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

• Published in: Drug design, development and therapy Vol. 12; pp. 1119 - 1133
• Main Authors: Kamalidehghan, Behnam, Ghafouri-Fard, Soudeh, Motevaseli, Elahe, Ahmadipour, Fatemeh
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01-01-2018; Dove Medical Press
• Subjects: Acridine orange; Activation; Aldehyde dehydrogenase; Androgens; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Assaying; Bax protein; Bcl-2 protein; Biological activity; Bioluminescence; Breast cancer; Cancer therapies; Carbazoles - chemistry; Carbazoles - isolation & purification; Carbazoles - pharmacology; Caspase; Caspase-3; Caspase-9; CD44+/CD133+ surface markers; Cell adhesion & migration; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytochrome; Cytochrome c; Cytochromes; Cytoplasm; Diet; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flow cytometry; G1 phase; Hsp70 protein; Humans; Immunoblotting; Immunoglobulins; In vitro methods and tests; Inhibition; Iodides; Koenimbin; Male; Medicine; Metastasis; Molecular Structure; Murraya - chemistry; Murraya koenigii; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; NF-κB protein; Original Research; Polyimide resins; Polymerase chain reaction; Propidium iodide; Prostate cancer; prostate cancer stem cells; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Proteins; Reverse transcription; Stem cells; Structure-Activity Relationship; Translocation; Tumor Cells, Cultured; Iran; United States > US; Malaysia; ALDH; NF-κB; nuclear factor-kappa; prostasphere formation; aldehyde dehydrogenase activity; CD44+/CD133+ surface markers
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S156826

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
(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.
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.
Koenimbin remarkably inhibited cell proliferation in a dose-dependent manner. Koenimbin induced nuclear condensation, formation of apoptotic bodies, and G
/G
phase arrest of PC-3 cells. Koenimbin triggered the activation of caspase-3/7 and caspase-9 and the release of cytochrome
, 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 (
<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.
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.