Norchelerythrine from Corydalis incisa (Thunb.) Pers. promotes differentiation and apoptosis by activating DNA damage response in acute myeloid leukemia.

Abstract

Acute myeloid leukemia (AML) is the most prevalent form of leukemia in adults. The cornerstone of first‑line chemotherapy for AML has poor survival rates, underscoring the urgent need for development of novel therapeutic agents. Differentiation therapy targets the blockade of differentiation in myeloid progenitor cells. The present study screened 100 plant extracts native to South Korea to search for those with differentiation‑inducing activity in AML. Differentiation‑inducing activity was assessed by measuring CD11b expression using fluorescence activated cell sorting. Of these, Corydalis incisa (Thunb.) Pers. (CIP) exhibited the highest efficacy. CIP induced myeloid differentiation, decreased viability and increased cell apoptosis and cell cycle arrest in HL‑60, U937 and THP‑1 cells. Furthermore, ultra‑performance liquid chromatography‑quadrupole time‑of‑flight mass spectrometry identified norchelerythrine as the primary anti‑leukemic compound in CIP. Norchelerythrine induced differentiation and promoted cell cycle arrest and apoptosis, mirroring the tumor‑suppressive effects of CIP, and notably decreased cell viability in patients with various genetic abnormalities. The present mechanistic study showed that norchelerythrine stimulated reactive oxygen species generation, leading to activation of DNA damage signaling and upregulation of p21^cip1, a cyclin‑dependent kinase inhibitor. Overall, norchelerythrine isolated from CIP may be a novel therapeutic option in AML.