor effect of RAB in combination with current chemotherapeutics.

Knockdown of ubiquitin‑specific protease 51 attenuates cisplatin resistance in lung cancer through ubiquitination of zinc‑finger E‑box binding homeobox 1

“…In addition, multiple anti-cancer agents have been revealed to be used in combination with ddP to enhance treatment. For example, retigeric acid B, a topoisomerase ii inhibitor, can enhance the cytotoxicity of ddP in prostate cancer (47), while ursane triterpenoid can be combined with DDP in bladder cancer (48). Consistent with the studies that revealed that USP7 inhibitor can overcome bortezomib resistance in multiple myeloma cells (49), the present findings indicated the pharmacological potential of uSP51 inhibitors in the treatment of lung cancer.…”

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

“…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).…”

Synergistic effects of natural products in combination with anticancer agents in prostate cancer: A scoping review

“…Retigeric acid B, a natural pentacyclic triterpene acid isolated from the Lobaria, is a promising anticancer agent in prostate cancer cells. Liu et al (2018) have reported that when retigeric acid B was combined with cisplatin, which is also an anticancer treatment, including against prostate cancer, anticancer efficacy increased against PC-3 and DU-145, prostate cancer cells. Doxorubicin, etoposide, docetaxel, and vincristine were tested in combination.…”