Daurinol is a natural product isolated from a traditional ethnopharmacological plant and a novel topoisomerase IIα inhibitor, having potent antitumor effects with low hematological toxicity. Daurinol could be a novel alternative to the clinical anti-cancer agent such as etoposide.
Background and unmet needs
Myelosuppression is one of the most common and serious side effects of cancer chemotherapy. Clinically, myelosuppression is characterized by hematological changes, such as a decrease in the number of red blood cells (anemia), white blood cells (leucopenia or neutropenia), and platelets (thrombocytopenia). Etoposide (VP-16), a clinical anti-tumor drug, is famous for topoisomerase II posion and used to treat various human cancers including small cell lung cancer and testicular cancer. In spite of its potent anti-tumor activity, clinical use of etoposide is limited due to its side effects such as myelosuppression and the development of secondary cancers, particularly etoposide-induced leukemia. Therefore, discovery of a novel alternative, which has low side effects or ameliorate hematological damages induced by chemotherpy, is one of the most important topics in cancer research.
Discovery and Achievements
Both daurinol and etoposide inhibited proliferation of various cancer cells in vitro via interruption of DNA synthesis by inhibition of human topoisomerase IIα. Etoposide is a topoisomerase II poison, on the other hand, daurinol is a catalytic inhibitor of topoisomerase IIα.
Etoposide induces G2/M arrest, severe DNA damage, and the formation of giant nuclei in HCT116 cells in vitro. The induction of DNA damage and nuclear enlargement due to abnormal chromosomal conditions should give rise to genomic instability, resulting in the toxic side effects of etoposide. In contrast, daurinol induces S arrest but does not induce DNA damage and formation of giant nucleus. Therefore, we speculated that daurinol has less side effects compared to etoposide due to these differences.
Finally, we confirmed the in vivo anti-tumor effects and side effects of daurinol and etoposide in nude mice xenograft models. Daurnol (1, 5, 10, 20 mg/kg) and etoposide (20 mg/kg) were administered by intraperitoneal injection twice to three times a week to the total 120 mg/kg dosage (maximum). Daurinol displayed potent anti-tumor effects without any significant loss of body weight and changes in hematological parameters, whereas etoposide treatment led to decreased body weight and white blood cell, red blood cell, and hemoglobin concentration.
- Further toxicological studies are needed.
- Daurinol did not induce toxic phenotypes such as weight loss and hair loss.
- Daurinol did not induce any significant damage on normal tissues including liver, kidney, and colon in nude mice xenograft model.