Growth Of Prostate Carcinoma Cells Research Articles

Clinical Significance of High Expression of tRF-Glu-TTC-2 in Prostate Carcinoma and its Effect on Growth.

The tRNA-derived fragments (tRFs) are a new class of regulatory noncoding RNAs and have different biological functions in cancer. This article investigated the expression and clinicopathological significance of tRF-Glu-TTC-2 in prostate carcinoma (PCa), and its effect on tumor growth. Expression profiles of tRFs and tiRNAs were analyzed by tRF and tiRNAs microarray in PCa samples, and then the expression was confirmed by qRT-PCR; RNA in situ hybridization was used to detect the positive expression of tRF-Glu-TTC-2 and to analyze the correlation between the expression level of tRF-Glu-TTC-2 and clinicopathological parameters. CCK-8 experiment was used to detect the effect of tRF-Glu-TTC-2 on the proliferation of PCa cells, and nude mice subcutaneous tumor model was used to detect the effect of tRF-Glu-TTC-2 on the growth of PCa cells. The results showed that tRF-Glu-TTC-2 was mainly positive and its expression level increased in PCa. The high expression was closely related to the tumor size (p < .05). Overexpression of tRF-Glu-TTC-2 promoted the proliferation of PCa cells, and decreased expression of tRF-Glu-TTC-2 inhibited the proliferation of PCa cells (p < .05). The results of subcutaneous tumor transplantation in nude mice showed that the tumor volume and weight of the knockdown group were smaller than those of the control group(all ps < .05). Ki-67 staining showed that the proportion of Ki-67-positive cells in the reduced tRF-Glu-TTC-2 group was lower than that in the control group (p < .05). The tRF-Glu-TTC-2 may be a new oncogene that can promote growth and proliferation of PCa. It provides a new idea for the treatment of PCa.

WNT1 Inducible Signaling Pathway Protein 1 Is a Stroma-Specific Secreting Protein Inducing a Fibroblast Contraction and Carcinoma Cell Growth in the Human Prostate.

The WNT1 inducible signaling pathway protein 1 (WISP1), a member of the connective tissue growth factor family, plays a crucial role in several important cellular functions in a highly tissue-specific manner. Results of a RT-qPCR indicated that WISP1 expressed only in cells of the human prostate fibroblasts, HPrF and WPMY-1, but not the prostate carcinoma cells in vitro. Two major isoforms (WISP1v1 and WISP1v2) were identified in the HPrF cells determined by RT-PCR and immunoblot assays. The knock-down of a WISP1 blocked cell proliferation and contraction, while treating respectively with the conditioned medium from the ectopic WISP1v1- and WISPv2-overexpressed 293T cells enhanced the migration of HPrF cells. The TNFα induced WISP1 secretion and cell contraction while the knock-down of WISP1 attenuated these effects, although TNFα did not affect the proliferation of the HPrF cells. The ectopic overexpression of WISP1v1 but not WISP1v2 downregulated the N-myc downstream regulated 1 (NDRG1) while upregulating N-cadherin, slug, snail, and vimentin gene expressions which induced not only the cell proliferation and invasion in vitro but also tumor growth of prostate carcinoma cells in vivo. The results confirmed that WISP1 is a stroma-specific secreting protein, enhancing the cell migration and contraction of prostate fibroblasts, as well as the proliferation, invasion, and tumor growth of prostate carcinoma cells.

Hsa_circ_0102485 inhibits the growth of cancer cells by regulating the miR-188–3p/ARID5B/AR axis in prostate carcinoma

BackgroundStudies have shown that circular RNAs (circRNAs) have significant potential as novel molecular markers for the diagnosis, treatment, and prognosis of prostate carcinoma (PCa). However, the role and mechanism of circRNA hsa_circ_0102485 in PCa remains unclear. Materials & methodsThe real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to quantify hsa_circ_0102485 expression in PCa. The potential mechanisms and roles of hsa_circ_0102485 in tumor growth were explored using dual-luciferase-reporter and subcutaneous-xenograft assays, rescue experiments, and immunohistochemical staining. Clinical correlations were assessed by tissue-on-a-chip in-situ hybridization and Fisher’s exact test. ResultsHsa_circ_0102485 expression was decreased in PCa, and overexpression of hsa_circ_0102485 suppressed the proliferation, metastasis, invasion, and antiapoptotic abilities of PCa cells. MicroRNA 188–3p (MiR-188–3p) is a direct target of hsa_circ_0102485, and cotransfection of hsa_circ_0102485 in PCa cells overexpressing miR-188–3p inhibited its promotive effects. Hsa_circ_0102485 indirectly promotes the expression of AT-rich interaction domain 5B (ARID5B) and androgen receptor (AR) by sponging miR-188–3p and inhibiting PCa cell growth. Correlation analysis showed that hsa_circ_0102485 expression in PCa was not significantly correlated with the age, International Society of Urologic Pathologists (ISUP) grade, Gleason score, or lymph node metastasis status of PCa patients. ConclusionHsa_circ_0102485 plays an inhibitory role in PCa by regulating the Mir-188–3p/ARID5B/AR axis and may be a potential diagnostic biomarker and therapeutic target for PCa that requires further study.

LncRNA FGF14-AS2 represses growth of prostate carcinoma cells via modulating miR-96-5p/AJAP1 axis.

ObjectiveThis investigation devoted to lncRNA FGF14 antisense RNA 2 (FGF14‐AS2) in prostate carcinoma progression.MethodsThe levels of lncRNA FGF14‐AS2, miR‐96‐5p, and Adherens junction‐associated protein‐1 (AJAP1) in prostate carcinoma were tested by Western blot and qRT‐PCR. How these two genes interacted was confirmed by RNA immunoprecipitation and dualluciferase gene methods. The effect of FGF14‐AS2/miR‐96‐5p/AJAP1 axis in prostate carcinoma progression was determined by MTT, Transwell, and nude mice tumor model.ResultsFGF14‐AS2 was a downregulated lncRNA in prostate carcinoma tissue and cells. FGF14‐AS2 could restrain miR‐96‐5p expression while miR‐96‐5p hampered AJAP1. FGF14‐AS2 could effectively decrease the biological behaviors of prostate carcinoma cells, while knock‐down of FGF14‐AS2 triggered opposite results. Moreover, miR‐96‐5p mimic presented a cancer promoter role in prostate carcinoma cells. AJAP1 expression level could affect levels of proteins related to epithelial‐mesenchymal transition. In vivo experiment suggested that overexpressing FGF14‐AS2 could reverse the promotion of silenced AJAP1 on prostate carcinoma cell metastasis, thus to inhibit tumor growth.ConclusionlncRNA FGF14‐AS2 was a downregulated lncRNA in prostate carcinoma and influenced cell proliferation and metastasis. The influence relied on modulating miR‐96‐5p and its target gene AJAP1.

TU52. GENE EXPRESSION CHANGES ASSOCIATED WITH TRAJECTORIES OF PSYCHOPATHOLOGY IN A LONGITUDINAL COHORT OF CHILDREN AND ADOLESCENTS

Four new 4,5-dihydro-1,3-oxazole, and four new benzo-[d]-oxazole derivatives of [17(20)E]-21-norpregnene, differing in the structure of steroid moiety, were synthesized and evaluated for their potency to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity. Among new compounds, the only oxazolinyl derivative comprising 5-oxo-4,5-seco-3-yn- moiety potently inhibited CYP17A1. Binding modes of the oxazolinyl derivatives of [17(20)E]-21-norpregnene were analyzed by molecular dynamics simulations, and model of alternate, water-bridged type II interaction was proposed for these compounds. Eight new compounds, together with two CYP17A1-inhibiting oxazolinyl derivatives synthesized earlier, abiraterone and galeterone were evaluated for their potency to inhibit prostate carcinoma PC-3 and LNCaP cells growth. Oxazolinyl and benzoxazolyl derivatives comprising 3β-hydroxy-5-ene moieties potently inhibited prostate carcinoma cell growth; inhibitory potencies of 3-oxo-4-en- and 5-oxo-4,5-seco-3-yn- derivatives were significantly lower.

Klinički značaj cirkulišućih miR-21, miR-142, miR-143 i miR-146a u pacijenata sa karcinomom prostate

BackgroundProstate cancer (PCa) is the most common type of solid tissue cancer among men in western countries. In this study, we determined the levels of circulating miR-21, miR-142, miR-143, miR-146a, and RNU 44 levels as controls for early diagnosis of PCa.MethodsThe circulating miRNA levels in peripheral blood samples from 43 localized PCa patients, 12 metastatic PCa (MET) patients, and a control group of, 42 benign prostate hyperplasia (BPH) patients with a total of 97 volunteers were determined the by PCR method.ResultsNo differences in the DCT values were found among the groups. In PCa and PCaMet groups the expression of miR21 and miR142 were higher compared to the BHP group. No other differences were observed among the other groups. miR21 expression in the PCa group was 6.29 folds upregulated whereas in the PCaMet group 10.84 folds up-regulated. When the total expression of miR142 is evaluated, it showed a positive correlation with mir21 and mir 146 (both p<0.001). Also, the expression of miR146 shows a positive correlation with both miR21 and miR143 (both p<0.001). Expression of miRNAs was found to be an independent diagnostic factor in patients with Gleason score, PSA, and free PSA levels.ConclusionsOur study showed that co-expression of miR21, miR-142, miR-143, and miR-146a and the upregulation of miR-21 resulted in increased prostate carcinoma cell growth. In the PCaMet group, miR21 is the most upregulated of all miRNAs. These markers may provide a novel diagnostic tool to help diagnose PCa with aggressive behavior.

LINC00467 Promotes Prostate Cancer Progression via M2 Macrophage Polarization and the miR-494-3p/STAT3 Axis.

BackgroundThe long non-coding RNA LINC00467 plays a vital role in many malignancies. Nevertheless, the role of LINC00467 in prostate carcinoma (PC) is unknown. Herein, we aimed to explore the mechanism by which LINC00467 regulates PC progression.MethodsWe used bioinformatics analyses and RT-qPCR to investigate the expression of LINC00467 in PC tissues and cells. The function of LINC00467 in the progression of PC was confirmed by loss-of-function experiments. PC cell proliferation was assessed by CCK-8 and EdU assays. The cell cycle progression of PC cells was examined by flow cytometry. Moreover, Transwell assays were used to investigate the migration and invasion of PC cells. Western blot assays were used to detect the expression of factors associated with epithelial–mesenchymal transition. The interactions of LINC00467 with prostate cancer progression and M2 macrophage polarization were confirmed by RT-qPCR. The subcellular localization of LINC00467 was investigated via the fractionation of nuclear and cytoplasmic RNA. Bioinformatics data analysis was used to predict the correlation of LINC00467 expression with miR-494-3p expression. LINC00467/miR-494-3p/STAT3 interactions were identified by using a dual-luciferase reporter system. Finally, the influence of LINC00467 expression on PC progression was investigated with an in vivo nude mouse model of tumorigenesis.ResultsWe established that LINC00467 expression was upregulated in PC tissues and cells. Downregulated LINC00467 expression inhibited PC cell growth, cell cycle progression, migration, and invasion. Downregulated LINC00467 expression similarly inhibited PC cell migration via M2 macrophage polarization. Western blot analysis showed that LINC00467 could regulate the STAT3 pathway. We established that LINC00467 is mainly localized to the cytoplasm. Bioinformatics analysis and rescue experiments indicated that LINC00467 promotes PC progression via the miR-494-3p/STAT3 axis. Downregulated LINC00467 expression was also able to suppress PC tumor growth in vivo.ConclusionsOur study reveals that LINC00467 promotes prostate cancer progression via M2 macrophage polarization and the miR-494-3p/STAT3 axis.

Synergistic Impact of Xanthorrhizol and d-δ-Tocotrienol on the Proliferation of Murine B16 Melanoma Cells and Human DU145 Prostate Carcinoma Cells

Isoprenoids suppress the mevalonate pathway that provides prenyl groups for the posttranslational modification of growth-regulating proteins. We hypothesize that xanthorrhizol and d-δ-tocotrienol synergistically suppress the growth of murine B16 melanoma and human DU145 prostate carcinoma cells. Xanthorrhizol (0–200 µmol/L; half maximal inhibitory concentration [IC50] = 65 µmol/L) and d-δ-tocotrienol (0–40 µmol/L; IC50 = 20 µmol/L) each induced a concentration-dependent suppression of the proliferation of B16 cells and concurrent cell cycle arrest at the G1 phase. A blend of 16.25 µmol/L xanthorrhizol and 10 µmol/L d-δ-tocotrienol suppressed B16 cell proliferation by 69%, an impact greater than the sum of those induced by xanthorrhizol (15%) and d-δ-tocotrienol (12%) individually. The blend cumulatively reduced the levels of cyclin-dependent kinase four and cyclin D1, key regulators of cell cycle progression at the G1 phase. The expression of RAS and extracellular signal-regulated kinase (ERK1/2) in the proliferation-stimulating RAS-RAF-MEK-ERK pathway was downregulated by the blend. Xanthorrhizol also induced a concentration-dependent suppression of the proliferation of DU145 cells with concomitant morphological changes. Isobologram confirmed the synergistic effect of xanthorrhizol and d-δ-tocotrienol on DU145 cell proliferation with combination index values ranging 0.61-0.94. Novel combinations of isoprenoids with synergistic actions may offer effective approaches in cancer prevention and therapy.

Abstract 6327: Artesunate reduces tumor growth and induces different kinds of cell death in docetaxel-resistant prostate carcinoma cells

Abstract Introduction: Prostate carcinoma (PCa) is the most common cancer in men. The therapeutic effect of approved compounds, such as docetaxel, is limited due to the development of therapy resistance, making new treatment options essential. Artesunate (ART), used in Traditional Chinese Medicine, has shown anti-tumor activity in several tumor types. However, little is known about the efficacy of ART on therapy-resistant PCa. Therefore, the impact of ART on docetaxel-resistant PCa cells was investigated. Material and Methods: Parental (=sensitive) and docetaxel-resistant PCa cell lines, PC3, DU145, and LNCaP, were exposed to ART [1-100 µM] for 24, 48, or 72 hours. Cells not exposed to ART served as controls. Tumor cell growth, proliferation, cell cycling, and the expression of cell cycle regulating proteins were assessed. Apoptotic, ferroptotic, and necrotic effects were also evaluated. Results: Exposure to ART significantly reduced tumor cell growth and proliferation of parental and docetaxel-resistant PCa cells in a time- and dose-dependent manner. Cell cycle arrest in the G0/G1 phase after 48h exposure to 37.5 µM ART was observed in parental LNCaP and in all three resistant cell lines. The observed changes in cell growth and cell cycle phases were accompanied by marked modulation of cell cycle regulating proteins. Significant apoptotic effects were observed in parental PC3 and both parental and resistant LNCaP, whereas ferroptosis was apparent in parental and resistant DU145 after exposure to ART. Necrotic events were not detectable in the PCa cells after ART exposure. Conclusion: ART induced anti-tumor effects, though differing according to the cell line, were apparent in not only parental but also in docetaxel-resistant PCa cells. Thus, adding ART to standard therapies might be a promising treatment strategy for patients with advanced prostate cancer. Further investigations are necessary to verify our findings. Citation Format: Vitus Braeunig, Patricia Schupp, Sascha Markowitsch, Olesya Vakhrusheva, Holger Erb, Thomas Efferth, Axel Haferkamp, Eva Juengel. Artesunate reduces tumor growth and induces different kinds of cell death in docetaxel-resistant prostate carcinoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6327.

Physical activity and advanced cancer: evidence of exercise-sensitive genes regulating prostate cancer cell proliferation and apoptosis.

Physical activity is known to protect against cancer. The resistance exercise method whole-body electromyostimulation (WB-EMS) has a significant anti-cancer effect. WB-EMS-conditioned serum from advanced prostate cancer patients decreased human prostate carcinoma cell growth and viability in vitro. Multiplex analysis revealed that genes associated with human prostate cancer cell proliferation and apoptosis are sensitive for exercise. Feasible exercise should be part of multimodal anti-cancer therapies, also for physically weakened patients. Regular physical activity is known to protect against cancer development. In cancer survivors, exercise reduces the risk of cancer recurrence and mortality. However, the link between exercise and decreased cancer risk and improved survival is still not well understood. Serum from exercising healthy individuals inhibits proliferation and activates apoptosis in various cancer cells, suggesting that mechanisms regulating cancer cell growth are affected by exercise. For the first time, we analysed serum from advanced-stage cancer patients with prostate (exercise group n = 8; control group n = 10) or colorectal (exercise n = 6; control n = 6) cancer, after a 12-week whole-body electromyostimulation training (20 min/session, 2×/week; frequency 85 Hz; pulse width 350 µs; 6 s stimulation, 4 s rest), a tolerable, yet effective, resistance exercise for physically weakened patients. We report that serum from these advanced cancer patients inhibits proliferation and enhances apoptosis of human prostate and colon cancer cells in vitro using cell growth and death assays (5-bromo-2'-deoxyuridine incorporation, cell counting, DNA fragmentation). Exercise-mimicking electric pulse stimulation of human primary myotubes showed that electric pulse stimulation-conditioned myotube medium also impairs human cancer cell viability. Gene expression analysis using a multiplex array of cancer-associated genes and subsequent quantitative RT-PCR revealed the presence of exercise-sensitive genes in human prostate cancer cells that potentially participate in the exercise-mediated regulation of malignant cell growth and apoptosis. Our data document the strong efficiency of the anti-oncogenic effects of physical activity and will further support the application of regular therapeutic exercise during cancer disease.

Mesenchymal stem cells inhibit the growth of prostate carcinoma cells in a long-term cultivation

Mesenchymal stem cells (MSCs) migrate to sites of inflammation and tumor formation in the body. In this way, MSCs become activated and release a plethora of growth factors and cytokines that are involved in the regulation and remodeling of the tumor microenvironment. The effect of MSCs on tumor cells is bipolar by nature and the data on this interaction is quite contradictory. The purpose of this work is to investigate the interaction between MSCs of different origin (bone marrow, adipose tissue) and PC-3 tumor cell line derived from prostate cancer in a long-term (9 days) cultivation. Our study assessed the proliferation, vitality and apoptosis of PC-3 tumor cells exposed to MSCs’ contact and products. As a result, we observed a significant growth inhibitory effect on PC-3 cells due to cell-to-cell contact with MSCs. Furthermore, tumor cells also showed contact-mediated increase in apoptosis levels. In addition, bone marrow-derived MSCs had a stronger effect on the PC-3 cell line compared to adipose tissue-derived MSCs.

Bioguided identification of daucosterol, a compound that contributes to the cytotoxicity effects of Crateva adansonii DC (capparaceae) to prostate cancer cells.

Crateva adansonii DC (Capparaceae) is a shrub used to treat tumors in Cameroon. In our previous reports, a Crateva adansonii dichloromethane-methanol (DCM/MeOH) extract was shown to prevent chemically induced tumors in Wistar rats. To determine the bioactive principle of Crateva adansonii extract and to elucidate its underlying mechanism. An activity-guided fractionation was realized using MTT assay. To investigate if the bioactive compound daucosterol (CA2) accounted for the previously observed anticancer effects of the C. adansonii extract, it was tested on cell growth, cell proliferation, cell cycle, cell death mechanism and cell migration. In addition, cell cycle- and apoptosis-regulating proteins were assessed by Western blotting. Daucosterol (CA2), a steroid saponin, was identified as major anticancer principle of the C. adansonii extract. Daucosterol significantly inhibited LNCaP, DU145 and PC3 prostate carcinoma cell growth and proliferation at the optimal concentration of 1 μg/mL. It also significantly increased the number of late apoptotic (DU145) and apoptotic (PC3) cells. The number of cells in S phase increased in DU145, while the number of G0/G1 cells decreased. Cell cycle proteins (cdk1, pcdk1, cyclin A and B) were down-regulated in DU145 and PC3 cells, whereas only cdk2 was down-regulated in PC3 cells. Moreover, the anti-apoptotic Akt, pAKT and Bcl-2 proteins were down-regulated, while the pro-apoptotic protein Bax was up-regulated. CA2 induced anti-metastatic effects by decreasing chemotaxis and cell migration, while it increased cell adhesion to fibronectin and collagen matrix. These results suggest that daucosterol is the major active principle responsible at least in part for the anticancer effect of the extract of Crateva adansonii.

LncRNA GASL1 inhibits growth and promotes expression of apoptosis-associated proteins in prostate carcinoma cells through GLUT-1.

Growth-arrest-associated long non-coding (lnc)RNA 1 (GASL1) is as newly identified lncRNA that is associated with liver cancer. The present study aimed to investigate the role of GASL1 in prostate carcinoma (PC). Expression levels of GASL1 in prostate tissues and sera from patients with PC and from healthy subjects were detected by reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic and survival curve analyses were performed to evaluate the diagnostic and prognostic values of GASL1 for patients with PC. A GASL1 expression vector was transfected into PC cells prior to assessment of cell proliferation and expression of B cell lymphoma 2 (Bcl-2) and glucose transporter 1 (GLUT-1) by Cell Counting Kit-8 and western blotting, respectively. The results demonstrated that GASL1 was significantly downregulated in the tissue and serum of patients with PC compared to those of healthy subjects. In addition, GASL1 was used to distinguish patients with PC from healthy controls, and low expression levels of GASL1 were associated with short survival time. Expression levels of GASL1 were significantly associated with tumor size. GASL1 overexpression inhibited PC cell growth. Overexpression of GASL1 upregulated Bcl-2 expression and downregulated GLUT-1 expression. In conclusion, these data suggested that lncRNA GASL1 may inhibit PC cell proliferation by targeting GLUT-1.

Transcription factor KLF13 inhibits AKT activation and suppresses the growth of prostate carcinoma cells.

BACKGROUND: Krüppel-like factor 13 (KLF13), a member of the KLF family, is involved in the development of immunological diseases and tumor progression. However, the expression patterns and potential functions of KLF13 in prostate carcinoma are still unknown. Here, we aimed to study the roles and mechanisms of KLF13 in prostate cancer.METHODS: The expression levels of KLF13 was detected by Immunohistochemistry in prostate tumor tissues and the paired non-tumor tissues. The effects of KLF13 up-regulation was tested by performing CCK8, cell colon formation, flow cytometric analysis and measurement of tumor proliferation in nude mice. Signaling pathway was analyzed by Western blot.RESULTS: The current study, for the first time, found that KLF13 was downregulated in prostate tumor tissues as compared to the paired non-tumor tissues. The overexpression of KLF13 dramatically inhibited cell proliferation and induced apoptosis by suppressing the AKT pathway in human prostate cancer cells. Moreover, the ectopic expression of KLF13 efficiently delayed the onset of PC3 xenografts and inhibited the tumor growth in vivo.CONCLUSIONS: KLF13 functions as a tumor suppressor protein in PCa, and the pharmacological activation of KLF13 might represent a potential approach for the treatment of prostate cancer.

New azole derivatives of [17(20)E]-21-norpregnene: Synthesis and inhibition of prostate carcinoma cell growth

A number of isoxazole, 1,2,3-triazole, tetrazole, and 1,2,4-oxadiazole derivatives of [17(20)E]-21-norpregnene comprising 3β-hydroxy-5-ene and 3-oxo-4-ene fragments were prepared. Among the key steps for the synthesis of isoxazoles, 1,2,3-triazoles, and tetrazoles were (i) 1,3-dipolar cycloaddition of nitrile oxides or azides to acetylenes or nitriles and ii) dehydration of 17β-hydroxy-17α-methylene-azoles to [17(20)E]-21-norpregnene derivatives. 1,2,4-Oxadiazoles were prepared through the formation of acetimidamides. Potency of the synthesized compounds to inhibit CYP17A1 and to suppress growth of prostate carcinoma cells was investigated. Among the new azole derivatives, four compounds were found possessing high anti-proliferative activity.

Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators

Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer-related deaths in American men. Proliferating cells have higher need for nutrients and oxygen, triggering angiogenesis that plays a critical role in tumor growth, progression and metastasis. Consequently, immense focus has converged onto inhibitors of angiogenesis in cancer treatment, such as Nintedanib, which has shown exceptional antitumor activity via inhibiting cell proliferation and the resulting tumor growth, primarily due to its combined action on tumor cells, endothelial cells and pericytes. Accordingly, here we assessed both in vitro and in vivo efficacy of Nintedanib in PCa. The results showed that Nintedanib decreased cell viability in both androgen dependent- and -independent PCa cells, together with a decrease in cell motility and invasiveness. Nintedanib also reduced the expression of significant genes responsible for cell cycle progression. PCa PC3 xenograft-carrying nude mice treated with Nintedanib showed significantly decreased tumor volume and cell proliferation alongside diminished levels of pro-angiogenic molecules and blood vessel densities. In conclusion, we report that Nintedanib has strong efficacy against PCa in pre-clinical models via modulation of various pathways, and that it could be employed as a promising new strategy to manage PCa clinically.

Comparison of [17(20)E]-21-Norpregnene oxazolinyl and benzoxazolyl derivatives as inhibitors of CYP17A1 activity and prostate carcinoma cells growth

Four new 4,5-dihydro-1,3-oxazole, and four new benzo-[d]-oxazole derivatives of [17(20)E]-21-norpregnene, differing in the structure of steroid moiety, were synthesized and evaluated for their potency to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity. Among new compounds, the only oxazolinyl derivative comprising 5-oxo-4,5-seco-3-yn- moiety potently inhibited CYP17A1. Binding modes of the oxazolinyl derivatives of [17(20)E]-21-norpregnene were analyzed by molecular dynamics simulations, and model of alternate, water-bridged type II interaction was proposed for these compounds. Eight new compounds, together with two CYP17A1-inhibiting oxazolinyl derivatives synthesized earlier, abiraterone and galeterone were evaluated for their potency to inhibit prostate carcinoma PC-3 and LNCaP cells growth. Oxazolinyl and benzoxazolyl derivatives comprising 3β-hydroxy-5-ene moieties potently inhibited prostate carcinoma cell growth; inhibitory potencies of 3-oxo-4-en- and 5-oxo-4,5-seco-3-yn- derivatives were significantly lower.

Synergistic Impact of d-δ-Tocotrienol and Geranylgeraniol on the Growth and HMG CoA Reductase of Human DU145 Prostate Carcinoma Cells

ABSTRACTThe growth-suppressive effect of d-δ-tocotrienol and geranylgeraniol is at least partially attributed to their impact on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the posttranslational modification of growth-related proteins including RAS. We hypothesize that these agents synergistically impact cell growth based on their complementary mechanisms of action with HMG CoA reductase. d-δ-tocotrienol (0–40 µmol/L; half maximal inhibitory concentration [IC50] = 15 µmol/L) and geranylgeraniol (0–100 µmol/L; IC50 = 60 µmol/L) each induced concentration-dependent suppression of the growth of human DU145 prostate carcinoma cells. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values ranging 0.67–0.75. While 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol individually had no impact on cell cycle distribution in DU145 cells, a blend of the agents induced cell cycle arrest at the G1 phase. The synergistic downregulation of the expression of HMG CoA reductase by 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol was accompanied by a reduction in membrane K-RAS protein. Our finding supports the cancer chemopreventive action of plant-based diets and their isoprenoid constituents. Properly formulated isoprenoids and derivatives may provide novel approaches in prostate cancer prevention and therapy.

Phytochemical and Biochemical Studies of Sage (Salvia officinalis L.)

Salvia is one of the major genuses belonging to Lamiaceae family. It is historically well known by its therapeutic applications. Salvia officinalis L. is a common herbal plant known as common sage. It is used in the food and beverage industries due to its powerful antimicrobial activity against several gram positive and negative bacteria. It contains high percentage of the essential oil due to the presence of external glandular structures that produce volatile oil. It is rich in the biologically active constituents which are represented mainly by polyphenolic compounds. These phenolic compounds are characterized by presence of one or more aromatic rings with one or more hydroxyl groups. The previous studies showed that water extract of this plant prevented growth of colorectal cancer and human prostate carcinoma cells. This might refer to its ability to decrease the tissue lesions occurred as a result of oxidative stress. It showed radioprotective effect against irradiation through lowering lipid peroxidation, protein carbonyl and NO in brain tissue and elevating activities of the antioxidant enzymes. It showed antiinflammatory effects by reducing marrow acute phase response and NO synthesis. Also, it showed antagonistic effect against Aluminum neurotoxicity due to reducing the oxidative stress and improving the antioxidant status and particularly by inhibiting the acetylcholinesterase activity.

MiR-96 promotes the growth of prostate carcinoma cells by suppressing MTSS1

Prostate carcinoma (PC) is one of the most common cancers for males. However, the molecular mechanisms of PC progression are still to be uncovered. MicroRNA (miRNA) has been shown to be associated with the initiation and progression of prostate cancer. Among the identified tumor-promoting miRNAs, miR-96 has been well established to contribute to PC by reducing FOXO1 expression. This study is aimed to study if miR-96 can promote the progression of PC through other pathways. Our data reinforced the finding that the level of miR-96 was higher in PC samples and cell lines than in non-cancerous tissues and normal prostate epithelial cells. In addition, serum miR-96 abundance was also found to be elevated in PC patients. Decreasing miR-96 expression was able to suppress the proliferation, clonogenicity, and invasion of PC cells. Overexpressing miR-96 led to increased proliferation and colony formation of normal prostate epithelial cells. miR-96 level was found to be inversely associated with the abundance of metastasis suppressor protein 1 (MTSS1) messenger RNA (mRNA), which has been proved to be a tumor suppressor for PC. Predictive analysis indicated that there was a potential miRNA response elements (MREs) located within 3'UTR of MTSS1 mRNA. The changes in miR-96 expression can affect the levels of MTSS1 both at mRNA and protein levels. miR-96 also suppressed the activity of luciferase reporter under the regulation of 3'UTR of MTSS1. Further studies showed that MTSS1 restoration accounted for the effect of miR-96 reduction on PC cells. The overexpression of a recombinant MTSS1 resistant against miRNA regulation was also demonstrated to abolish the transforming effect of miR-96 on prostate epithelial cells. Taken together, we found that miR-96 has a higher abundance in serum samples of PC patients than healthy controls, implying that it may be used as a prognostic marker. MTSS1 is a new authentic target of miR-96 in PC. The above findings suggested that targeting miR-96 may be a promising strategy for PC treatment.