Inhibition of human prostate cancer (PC-3) cells and targeting of PC-3-derived prostate cancer stem cells with koenimbin, a natural dietary compound from Murraya koenigii (L) Spreng
Authors Kamalidehghan B, Ghafouri-Fard S, Motevaseli E, Ahmadipour F
Received 12 November 2017
Accepted for publication 8 March 2018
Published 4 May 2018 Volume 2018:12 Pages 1119—1133
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Palas Chanda
Peer reviewer comments 3
Editor who approved publication: Dr Anastasios Lymperopoulos
Behnam Kamalidehghan,1 Soudeh Ghafouri-Fard,1 Elahe Motevaseli,2,3 Fatemeh Ahmadipour4
1Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; 3Food Microbiology Research Center, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Background: Inhibition of prostate cancer stem cells (PCSCs) is an efficient curative maintenance protocol for the prevention of prostate cancer. The objectives of this study were to assess the efficiency of koenimbin, a major biologically active component of Murraya koenigii (L) Spreng, in the suppression of PC-3 cells and to target PC-3-derived cancer stem cells (CSCs) through apoptotic and CSC signaling pathways in vitro.
Materials and methods: The antiproliferative activity of koenimbin was examined using MTT, and the apoptotic detection was carried out by acridine orange/propidium iodide (AO/PI) double-staining and multiparametric high-content screening (HCS) assays. Caspase bioluminescence assay, reverse transcription polymerase chain reaction (RT-PCR), and immunoblotting were conducted to confirm the expression of apoptotic-associated proteins. Cell cycle analysis was investigated using flow cytometry. Involvement of nuclear factor-kappa B (NF-κB) was analyzed using HCS assay. Aldefluor™ and prostasphere formation examinations were used to evaluate the impact of koenimbin on PC-3 CSCs in vitro.
Results: Koenimbin remarkably inhibited cell proliferation in a dose-dependent manner. Koenimbin induced nuclear condensation, formation of apoptotic bodies, and G0/G1 phase arrest of PC-3 cells. Koenimbin triggered the activation of caspase-3/7 and caspase-9 and the release of cytochrome c, decreased anti-apoptotic Bcl-2 and HSP70 proteins, increased pro-apoptotic Bax proteins, and inhibited NF-κB translocation from the cytoplasm to the nucleus, leading to the activation of the intrinsic apoptotic pathway. Koenimbin significantly (P<0.05) reduced the aldehyde dehydrogenase-positive cell population of PC-3 CSCs and the size and number of PC-3 CSCs in primary, secondary, and tertiary prostaspheres in vitro.
Conclusion: Koenimbin has chemotherapeutic potential that may be employed for future treatment through decreasing the recurrence of cancer, resulting in the improvement of cancer management strategies and patient survival.
Keywords: aldehyde dehydrogenase activity, ALDH, nuclear factor-kappa, NF-κB, prostasphere formation, CD44+/CD133+ surface markers
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