scholarly journals Disrupting Androgen Receptor Functionality with Xanthones from the Mangosteen (Garcinia mangostana) Fruit

Proceedings ◽  
2020 ◽  
Vol 40 (1) ◽  
pp. 50
Author(s):  
Jeremy J. Johnson
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cellular Proliferation ◽  
Xenograft Model ◽  
Pharmacokinetic Studies ◽  
Garcinia Mangostana ◽  
Optimal Dosing ◽  
Anti Cancer

The Southeast Asian mangosteen (Garcinia mangostana) contains a class of phytochemicals known as xanthones that possess extensive biological activity. Applications of xanthones, including the most prominent, alpha-mangostin, have been shown to possess anti-cancer, anti-oxidant, and anti-proliferation properties. To confirm the anti-cancer activity of xanthones we have evaluated 9 xanthones for decreasing cellular proliferation of cancer cells. These xanthones include alpha-mangostin, gartanin, 9-hydroxycalabaxanthone, garcinone C, garcinone D, and others. Using this approach, we have focused on understanding the ability of xanthones to disrupt androgen receptor in prostate cancer cells with a combination of cell free and cell-based assays. In addition, we have performed pharmacokinetic studies in mice with alpha-mangostin to characterize the optimal dosing strategy. Taken together, we have identified individual xanthones as capable of disrupting kinases, including CDK4, using cell free biochemical models and cell-based animal models. These results have been further validated in an in vivo xenograft model. Taken together, we have begun to describe the anti-cancer potential of xanthones for prostate cancer.

scholarly journals Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1550 ◽  
Author(s):  
Tomomi Sanomachi ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Asuka Sugai ◽  
Shizuka Seino ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Survivin Expression ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
Underlying Mechanisms

Spironolactone, a classical diuretic drug, is used to treat tumor-associated complications in cancer patients. Spironolactone was recently reported to exert anti-cancer effects by suppressing DNA damage repair. However, it currently remains unclear whether spironolactone exerts combinational effects with non-DNA-damaging anti-cancer drugs, such as gemcitabine and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Using the cancer cells of lung cancer, pancreatic cancer, and glioblastoma, the combinational effects of spironolactone with gemcitabine and osimertinib, a third-generation EGFR-TKI, were examined in vitro with cell viability assays. To elucidate the underlying mechanisms, we investigated alterations induced in survivin, an anti-apoptotic protein, by spironolactone as well as the chemosensitization effects of the suppression of survivin by YM155, an inhibitor of survivin, and siRNA. We also examined the combinational effects in a mouse xenograft model. The results obtained revealed that spironolactone augmented cell death and the suppression of cell growth by gemcitabine and osimertinib. Spironolactone also reduced the expression of survivin in these cells, and the pharmacological and genetic suppression of survivin sensitized cells to gemcitabine and osimertinib. This combination also significantly suppressed tumor growth without apparent adverse effects in vivo. In conclusion, spironolactone is a safe candidate drug that exerts anti-cancer effects in combination with non-DNA-damaging drugs, such as gemcitabine and osimertinib, most likely through the suppression of survivin.

scholarly journals Two-stage nanoparticle delivery of piperlongumine and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) anti-cancer therapy

TECHNOLOGY ◽  
2016 ◽  
Vol 04 (01) ◽  
pp. 60-69 ◽  
Author(s):  
Charles C. Sharkey ◽  
Jiahe Li ◽  
Sweta Roy ◽  
Qianhui Wu ◽  
Michael R. King
Keyword(s):  
Cancer Cells ◽  
Survival Rates ◽  
Xenograft Model ◽  
Plga Nanoparticles ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
In Vivo Testing ◽  
Hct116 Cells

This study outlines a drug delivery mechanism that utilizes two independent vehicles, allowing for delivery of chemically and physically distinct agents. The mechanism was utilized to deliver a new anti-cancer combination therapy consisting of piperlongumine (PL) and TRAIL to treat PC3 prostate cancer and HCT116 colon cancer cells. PL, a small-molecule hydrophobic drug, was encapsulated in poly (lactic-co-glycolic acid) (PLGA) nanoparticles. TRAIL was chemically conjugated to the surface of liposomes. PL was first administered to sensitize cancer cells to the effects of TRAIL. PC3 and HCT116 cells had lower survival rates in vitro after receiving the dual nanoparticle therapy compared to each agent individually. In vivo testing involved a subcutaneous mouse xenograft model using NOD-SCID gamma mice and HCT116 cells. Two treatment cycles were administered over 48 hours. Higher apoptotic rates were observed for HCT116 tumor cells that received the dual nanoparticle therapy compared to individual stages of the nanoparticle therapy alone.

Androgen-dependent regulation of Her-2/neu in prostate cancer cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10099-10099
Author(s):  
R. Berger ◽  
D. I. Lin ◽  
M. Nieto ◽  
S. Signoretti ◽  
W. C. Hahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Prostate Cancer Cells ◽  
In Vivo Experiments ◽  
Her 2

10099 Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells. No significant financial relationships to disclose.

scholarly journals AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

2018 ◽  
Vol 50 (2) ◽  
pp. 798-809 ◽  
Author(s):  
Gang Shen ◽  
Jianchun Chen ◽  
Yongqiang Zhou ◽  
Zhenfan Wang ◽  
Zheng Ma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Nude Mice ◽  
Xenograft Model ◽  
Specific Inhibitor ◽  
Tunel Staining ◽  
Prostate Cancer Cells ◽  
Primary Prostate Cancer

Backgrounds/Aims: Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor. Methods: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H3] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153’s activity in vivo. Results: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206. Conclusion: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells.

scholarly journals Inhibition of Autophagy Promotes Hemistepsin A-Induced Apoptosis via Reactive Oxygen Species-Mediated AMPK-Dependent Signaling in Human Prostate Cancer Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1806
Author(s):  
Kwang-Youn Kim ◽  
Un-Jung Yun ◽  
Seung-Hee Yeom ◽  
Sang-Chan Kim ◽  
Hu-Jang Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Xenograft Model ◽  
Underlying Mechanism ◽  
Ros Generation ◽  
Prostate Cancer Cells ◽  
Ros Scavenger ◽  
Induced Apoptosis

Chemotherapy is an essential strategy for cancer treatment. On the other hand, consistent exposure to chemotherapeutic drugs induces chemo-resistance in cancer cells through a variety of mechanisms. Therefore, it is important to develop a new drug inhibiting chemo-resistance. Although hemistepsin A (HsA) is known to have anti-tumor effects, the molecular mechanisms of HsA-mediated cell death are unclear. Accordingly, this study examined whether HsA could induce apoptosis in aggressive prostate cancer cells, along with its underlying mechanism. Using HsA on two prostate cancer cell lines, PC-3 and LNCaP cells, the cell analysis and in vivo xenograft model were assayed. In this study, HsA induced apoptosis and autophagy in PC-3 cells. HsA-mediated ROS production attenuated HsA-induced apoptosis and autophagy after treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, autophagy inhibition by 3-MA or CQ is involved in accelerating the apoptosis induced by HsA. Furthermore, we showed the anti-tumor effects of HsA in mice, as assessed by the reduced growth of the xenografted tumors. In conclusion, HsA induced apoptosis and ROS generation, which were blocked by protective autophagy signaling.

scholarly journals Human Checkpoint Protein hRad9 Functions as a Negative Coregulator To Repress Androgen Receptor Transactivation in Prostate Cancer Cells

2004 ◽  
Vol 24 (5) ◽  
pp. 2202-2213 ◽  
Author(s):  
Liang Wang ◽  
Cheng-Lung Hsu ◽  
Jing Ni ◽  
Peng-Hui Wang ◽  
Shuyuan Yeh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Specific Antigen ◽  
Luciferase Reporter ◽  
Signal Pathways ◽  
Prostate Cancer Cells ◽  
C Terminus ◽  
Two Hybrid

ABSTRACT Positive responses to combined androgen elimination therapy and radiation therapy have been well documented in the treatment of prostate cancer patients. The detailed mechanisms how androgen-androgen receptor (AR) cross talks to the radiation-related signal pathways, however, remain largely unknown. Here we report the identification of hRad9, a key member of the checkpoint Rad protein family, as a coregulator to suppress androgen-AR transactivation in prostate cancer cells. In vivo and in vitro interaction assays using Saccharomyces cerevisiae two-hybrid, mammalian two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation methods prove that AR can interact with the C terminus of hRad9 via its ligand binding domain. The FXXLF motif within the C terminus of hRad9 interrupts the androgen-induced interaction between the N terminus and C terminus of AR. This interaction between AR and hRad9 may result in the suppression of AR transactivation, demonstrated by the repressed AR transactivation in androgen-induced luciferase reporter assay and the reduced endogenous prostate-specific antigen expression in Western blot assay. Addition of small interfering RNA of hRad9 can reverse hRad9 suppression effects, which suggests that hRad9 functions as a repressor of AR transactivation in vivo. Together, our data provide the first linkage between androgen-AR signals and radiation-induced responses. Further studies of the influence of hRad9 on prostate cancer growth may provide potential new therapeutic approaches.

Anticancer activity of the selective CYP17A1 inhibitor, VT-464, in preclinical models of castrate-resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Paul Toren ◽  
Steven Pham ◽  
Soojin Kim ◽  
Hans Adomat ◽  
Amina Zoubeidi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Xenograft Model ◽  
Resistant Cell ◽  
Anti Cancer ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Cancer Activity

104 Background: Castrate resistant prostate cancer (CRPC) continues to be sensitive to anti-androgen therapy as evidenced by the recent successes of abiraterone acetate (AA) and enzalutamide (ENZ). VT-464 is a novel, non-steroidal, small molecule CYP17A1 inhibitor with selectivity for the lyase activity of this dual enzyme. The objective of this study was to evaluate the anti-cancer activity of VT-464 compared to AA in CRPC in vitro models that are ENZ-responsive and ENZ-resistant and in an ENZ-resistant xenograft model. Methods: In vitro studies used the human CRPC, C4-2, and ENZ-resistant cell lines, MR49C and MR49F cells, in androgen-free media. AR transcriptional activity was assessed by probasin luciferase. AR-related and steroidogenesis pathways were assessed by western blot and/or qRT-PCR. A MR49F xenograft model in castrate mice compared oral VT-464 treatment to vehicle and AA. Steroid concentrations were measured using LC-MS chromatography. Results: VT-464 demonstrated a greater decrease in AR transactivation compared to AA in C4-2 and both ENZ-resistant cell lines. A greater decrease in AR-dependent gene transcription occurred with VT-464 treatment compared to AA in all cell lines. Prostate-specific antigen (PSA) protein levels in vitro were also lower with VT-464. Gene transcripts StAR, CYP17A1, HSD17B3 and SRD5A1 increased following treatment with VT-464 both in vitro and in vivo. A greater increase was seen with VT-464 treatment compared to AA. In vivo results demonstrated greater tumor growth inhibition and decreased serum PSA levels in mice treated with oral VT-464 compared to AA. Steroid analysis revealed lower testosterone (T) and dihydrotestosterone (DHT) concentrations in C4-2 cells with VT-464 treatment compared to AA. In vivo, the intra-tumoral DHT and T levels were significantly lower in response to VT-464 or AA compared to vehicle, with the greatest decrease seen with VT-464. Conclusions: The selective CYP17 inhibitor VT-464 demonstrated anti-cancer activity in pre-clinical models of CRPC, lowering intratumoral T and DHT concentrations significantly in castrate mice. These results suggest greater androgen suppression and inhibition of AR axis signaling by VT-464 than by AA.

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