scholarly journals Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells

2021 ◽  
Vol 14 (10) ◽  
pp. 949
Author(s):  
Sergey A. Dyshlovoy ◽  
Dmitry N. Pelageev ◽  
Lea S. Jakob ◽  
Ksenia L. Borisova ◽  
Jessica Hauschild ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitor ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Anticancer Properties ◽  
Highly Active ◽  
Development Of Resistance ◽  
Castration Resistant ◽  
Hybrid Molecules

Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, 30 and 32, were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib and resensitized AR-V7-expressing PCa cells to antiandrogen enzalutamide, as well as to a combination of enzalutamide and an AKT inhibitor. This was at least in part exerted via down-regulation of AR-V7 expression and inhibition of AR signaling. Mild antagonism was observed in combination with platinum- or taxane-based chemotherapy, which was putatively related to treatment-induced activation of p38, JNK1/2, ERK1/2, MEK1/2, and AKT, functioning as potential pro-survival factors. Thus, the synthesized (2-chloroethylthio)-1,4-naphthoquinone derivatives exhibit promising anticancer properties in vitro, suggesting their further development as potential therapeutics for the treatment of castration-resistant PCa.

scholarly journals In Vitro Anticancer Properties of Table Grape Powder Extract (GPE) in Prostate Cancer

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1804 ◽  
Author(s):  
Avinash Kumar ◽  
Melinee D’silva ◽  
Kshiti Dholakia ◽  
Anait Levenson
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Epidemiological Data ◽  
Grape Seed ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Anticancer Properties ◽  
Vegetables And Fruits ◽  
Powder Extract

Although the link between diet and cancer is complex, epidemiological data confirm that diet is a risk factor for prostate cancer and indicate a reduced prostate cancer incidence associated with a diet rich in vegetables and fruits. Because of the known protective effect of grape seed extract (GSE) against prostate cancer, we evaluated the effects of grape powder extract (GPE) on cell viability, proliferation, and metastatic capability. Importantly, we explored the possible novel mechanism of GPE through metastasis-associated protein 1 (MTA1) downregulation in prostate cancer, since our previous studies indicated resveratrol (Res)- and pterostilbene (Pter)-induced MTA1-mediated anticancer activities in prostate cancer. We found that GPE inhibited the cell viability and growth of prostate cancer cells only at high 100 μg/mL concentrations. However, at low 1.5–15 μg/mL concentrations, GPE significantly reduced the colony formation and wound healing capabilities of both DU145 and PC3M cells. Moreover, we found that GPE inhibited MTA1 in a dose-dependent manner in these cells, albeit with considerably less potency than Res and Pter. These results indicate that stilbenes such as Res and Pter specifically and potently inhibit MTA1 and MTA1-associated proteins compared to GPE, which contains low concentrations of Res and mainly consists of other flavonoids and anthocyanidins. Our findings support continued interest in GPE as a chemopreventive and anti-cancer agent against prostate cancer but also emphasize the unique and specific properties of stilbenes on MTA1-mediated anticancer effects on prostate cancer.

scholarly journals PEG10 is associated with treatment-induced neuroendocrine prostate cancer

2019 ◽  
Vol 63 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Soojin Kim ◽  
Daksh Thaper ◽  
Samir Bidnur ◽  
Paul Toren ◽  
Shusuke Akamatsu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Resistant Cell ◽  
Dependent Manner ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer ◽  
Marker Status ◽  
Dose Dependent

Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42DENZR and 42FENZR compared to LNCaP and castration-resistant 16DCRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16DCRPC. Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro- and in vivo-attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.

scholarly journals NCL1, A Highly Selective Lysine-Specific Demethylase 1 Inhibitor, Suppresses Castration-Resistant Prostate Cancer Growth via Regulation of Apoptosis and Autophagy

2019 ◽  
Vol 8 (4) ◽  
pp. 442 ◽  
Author(s):  
Toshiki Etani ◽  
Taku Naiki ◽  
Aya Naiki-Ito ◽  
Takayoshi Suzuki ◽  
Keitaro Iida ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Neuroendocrine Differentiation ◽  
Cancer Growth ◽  
Dependent Manner ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.

scholarly journals SLX4IP-mediated telomere maintenance is essential for androgen receptor-independent castration-resistant prostate cancer

2020 ◽  
Author(s):  
Tawna L. Mangosh ◽  
Wisam N. Awadallah ◽  
Magdalena M. Grabowska ◽  
Derek J. Taylor
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Neuroendocrine Differentiation ◽  
Telomere Maintenance ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Alternative Lengthening

ABSTRACTIn advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer, and defining mechanisms critical for its survival is of utmost importance for targeting this lethal disease. Our studies have focused on defining the telomere maintenance mechanism (TMM) required for castration-resistant prostate cancer (CRPC) cell survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC exhibits ALT hallmarks and limited telomerase expression and activity, whereas AR-dependent models use telomerase for telomere maintenance. AR-independent CRPC exhibited elevated levels of SLX4IP, a protein implicated in TMM switching. SLX4IP overexpression in AR-dependent CRPC C4-2B cells promoted ALT hallmarks in vitro. SLX4IP knockdown in AR-independent CRPC cells (DU145 and PC-3) led to the loss of ALT hallmarks, dramatic telomere shortening, induction of senescence, and reduced tumor volume. Using an in vitro model of CRPC progression, induction of neuroendocrine differentiation in AR-dependent CRPC cells promoted ALT hallmarks in an SLX4IP-dependent manner. Lack of sufficient SLX4IP expression prevented ALT hallmarks rendering a TMM deficient environment, thus inducing senescence. This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT. Furthermore, ALT hallmark inhibition via SLX4IP induces senescence, thereby abolishing the replicative immortality of AR-independent CRPC.

scholarly journals Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Therapy Resistance ◽  
Calcium Signal ◽  
Signal Transducer ◽  
Castration Resistance ◽  
Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

scholarly journals Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3975
Author(s):  
Marco A. De Velasco ◽  
Yurie Kura ◽  
Naomi Ando ◽  
Noriko Sako ◽  
Eri Banno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Late Stage ◽  
Early Stage ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Molecular Features ◽  
Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

Abstract P014: Oxidative Stress Mediated Regulation of Antioxidants in Cardiac Progenitor Cells

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Gokulakrishnan Iyer ◽  
Michael E Davis
Keyword(s):  
Oxidative Stress ◽  
Xanthine Oxidase ◽  
Progenitor Cells ◽  
Cardiac Progenitor Cells ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Differentiation Potential ◽  
Lineage Differentiation ◽  
Phosphorylated Akt

Cardiac diseases are the leading causes of death throughout the world and transplantation of endogenous myocardial progenitor population with robust cardiovascular lineage differentiation potential is a promising therapeutic strategy. Therefore, in vitro expansion and transplantation of cardiac progenitor cells (CPCs) is currently in early clinical testing as a potential treatment for severe cardiac dysfunction. However, poor survival and engraftment of cells is one of the major limitations of cell transplantation therapy. Oxidative stress is increased in the ischemic myocardium and indirect inferences suggest the vulnerability of CPCs to oxidative stress. In this study, we show that in vitro, resident c-kit positive CPCs isolated from rat myocardium are significantly (p<0.05) resistant to superoxide-induced apoptosis compared to cardiomyocytes as analyzed by the number of sub-G1 population following xanthine/xanthine oxidase treatment. Interestingly, CPCs have two to four fold higher basal SOD1 and SOD2 activities (p<0.01) compared to cardiomyocytes and endothelial cells. Superoxide treatment increased expression of SOD1 (p<0.01), SOD2 (p<0.01), and glutathione peroxidase (p<0.05) mRNAs within 6 h of treatment compared to control cells. Recent studies suggest the involvement of AKT in controlling cell death, survival and also expression of SOD enzymes. Therefore, we investigated the involvement of AKT in CPCs subjected to oxidative stress. Western blot analysis revealed that the amount of phosphorylated AKT increased significantly within 10 minutes of xanthine/xanthine oxidase treatment. In addition, treatment with LY294002 - a PI3 kinase/AKT inhibitor, increased apoptosis in CPCs treated with superoxide. Our studies demonstrate a novel finding in which resident progenitor cells are protected from oxidative injury by containing higher basal levels of antioxidants as compared to myocytes. Moreover, under oxidant challenge antioxidant levels are regulated, possibly in an AKT-dependent manner. Further elucidation of this pathway may lead to novel therapeutic opportunities.

scholarly journals Demethylzeylasteral (T-96) Initiates Extrinsic Apoptosis Against Prostate Cancer cells by Inducing ROS-Mediated ER Stress and Suppressing Autophagic Flux

2021 ◽  
Author(s):  
Dong-Lin Yang ◽  
Ya-jun Zhang ◽  
Liu-jun He ◽  
Chun-sheng Hu ◽  
Li-xia Gao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Mechanistic Investigation ◽  
Potential Applications ◽  
Extrinsic Apoptosis ◽  
Pharmacologically Active

Abstract Demethylzeylasteral (T-96), a pharmacologically active triterpenoid monomer extracted from Tripterygiumwilfordii Hook F (TWHF), has been reported to exhibit anti-neoplastic effect on several types of cancer cells. However,whether it has the anti-tumour capability in human Prostate cancer (CaP)cells and what’s the precise regulatory mechanisms underlying the anti-proliferation effect of T-96 on human CaP. In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Furthermore, mechanistic investigation indicated that through inducing endoplasmic reticulum (ER) stress caused by intracellular accumulation of reactive oxygen species (ROS), T-96 significantly promoted autophagy initiation while blocked the autophagic flux and finally caused extrinsic apoptosis in CaP cells, implying that ER stress induced byT-96 initiated caspase dependent apoptosis to inhibit CaP cells. Moreover, as a novel lethal ER stress inducer, T-96 was capable to enhance the sensitivity of CaP cells to chemotherapeutic drug cisplatin. Taken together, our data implied that T-96 is a novel ER stress and autophagy modulator, and has the potential applications for CaP therapy in clinic.

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