Induction of Apoptosis, Autophagy and Ferroptosis by Thymus vulgaris and Arctium lappa Extract in Leukemia and Multiple Myeloma Cell Lines.

Aveen N Adham,Alaadin M Naqishbandi,Mohamed Elamir F Hegazy,Thomas Efferth

doi:10.3390/molecules25215016

Aveen N Adham, Alaadin M Naqishbandi + Show 2 more

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https://doi.org/10.3390/molecules25215016

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Abstract

Thymus vulgaris and Arctium lappa have been used as a folk remedy in the Iraqi Kurdistan region to deal with different health problems. The aim of the current study is to investigate the cytotoxicity of T. vulgaris and A. lappa in leukemia and multiple myeloma (MM) cell lines and determine the mode of cell death triggered by the most potent cytotoxic fractions of both plants in MM. Resazurin assay was used to evaluate cytotoxic and ferroptosis activity, apoptosis, and modulation in the cell cycle phase were investigated via Annexin V-FITC/PI dual stain and cell-cycle arrest assays. Furthermore, we used western blotting assay for the determination of autophagy cell death. n-Hexane, chloroform, ethyl acetate, and butanol fractions of T. vulgaris and A. lappa exhibited cytotoxicity in CCRF-CEM and CEM/ADR 5000 cell lines at concentration range 0.001–100 μg/mL with potential activity revealed by chloroform and ethyl acetate fractions. NCI-H929 displayed pronounced sensitivity towards T. vulgaris (TCF) and A. lappa (ACF) chloroform fractions with IC50 values of 6.49 ± 1.48 and 21.9 ± 0.69 μg/mL, respectively. TCF induced apoptosis in NCI-H929 cells with a higher ratio (71%), compared to ACF (50%) at 4 × IC50. ACF demonstrated more potent autophagy activity than TCF. TCF and ACF induced cell cycle arrest and ferroptosis. Apigenin and nobiletin were identified in TCF, while nobiletin, ursolic acid, and lupeol were the main compounds identified in ACF. T. vulgaris and A. lappa could be considered as potential herbal drug candidates, which arrest cancer cell proliferation by induction of apoptosis, autophagic, and ferroptosis.

Highlights

Hematologic malignancies are sorts of cancer that originate in the blood-forming tissue such as the bone marrow or the lymph system, and include leukemia, lymphoma, and multiple myeloma (MM) [1].MM is one of the most common types of hematological cancer and globally accounts for about 10% of all hematologic malignancies
Our study showed that ferroptosis cell death in addition to apoptosis was involved in the tumor-suppressive activities of Thymus chloroform fraction (TCF) and Arctium chloroform fraction (ACF)
Our study demonstrated that both plants possess potent cytotoxic activity against hematologic malignancies, the results were supported by an evaluation of their mechanism of action

Summary

Introduction

Hematologic malignancies are sorts of cancer that originate in the blood-forming tissue such as the bone marrow or the lymph system, and include leukemia, lymphoma, and multiple myeloma (MM) [1]. MM is one of the most common types of hematological cancer and globally accounts for about 10% of all hematologic malignancies. Molecules 2020, 25, 5016 life-threatening hematological malignancy, characterized by abnormal elevation number of leucocytes in the blood and bone marrow, resulting from a combination of environmental and genetic factors [3]. Leukemia occurs in adults over the age of 55 years but is the most predominant cancer in children younger than 15 years of age. Among the most common types of leukemia are acute lymphoblastic leukemia and acute myeloid leukemia with a five-year survival rate of 68.2 and 26.9%, respectively [4]

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