Luteolin Induces Cytotoxicity in Mix Cellularity Classical Hodgkin's LymphomaviaCaspase Activated-cell Death

Abstract

Background/Aim: We investigated the effects of luteolin (LUT) on classical Hodgkin's lymphoma (cHL), since such studies in malignant lymphomas are lacking. Materials and Methods: Effect of LUT on cell growth was assessed with water-soluble tetrazolium 1 (WST-1) cell proliferation assay and automated hemocytometry on trypan blue-exclusion assay. Cell death was investigated with acridine orange/ethidium bromide live-dead assay, propidium iodide (PI) flow cytometry, and Annexin-V-PI microscopy. Caspase activation was studied using CellEvent Caspase-3/7 Green detection reagent. High resolution immunofluorescence microscopy was used to detect cleaved-PARP-1. Results: LUT induced a dosedependent decrease in the growth of KMH2 and L428 cells, cellular models of mix-cellularity (MC) and nodular sclerosis (NS) cHL, respectively. However, LUT induced cell death only in KMH2, at a higher concentration, and this was associated with caspase activation and cleaved PARP-1. Conclusion: LUT induces cytotoxicity in the MC-cHL cellular model KMH2 via caspase activation. While current frontline treatment regimens, which include ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) result in a high cure rate in classical Hodgkin's lymphoma (cHL) (1), disease relapse, refractory disease, treatment-related toxicities, and development of secondary neoplasms, remain significant concerns (2). In addition, only less than 50% patients who fail frontline therapy and subsequently treated with either autologous stem cell transplant (ASCT) or Brentuximab vedotin show clinical responses (3, 4). To mitigate these concerns associated with poor clinical responses in cHL, one line of research is focused on the development and discovery of new therapeutic approaches. Luteolin (3,4,5,7-tetrahydroxy flavone, LUT), a flavonoid found in common foods, has been widely studied for its anticancer potential, as demonstrated in studies in multiple human malignancies such as lung, breast, glioblastoma, prostate, colon, and pancreatic cancers (5). LUT has been shown to trigger apoptosis (6, 7), inhibit cell growth, stimulate cell cycle arrest (6, 7) and disrupt metastasis (8) and cell migration (8, 9). However, although increased dietary intake of flavonoids was associated with reduced risk of disease occurrence in non-Hodgkin's lymphoma, (10), there is very limited information about the effects of LUT on hematological malignancies. In myeloid leukemia, LUTinduced apoptosis is modulated by the differential expression of the oncoprotein PTTG1 (pituitary tumor-transforming gene 1) (11). In multiple myeloma, LUT causes cell death by apoptosis and autophagy (12). To date however, there is no study on the effect of LUT on malignant lymphomas. Therefore, the goal of this current study was to investigate the potential anti-cancer effects of LUT on cHL. Materials and Methods Drug. LUT was purchased from SelleckChem (Houston, TX, USA) and dissolved in DMSO (Sigma-Aldrich, St. Louis, MO, USA) to prepare a 50-mM stock, which was aliquoted and stored at −20˚C until rea...

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