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Fulltext Alpha-tomatine induces apoptosis and inhibits nuclear factor-kappa B activation on human prostatic adenocarcinoma PC-3 cells

Lee ST, Wong PF, Cheah SC, Mustafa MR

PLoS One, 2011;6(4):e18915.
PMID: 21541327 DOI: 10.1371/journal.pone.0018915

Alpha-tomatine (α-tomatine) is the major saponin in tomato (Lycopersicon esculentum). This study investigates the chemopreventive potential of α-tomatine on androgen-independent human prostatic adenocarcinoma PC-3 cells.

Matched MeSH terms: Prostatic Neoplasms/pathology*
Differential receptor dependencies: expression and significance of muscarinic M1 receptors in the biology of prostate cancer

Mannan Baig A, Khan NA, Effendi V, Rana Z, Ahmad HR, Abbas F

Anticancer Drugs, 2017 01;28(1):75-87.
PMID: 27606721

Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer. Growth assays showed that pilocarpine stimulates the proliferation of prostate cancer. Moreover, it shows that carbachol exerts an additional agonistic action on nicotinic cholinergic receptor of prostate cancer cells that can be blocked by tubocurarine. With the use of selective CHRM1 antagonists such as pirenzepine and dicyclomine, a considerable inhibition of proliferation of prostate cancer cell lines was observed in dose ranging from 15-60 µg/ml of dicyclomine. The microarray database of prostate cancer shows a dominant expression of CHRM1 in prostate cancer compared with other cholinergic subtypes. The bioinformatics of prostate cancer and CHRM pathways show that the downstream signalling include PIP3-AKT-CaM-mediated growth in LNCaP and PC3 cells. Our study suggests that antagonism of CHRM1 may be a potential therapeutic target against prostate cancer.

Matched MeSH terms: Prostatic Neoplasms/pathology
Fulltext 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

Kamalidehghan B, Ghafouri-Fard S, Motevaseli E, Ahmadipour F

Drug Des Devel Ther, 2018;12:1119-1133.
PMID: 29765202 DOI: 10.2147/DDDT.S156826

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.

Matched MeSH terms: Prostatic Neoplasms/pathology
Early salvage hormonal therapy for biochemical failure improved survival in prostate cancer patients after neoadjuvant hormonal therapy plus radiation therapy--a secondary analysis of irish clinical oncology research group 97-01

Mydin AR, Dunne MT, Finn MA, Armstrong JG

Int J Radiat Oncol Biol Phys, 2013 Jan 1;85(1):101-8.
PMID: 22658512 DOI: 10.1016/j.ijrobp.2012.03.001

PURPOSE: To assess the survival benefit of early vs late salvage hormonal therapy (HT), we performed a secondary analysis on patients who developed recurrence from Irish Clinical Oncology Research Group 97-01, a randomized trial comparing 4 vs 8 months neoadjuvant HT plus radiation therapy (RT) in intermediate- and high-risk prostate adenocarcinoma.
METHODS AND MATERIALS: A total of 102 patients from the trial who recurred were analyzed at a median follow-up of 8.5 years. The patients were divided into 3 groups based on the timing of salvage HT: 57 patients had prostate-specific antigen (PSA)≤10 ng/mL and absent distant metastases (group 1, early), 21 patients had PSA>10 ng/mL and absent distant metastases (group 2, late), and 24 patients had distant metastases (group 3, late). The endpoint analyzed was overall survival (OS) calculated from 2 different time points: date of enrolment in the trial (OS1) and date of initiation of salvage HT (OS2). Survival was estimated using Kaplan-Meier curves and a Cox regression model.
RESULTS: The OS1 differed significantly between groups (P

Matched MeSH terms: Prostatic Neoplasms/pathology
Crocodiles and alligators: Antiamoebic and antitumor compounds of crocodiles

Siddiqui R, Jeyamogan S, Ali SM, Abbas F, Sagathevan KA, Khan NA

Exp Parasitol, 2017 Dec;183:194-200.
PMID: 28917711 DOI: 10.1016/j.exppara.2017.09.008

Crocodiles exist in unsanitary environments, feed on rotten meat, are often exposed to heavy metals such as arsenic, cadmium, cobalt, chromium, mercury, nickel, lead, selenium, tolerate high levels of radiation, and are amid the very few species to survive the catastrophic Cretaceous-Tertiary extinction event, nonetheless they can live for up to a 100 years. Moreover, as they live in unhygienic conditions, they regularly come across pathogens. Logically, we postulate that crocodiles possess mechanisms to defend themselves from noxious agents as well as protecting themselves from pathogens. To test this hypothesis, various organ lysates and serum of Crocodylus palustris were prepared. Amoebicidal assays were performed using Acanthamoeba castellanii belonging to the T4 genotype. Cytotoxicity assays were performed using Prostate cancer cells culture by measuring lactate dehydrogenase release as a marker for cell death. Growth inhibition assays were performed to determine the growth inhibitory effects of various organ lysates. Serum and heart lysates of Crocodylus palustris exhibited powerful anti-tumor activity exhibiting more than 70% Prostate cancer cell death (P

Matched MeSH terms: Prostatic Neoplasms/pathology
Fulltext Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival

Nalairndran G, Hassan Abdul Razack A, Mai CW, Fei-Lei Chung F, Chan KK, Hii LW, et al.

J Cell Mol Med, 2020 Oct;24(20):12188-12198.
PMID: 32926495 DOI: 10.1111/jcmm.15876

Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome-wide lentiviral small-hairpin RNA (shRNA) library screen, we identified phosphoinositide-dependent kinase-1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock-down of endogenous human PDPK1 induced significant tumour-specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE-1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid-regulated kinase 3 (SGK3). Knock-down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock-down. Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.

Matched MeSH terms: Prostatic Neoplasms/pathology*
Fulltext Subditine, a new monoterpenoid indole alkaloid from bark of Nauclea subdita (Korth.) Steud. induces apoptosis in human prostate cancer cells

Liew SY, Looi CY, Paydar M, Cheah FK, Leong KH, Wong WF, et al.

PLoS One, 2014;9(2):e87286.
PMID: 24551054 DOI: 10.1371/journal.pone.0087286

In this study, a new apoptotic monoterpenoid indole alkaloid, subditine (1), and four known compounds were isolated from the bark of Nauclea subdita. Complete (1)H- and (13)C- NMR data of the new compound were reported. The structures of isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS. All five compounds were screened for cytotoxic activities on LNCaP and PC-3 human prostate cancer cell-lines. Among the five compounds, the new alkaloid, subditine (1), demonstrated the most potent cell growth inhibition activity and selective against LNCaP with an IC50 of 12.24±0.19 µM and PC-3 with an IC50 of 13.97±0.32 µM, compared to RWPE human normal epithelial cell line (IC50 = 30.48±0.08 µM). Subditine (1) treatment induced apoptosis in LNCaP and PC-3 as evidenced by increased cell permeability, disruption of cytoskeletal structures and increased nuclear fragmentation. In addition, subditine (1) enhanced intracellular reactive oxygen species (ROS) production, as reflected by increased expression of glutathione reductase (GR) to scavenge damaging free radicals in both prostate cancer cell-lines. Excessive ROS could lead to disruption of mitochondrial membrane potential (MMP), release of cytochrome c and subsequent caspase 9, 3/7 activation. Further Western blot analyses showed subditine (1) induced down-regulation of Bcl-2 and Bcl-xl expression, whereas p53 was up-regulated in LNCaP (p53-wild-type), but not in PC-3 (p53-null). Overall, our data demonstrated that the new compound subditine (1) exerts anti-proliferative effect on LNCaP and PC-3 human prostate cancer cells through induction of apoptosis.

Matched MeSH terms: Prostatic Neoplasms/pathology*
Fulltext Alpha-tomatine attenuation of in vivo growth of subcutaneous and orthotopic xenograft tumors of human prostate carcinoma PC-3 cells is accompanied by inactivation of nuclear factor-kappa B signaling

Lee ST, Wong PF, He H, Hooper JD, Mustafa MR

PLoS One, 2013;8(2):e57708.
PMID: 23437404 DOI: 10.1371/journal.pone.0057708

Nuclear factor-kappa B (NF-κB) plays a role in prostate cancer and agents that suppress its activation may inhibit development or progression of this malignancy. Alpha (α)-tomatine is the major saponin present in tomato (Lycopersicon esculentum) and we have previously reported that it suppresses tumor necrosis factor-alpha (TNF-α)-induced nuclear translocation of nuclear factor-kappa B (NF-κB) in androgen-independent prostate cancer PC-3 cells and also potently induces apoptosis of these cells. However, the precise mechanism by which α-tomatine suppresses NF-κB nuclear translocation is yet to be elucidated and the anti-tumor activity of this agent in vivo has not been examined.

Matched MeSH terms: Prostatic Neoplasms/pathology