Dinaciclib, a Bimodal Agent Effective against Endometrial Cancer

Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II–IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.

Download Full-text

Induction of CABLES1 by the TKI Inhibits the Cell Cycle Progression and Induces Apoptosis In CML Cell.

Blood ◽

10.1182/blood.v116.21.1199.1199 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1199-1199

Author(s):

Tomonari Takemura ◽

Satoki Nakamura ◽

Yasuyuki Nagata ◽

Daisuke Yokota ◽

Isao Hirano ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Cell Proliferation ◽

Progenitor Cells ◽

Cell Lines ◽

Cell Cycle Progression ◽

Kinase Inhibitors ◽

Cycle Progression ◽

Abl Kinase ◽

Abl Kinase Inhibitors

Abstract Abstract 1199 [Background and Aims] CABLES1 (cyclin-dependent kinase (CDK)-5 and ABL enzyme 1) is a regulator of cell proliferation, apoptosis, and cell cycle, and it has been reported to be lost in a variety cancers. It has been also reported that knockout of the Cable1 gene has minimal to no effect on hematopoietic stem cells. However, we found that the expression of Cables1 gene and CABLES1 protein was suppressed in CML cells, and its function is little known in CML. In this study, we have investigated the function of CABLES1 in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of Cables1 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of p53 and some CDKIs in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Cables1 shRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with Cables1 cDNA or shiRNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of Cables1 mRNA and CABLES1 protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl shRNA. In CML cells transfected with the Cables1 cDNA, it is shown that CML cell proliferation was inhibited, and the phosphorylation levels of p53, and the expression of BAX and p21 protein were markedly increased compared to the untransfected cells. In addition, the overexpression of CABLES1 induced G1 cell cycle arrest and reduced the DiOC6 fluorescence, indicating breakdown of the mitochondrial membrane potential in CML cells. On the other hand, the changes of p73 and p27 protein expression were not detected. Moreover, in CML cells transfected with Cables1 shRNA, the inhibition of CML cell proliferation by the Abl kinase inhibitors were weakened. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of Cables1 mRNA was suppressed, and the transfection with Bcr-Abl shRNA or treatment with Abl kinase inhibitors increased the expression of Cables1 mRNA and CABLES1 protein, and decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of CABLES1, and the depletion of CABLES1 promotes cell cycle progression and p53-dependent apoptosis. Moreover, the induction of CABLES1 expression has the potentiality to eradicate CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

TReP-132 Controls Cell Proliferation by Regulating the Expression of the Cyclin-Dependent Kinase Inhibitors p21WAF1/Cip1 and p27Kip1

Molecular and Cellular Biology ◽

10.1128/mcb.25.11.4335-4348.2005 ◽

2005 ◽

Vol 25 (11) ◽

pp. 4335-4348 ◽

Cited By ~ 21

Author(s):

Florence Gizard ◽

Romain Robillard ◽

Olivier Barbier ◽

Brigitte Quatannens ◽

Anne Faucompré ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Lines ◽

Breast Tumor ◽

Cell Cycle Progression ◽

Kinase Inhibitors ◽

Mrna Levels ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

P27 Gene

ABSTRACT The transcriptional regulating protein of 132 kDa (TReP-132) has been identified in steroidogenic tissues, where it acts as a coactivator of steroidogenic factor 1 (SF-1). We show here that TReP-132 plays a role in the control of cell proliferation. In human HeLa cells, TReP-132 knockdown by using small interfering RNA resulted in increased G1→S cell cycle progression. The growth-inhibitory effects of TReP-132 was further shown to be mediated by induction of G1 cyclin-dependent kinase inhibitors p21WAF1 (p21) and p27KIP1 (p27) expression levels. As a consequence, G1 cyclin/cyclin-dependent kinase activities and pRB phosphorylation were markedly reduced, and cell cycle progression was blocked in the G1 phase. The stimulatory effect of TReP-132 on p21 and p27 gene transcription involved interaction of TReP-132 with the transcription factor Sp1 at proximal Sp1-binding sites in their promoters. Moreover, in different breast tumor cell lines, endogenous TReP-132 expression was positively related with a lower proliferation rate. In addition, TReP-132 knockdown resulted in enhanced cell proliferation and lowered p21 and p27 mRNA levels in the steroid-responsive and nonresponsive T-47D and MDA-MB-231 cell lines, respectively. Finally, a statistic profiling of human breast tumor samples highlighted that expression of TReP-132 is correlated with p21 and p27 levels and is associated with lower tumor incidence and aggressiveness. Together, these results identify TReP-132 as a basal cell cycle regulatory protein acting, at least in part, by interacting with Sp1 to activate the p21 and p27 gene promoters.

Download Full-text

Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

Pharmaceuticals ◽

10.3390/ph14070682 ◽

2021 ◽

Vol 14 (7) ◽

pp. 682

Author(s):

Jianling Bi ◽

Garima Dixit ◽

Yuping Zhang ◽

Eric J. Devor ◽

Haley A. Losh ◽

...

Keyword(s):

Cell Cycle ◽

Endometrial Cancer ◽

Tyrosine Kinase ◽

Cell Viability ◽

Cell Lines ◽

Cell Cycle Progression ◽

Kinase Inhibitor ◽

Cell Cycle Checkpoint ◽

Mitotic Catastrophe ◽

M Cell

Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. Cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib + chemotherapy, consistent with the abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy.

Download Full-text

Interleukin-2 expression in human carcinoma cell lines and its role in cell cycle progression

Oncogene ◽

10.1038/sj.onc.1203391 ◽

2000 ◽

Vol 19 (4) ◽

pp. 514-525 ◽

Cited By ~ 24

Author(s):

Torsten E Reichert ◽

Shigeki Nagashima ◽

Yoshiro Kashii ◽

Joanna Stanson ◽

Gui Gao ◽

...

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cell Cycle Progression ◽

Carcinoma Cell ◽

Interleukin 2 ◽

Cycle Progression ◽

Human Carcinoma ◽

Carcinoma Cell Lines ◽

Human Carcinoma Cell

Download Full-text

Delayed Cell Cycle Progression and Apoptosis Induced by Hemicellulase-TreatedAgaricus blazei

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nel059 ◽

2007 ◽

Vol 4 (1) ◽

pp. 83-94 ◽

Cited By ~ 14

Author(s):

Masaki Kawamura ◽

Hirotake Kasai

Keyword(s):

Cell Cycle ◽

P38 Mapk ◽

Cell Lines ◽

Cell Cycle Progression ◽

Combined Treatment ◽

Specific Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Activation Effect ◽

Cycle Progression ◽

Fraction H

We examined the effects of hemicellulase-treatedAgaricus blazei(AB fraction H, ABH) on growth of several tumor cell lines. ABH inhibited the proliferation of some cell lines without cytotoxic effects. It markedly prolonged the S phase of the cell cycle. ABH also induced mitochondria-mediated apoptosis in different cell lines. However, it had no impact on the growth of other cell lines. ABH induced strong activation of p38 mitogen-activated protein kinase (MAPK) in the cells in which it evoked apoptosis. On the other hand, ABH showed only a weak p38 activation effect in those cell lines in which it delayed cell cycle progression with little induction of apoptosis. However, p38 MAPK-specific inhibitor inhibited both ABH-induced effects, and ABH also caused apoptosis in the latter cells under conditions of high p38 MAPK activity induced by combined treatment with TNF-α. These results indicate that the responsiveness of p38 MAPK to ABH, which differs between cell lines, determines subsequent cellular responses on cell growth.

Download Full-text

Induction of cell cycle progression by adenovirus E1A gene 13S- and 12S-mRNA products in quiescent rat cells.

Molecular and Cellular Biology ◽

10.1128/mcb.7.10.3846 ◽

1987 ◽

Vol 7 (10) ◽

pp. 3846-3852 ◽

Cited By ~ 7

Author(s):

T Nakajima ◽

M Masuda-Murata ◽

E Hara ◽

K Oda

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cell Cycle Progression ◽

Adenovirus Type ◽

Inducible Promoter ◽

Similar Rate ◽

Cycle Progression ◽

Adenovirus E1a ◽

Tumor Virus ◽

E1a Gene

Rat 3Y1 cell lines that express either adenovirus type 12 E1A 13S mRNA or 12S mRNA in response to dexamethasone treatment were established by introduction of recombinant vector DNA containing the E1A 13S- or 12S-mRNA cDNA placed downstream of the hormone-inducible promoter of mouse mammary tumor virus. These cell lines were growth arrested, and the induction of cell cycle progression was analyzed by flow cytometry after switch on of the cDNA by the addition of dexamethasone. The results indicate that the 13S- or 12S-mRNA product alone has the ability to cause progression of the cell cycle at a similar rate. The simultaneous addition of epidermal growth factor accelerated the rate of cell cycle progression in the transition from the G0/G1 phase to the S phase.

Download Full-text

Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated withMelicope ptelefolialeaf extract reveals transcriptome profiles exhibiting anticancer activity

PeerJ ◽

10.7717/peerj.5203 ◽

2018 ◽

Vol 6 ◽

pp. e5203 ◽

Cited By ~ 6

Author(s):

Mohammad Faujul Kabir ◽

Johari Mohd Ali ◽

Onn Haji Hashim

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Dna Replication ◽

Cell Lines ◽

Microarray Data ◽

Expression Profiling ◽

Cell Cycle Progression ◽

Anticancer Activities ◽

Microarray Gene Expression ◽

Cycle Progression

BackgroundWe have previously reported anticancer activities ofMelicope ptelefolia(MP) leaf extracts on four different cancer cell lines. However, the underlying mechanisms of actions have yet to be deciphered. In the present study, the anticancer activity of MP hexane extract (MP-HX) on colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines was characterized through microarray gene expression profiling.MethodsHCT116 and HepG2 cells were treated with MP-HX for 24 hr. Total RNA was extracted from the cells and used for transcriptome profiling using Applied Biosystem GeneChip™ Human Gene 2.0 ST Array. Gene expression data was analysed using an Applied Biosystems Expression Console and Transcriptome Analysis Console software. Pathway enrichment analyses was performed using Ingenuity Pathway Analysis (IPA) software. The microarray data was validated by profiling the expression of 17 genes through quantitative reverse transcription PCR (RT-qPCR).ResultsMP-HX induced differential expression of 1,290 and 1,325 genes in HCT116 and HepG2 cells, respectively (microarray data fold change, MA_FC ≥ ±2.0). The direction of gene expression change for the 17 genes assayed through RT-qPCR agree with the microarray data. In both cell lines, MP-HX modulated the expression of many genes in directions that support antiproliferative activity. IPA software analyses revealed MP-HX modulated canonical pathways, networks and biological processes that are associated with cell cycle, DNA replication, cellular growth and cell proliferation. In both cell lines, upregulation of genes which promote apoptosis, cell cycle arrest and growth inhibition were observed, while genes that are typically overexpressed in diverse human cancers or those that promoted cell cycle progression, DNA replication and cellular proliferation were downregulated. Some of the genes upregulated by MP-HX include pro-apoptotic genes (DDIT3, BBC3, JUN), cell cycle arresting (CDKN1A, CDKN2B), growth arrest/repair (TP53, GADD45A) and metastasis suppression (NDRG1). MP-HX downregulated the expression of genes that could promote anti-apoptotic effect, cell cycle progression, tumor development and progression, which include BIRC5, CCNA2, CCNB1, CCNB2, CCNE2, CDK1/2/6, GINS2, HELLS, MCM2/10 PLK1, RRM2 and SKP2. It is interesting to note that all six top-ranked genes proposed to be cancer-associated (PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2) were downregulated by MP-HX in both cell lines.DiscussionThe present study showed that the anticancer activities of MP-HX are exerted through its actions on genes regulating apoptosis, cell proliferation, DNA replication and cell cycle progression. These findings further project the potential use of MP as a nutraceutical agent for cancer therapeutics.

Download Full-text

High Mobility Group A1 Chromatin Regulators Function As Critical Drivers of Leukemogenesis in Preclinical Models of Relapsed, Pediatric B-Cell ALL

Blood ◽

10.1182/blood-2019-130261 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3946-3946

Author(s):

Liping Li ◽

Katharina Hayer ◽

Lingling Xian ◽

Li Luo ◽

Leslie Cope ◽

...

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Cell Cycle Progression ◽

High Mobility ◽

Transcriptional Networks ◽

Rna Seq ◽

Cycle Progression ◽

Short Hairpin ◽

Reh Cells

Introduction: Acute B-cell lymphoblastic leukemia (B-ALL) is the most common form of childhood leukemia and the leading cause of death in children with cancer. While therapy is often curative, about 10-15% of children will relapse with recurrent disease and abysmal outcomes. Actionable mechanisms that mediate relapse remain largely unknown. The gene encoding the High Mobility Group A1(HMGA1) chromatin regulator is overexpressed in diverse malignancies where high levels portend poor outcomes. In murine models, we discovered thatHmga1 overexpression is sufficient for clonal expansion and progression to aggressive acute lymphoid leukemia (Cancer Res 2008,68:10121, 2018,78:1890; Nature Comm 2017,8:15008). Further, HMGA1 is overexpressed in pediatric B-ALL (pB-ALL) blasts with highest levels in children who relapse early compared to those who achieve chronic remissions. Together, these findings suggest that HMGA1 is required for leukemogenesis and may foster relapse in B-ALL. We therefore sought to: 1) test the hypothesis that HMGA1 is a key epigenetic regulator required for leukemogenesis and relapse in pB-ALL, and, 2) elucidate targetable mechanisms mediated by HMGA1 in leukemogenesis. Methods: We silenced HMGA1 via lentiviral delivery of short hairpin RNAs targeting 2 different sequences in cell lines derived from relapsed pB-ALL (REH, 697). REH cells harbor the TEL-AML1 fusion; 697 cells express BCL2, BCL3, and cMYC. Next, we assessed leukemogenic phenotypes in vitro (proliferation, cell cycle progression, apoptosis, and clonogenicity) and leukemogenesis invivo. To dissect molecular mechanisms underlying HMGA1, we performed RNA-Seq and applied in silico pathway analysis. Results: There is abundant HMGA1 mRNA and protein in both pB-ALL cell lines and HMGA1 was effectively silenced by short hairpin RNA. Further, silencing HMGA1 dramatically halts proliferation in both cell lines, leading to a decrease in cells in S phase with a concurrent increase in G0/S1. Apoptosis also increased by 5-10% after HMGA1 silencing based on flow cytometry for Annexin V. In colony forming assays, silencing HMGA1 impaired clonogenicity in both pB-ALL cell lines. To assess HMGA1 function in leukemogenesis in vivo, we implanted control pB-ALL cells (transduced with control lentivirus) or those with HMGA1 silencing via tail vein injection into immunosuppressed mice (NOD/SCID/IL2 receptor γ). All mice receiving control REH cells succumbed to leukemia with a median survival of only 29 days. At the time of death, mice had marked splenomegaly along with leukemic cells circulating in the peripheral blood and infiltrating both the spleen and bone marrow. In contrast, mice injected with REH cells with HMGA1 silencing survived for >40 days (P<0.001) and had a significant decrease in tumor burden in the peripheral blood, spleen, and bone marrow. Similar results were obtained with 697 cells, although this model was more fulminant with control mice surviving for a median of only 17 days. To determine whether the leukemic blasts found in mice injected with ALL cells after HMGA1 silencing represented a clone that expanded because it escaped HMGA1 silencing, we assessed HMGA1 levels and found that cells capable of establishing leukemia had high HMGA1 expression, with levels similar to those observed in control cells without HMGA1 silencing. RNA-Seq analyses from REH and 697 cell lines with and without HMGA1 silencing revealed that HMGA1 up-regulates transcriptional networks involved in RAS/MAPK/ERK signaling while repressing the IDH1 metabolic gene, the latter of which functions in DNA and histone methylation. Studies are currently underway to identify effective agents to target HMGA1 pathways. Conclusions: Silencing HMGA1 dramatically disrupts leukemogenic phenotypes in vitro and prevents the development of leukemia in mice. Mechanistically, RNA-Seq analyses revealed that HMGA amplifies transcriptional networks involved cell cycle progression and epigenetic modifications. Our findings highlight the critical role for HMGA1 as a molecular switch required for leukemic transformation in pB-ALL and a rational therapeutic target that may be particularly relevant for relapsed B-ALL. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Carvedilol Inhibits Angiotensin II-Induced Proliferation and Contraction in Hepatic Stellate Cells through the RhoA/Rho-Kinase Pathway

BioMed Research International ◽

10.1155/2019/7932046 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Ying Wu ◽

Zhen Li ◽

Sining Wang ◽

Aiyuan Xiu ◽

Chunqing Zhang

Keyword(s):

Cell Cycle ◽

Angiotensin Ii ◽

Liver Fibrosis ◽

Cell Cycle Progression ◽

Rho Kinase ◽

Cell Counting ◽

Type I ◽

Dependent Manner ◽

Ang Ii ◽

Cycle Progression

Aim. Carvedilol is a nonselective beta-blocker used to reduce portal hypertension. This study investigated the effects and potential mechanisms of carvedilol in angiotensin II- (Ang II-) induced hepatic stellate cell (HSC) proliferation and contraction. Methods. The effect of carvedilol on HSC proliferation was measured by Cell Counting Kit-8 (CCK-8). Cell cycle progression and apoptosis in HSCs were determined by flow cytometry. A collagen gel assay was used to confirm HSC contraction. The extent of liver fibrosis in mice was evaluated by hematoxylin-eosin (H&E) and Sirius Red staining. Western blot analyses were performed to detect the expression of collagen I, collagen III, α-smooth muscle actin (α-SMA), Ang II type I receptor (AT1R), RhoA, Rho-kinase 2 (ROCK2), and others. Results. The results showed that carvedilol inhibited HSC proliferation and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Carvedilol also modulated Bcl-2 family proteins and increased apoptosis in Ang II-treated HSCs. Furthermore, carvedilol inhibited HSC contraction induced by Ang II, an effect that was associated with AT1R-mediated RhoA/ROCK2 pathway interference. In addition, carvedilol reduced α-SMA expression and collagen deposition and attenuated liver fibrosis in carbon tetrachloride (CCl4)-treated mice. The in vivo data further confirmed that carvedilol inhibited the expression of angiotensin-converting enzyme (ACE), AT1R, RhoA, and ROCK2. Conclusions. The results indicated that carvedilol dose-dependently inhibited Ang II-induced HSC proliferation by impeding cell cycle progression, thus alleviating hepatic fibrosis. Furthermore, carvedilol could inhibit Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway.

Download Full-text

Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz030.p05-005-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Larissa Kido ◽

Eun-Ryeong Hahm ◽

Valeria Cagnon ◽

Mário Maróstica ◽

Shivendra Singh

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Cell Cycle Progression ◽

Cell Cycle Distribution ◽

Mutant P53 ◽

Wild Type ◽

Cycle Progression ◽

Cycle Arrest

Abstract Objectives Piceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. Methods Human PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 µM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. Results PIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. Conclusions While PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding Sources São Paulo Research Foundation (2018/09793-7).

Download Full-text