Abstract B126: The effects of Amaryllidaceae plant constituents narciclasine, lycorine and haemanthamine on chronic lymphocytic leukemia cells

Abstract Targeting translational machinery in cancer cells is an emerging area of fundamental and clinical research. One translation inhibitor, a ribosome-binding natural alkaloid homoharringtonine extracted from the Chinese shrub Cephalotaxus fortunei Hook, is approved for the treatment of chronic myeloid leukemia (CML). However, clinical application of homoharringtonine is constrained due to its limited solubility and cardiotoxicity. Our laboratories focus on developing agents with innovative targeting mechanisms for the treatment of chronic lymphocytic leukemia (CLL). Because CLL depends on short-lived anti-apoptotic proteins, such as Mcl-1 for survival, we are interested in investigating translation inhibitors as a strategy for targeting CLL. We have previously studied homoharringtonine as a potential agent to be used in CLL with promising results. Here, we present the results of our investigation of ribosome-binding Amaryllidaceae plant constituents narciclasine, lycorine and haemanthamine for their effects against CLL cells. The alkaloids were obtained by isolation from various daffodil bulbs purchased from commercial sources. Lycorine was obtained from dried bulbs of Sterbergia lutea Ker Gawl in the amount of 4.5 g per kg of dried bulbs using a literature procedure. Haemanthamine was obtained from Narcissus pseudonarcissus King Alfred in the amount of 465 mg per kg of dried bulbs using a literature procedure. Finally, the procedure for narciclasine isolation had to be developed as the literature protocol was found inefficient. We utilized a Soxhlet extraction with ethanol from dried Calton daffodil bulbs followed by a single column chromatography purification and recrystallization from acetic acid. This practical procedure was fast and high yielding giving us 150 mg per kg of dried bulbs. The three alkaloids were tested for antiproliferative activity against 8 primary CLL cells, OSU-CLL cell line generated from a previously treated CLL patient and HPRT1 cells line, derived from Richter’s transformation that develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL). The HPRT1 cells were the most sensitive, with narciclasine exhibiting the IC50 of 50 nM and lycorine and haemanthamine producing the IC50 in the single digit micromolar region. Evaluation of the alkaloids against normal B cells, T cells and other normal cells from healthy donors revealed that they are less sensitive to the antiproliferative effects of the compounds with the IC50 values 10-100 times higher. Finally, using the [3H]leucine incorporation assay, we showed that the antiproliferative action of the alkaloids in primary CLL and HPRT1 cells is likely due to the inhibition of the protein synthesis in these cancer cells. All studies were performed using homoharringtonine as positive control producing the expected results. The results presented herein support further medchem and translational studies of these alkaloids in CLL and argue that inhibition of translation in cancer cells should be an important pursuit in cancer drug discovery. Citation Format: Yuling Chen, Ryan J. Rutledge, Carson W. King, Ping Xiong, William Wierda, Puppala Sathish, Antonio Evidente, William K. Plunkett, Rong Chen, Alexander Kornienko. The effects of Amaryllidaceae plant constituents narciclasine, lycorine and haemanthamine on chronic lymphocytic leukemia cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B126.