Neferine in the Lotus Plumule Potentiates the Antitumor Effect of Imatinib in Primary Chronic Myeloid Leukemia Cells In Vitro

Abstract

Imatinib, the prototype BCR‐ABL tyrosine kinase inhibitor (TKI), is the first‐line treatment for Philadelphia chromosome‐positive chronic myeloid leukemia (CML) in the chronic phase. However, a subgroup of patients exhibit poor response or experience relapse. This issue may be overcome by combination therapy using natural compounds. Neferine, a major bisbenzylisoquinoline alkaloid extracted from “lotus plumule” (seed embryo of lotus) commonly used in traditional Chinese medicine and tea, was used herein in the combination treatment of CML. The MTT assay showed that neferine exerted cytotoxicity in primary CML cells in a dose‐dependent manner. Moreover, low concentrations of neferine (4 and 8 µM) sensitized primary CML cells to imatinib (CI < 1), and significantly decreased its IC50 from 0.70 ± 0.10 to 0.32 ± 0.06 µM and 0.16 ± 0.02 µM, respectively. Cotreatment of neferine and imatinib significantly decreased the expression of BCR‐ABL protein and its molecular chaperone heat shock protein 90 (Hsp90) mRNA and protein levels, and further decreased phospho‐extracellular regulated protein kinase 1/2 (p‐Erk1/2) and myeloid cell leukemia (Mcl‐1) expression. These results suggest that neferine might be a potential imatinib sensitizer in CML treatment. Practical application In China, Lotus plumule, the green embryo of lotus, is used as a tea and as a source of herbal medicine in the treatment of anxiety, insomnia, spermatorrhea, and thirst. Additional, neferine, a bisbenzylisoquinoline alkaloid extracted from lotus plumule has been shown to have antitumor potential. Herein, the effect of neferine and imatinib cotreatment on primary CML cells obtained from CML patients was assessed, with a synergistic effect being observed between the two compounds. Therefore, neferine might be a promising natural compound to potentiate imatinib in CML patients.

Neferine induces mitochondrial dysfunction to exert anti-proliferative and anti-invasive activities on retinoblastoma

“…Nef was reported to possess cytotoxicity in a dose-dependent manner in primary CML cells. 13,26 In term of cancers, Jun et al. 26 pointed out that alkaloid-rich fraction (ARF) from Nelumbo nucifera targets vascular smooth muscle cell (VSMC) proliferation and migration to suppress neo-intima formation followed by restenosis in balloon-injured rat carotid artery.…”

“…Mice transplanted successfully (v > 200 mm 3 ) were divided into four groups and injected intraperitoneally with Nef (0, 0.5, 1, 2 mg/kg) or an equal volume of ethanol every 3 days for 30 days. 13 Uninformed operators measured tumor weight, tumor volume, 14,15 and body weight every three days. Thirty days after xenotransplantation, tumors were harvested to measure tumor weight and performed immunohistochemical assessments.…”

Farnesiferol C Induces Apoptosis in Chronic Myelogenous Leukemia Cells as an Imatinib Sensitizer via Caspase Activation and HDAC (Histone Deacetylase) Inactivation

“…Though Imatinib has been extensively used for treatment of CML for years, recently combination therapy with low dose of Imatinib is attractive to reduce side effects due to its toxicity in normal cells [27,28]. In the same line, FC sensitized K562 cells to Imatinib induced apoptosis by inhibition of HDAC1, activation of Ac-H3K18, and PARP cleavage in K562 cells, strongly indicating combinatorial therapy potential of FC with Imatinib.…”

Neferine induces p38 MAPK/JNK1/2 activation to modulate melanoma proliferation, apoptosis, and oxidative stress

“…One week later, tumor size (volume >200 mm 3 ) was used to evaluate whether the tumors successfully formed, and neferine (5, 10, or 20 mg/kg) or the equivalent volume of ethanol was then injected intraperitoneally every 3 days for 30 consecutive days (18). After 30 days, the mice were killed by cervical dislocation, and tumors were harvested to assess tumor weight or size, followed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemical analysis.…”