Drug Repurposing of Pantoprazole and Vitamin C Targeting Tumor Microenvironment Conditions Improves Anticancer Effect in Metastatic Castration-Resistant Prostate Cancer

The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC.

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Statin inhibits the proliferation of human castration-resistant prostate cancer cells by controlling NFkB-LIN28B-let7 miRNA signaling pathway.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.269 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 269-269 ◽

Cited By ~ 1

Author(s):

Chang Wook Jeong ◽

Ja Hyeon Ku ◽

Hyeon Hoe Kim ◽

Cheol Kwak ◽

Minyong Kang

Keyword(s):

Prostate Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Cell Lines ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Simvastatin Treatment ◽

Castration Resistant

269 Background: Although statin use has been associated with improved outcomes in prostate cancer, the molecular mechanism of this action is still unclear. Based on previous findings, we aimed to investigate the potential role of NFkB-Lin28B-let7 miRNA signaling pathway in human prostate cancer, particularly, castration-resistant prostate cancer (CRPC) cells, as a molecular mechanism of statin effect. Methods: Various human CRPC cell lines (PC3, DU145, 22Rv1, C42B) were used in this study. Proliferation of prostate cancer cells were measured by MTT assay and colony formation assay. Lin28B and NF-κB expression were controlled by siRNA transfection and the expression on Lin28 and let-7 miRNA were quantitated using RT-PCR and western blotting. Results: Notably, simvastatin treatment on various CRPC cell lines decreased cell viabilities in a dose dependent manner. It also significantly inhibited cell growth in clonogenic assay. In these CRPC cells, LIN28 gene was highly expressed in mRNa and protein levels. Conversely, micro RNA (miRNA) expressions of let7 family were remarkably downregulated in CRPC cells. By simvastatin treatment, mRNA and protein level of Lin28B were decreased, while let7 miRNA expressions were restored, which was the key finding of the current study. Considering NFkB is the upstream molecule of Lin28B, we found that the double treatment of statin and NF-κB inhibitor (CAPE) resulted in decreased cell viability, Lin28B and cyclin D1 expression, synergistically. Of note, let-7 miRNA levels were restored after simvastatin treatment, and further increased their expression levels by CAPE double treatment. In order to confirm this mechanistic clue, we specifically inhibited Lin28B and NF-κB genes, respectively, resulting in increased cell apoptosis signaling in the Lin28b or NF-κB knock down cells by combined treatment with simvastatin. Conclusions: In conclusion, simvastatin inhibited the cell growth of various human CRPC cell lines by controlling NFkB-LIN28B-let7 miRNA signaling pathway, and therefore; concurrent NF-κB inhibition with simvastatin treatment induce the synergistic anti-cancer effects in human CRPC cells.

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Drug Repurposing of Asparaginase and Vitamin C Targeting Glutamine Synthetase Improves Anticancer Effect in Metastatic Castration-resistant Prostate Cancer

10.21203/rs.3.rs-1102647/v1 ◽

2022 ◽

Author(s):

Zhoulei Li ◽

Wanqing Shen ◽

Zhifeng Chen ◽

Gang Yuan ◽

Peng He ◽

...

Keyword(s):

Prostate Cancer ◽

Glutamine Synthetase ◽

Vitamin C ◽

Combined Therapy ◽

Drug Repurposing ◽

Castration Resistant Prostate Cancer ◽

Anticancer Effect ◽

18F Fdg

Abstract Background: Although in North America or Europe early dignosis of prostate cancer could sucessfully improves the therapeutic outcome. However, about 70-80% of patients still suffer from metastatic castration-resistant prostate cancer (mCRPC), because of the disproportionate medical care in China. Lutetium-177 (Lu-177) or Radium-223 (Ra-223) has been suggested as the most effective therapy for mCRPC. Unfortunately, they are either not been approved in a few countries or too expensive for patients with the financial issue. Drug repurposing has been recognized as a cost-effective and relatively low-risk alternative, gains a lot interesting recently. In this study, we explored the combined treatment with asparaginase (ASNase) and/or vitamin Cas an alternative therapeutic option for mCRPC management.Methods: Prostate cancer cell lines PC3 and DU145 were used to observe the therapeutic effect of ASNase and/or vitamin C on mCRPC in vitro and in vivo. Change of cell proliferation, cell death as well as expression of glutamine synthetase eunder different treatment conditions were detected to analyzed anticancer effect of combined therapy with ASNase and vitamin C on mCRPC. Intracellular oxidation was also observed with NADPH and NADP+ assay. Male BALB/c nude mice bearing prostate carcinoma xenografts (PC3 or DU145) were used to assess treatment response to vitamin C with or without ASNase through tumor growth, small animal PET/CT scans as well as Immunohistochemistry in vivo.Results: Our in vitro studies demonstrate that ASNase synergizes with vitamin C targeting expression of glutamine synthetase enhances redox imbalance and induces anticancer effect in mCRPC cells through regulation the glutamine synthetase (GS) expression. In vivo, combination of ASnase and vitamin C could provide a significant better therapeutic outcome in comparison with controls or single treated mice. 18F-FDG PET imaging illustrated that the treatment with combined therapy could significantly reduce the 18F-FDG uptake in tumor.Conclusions: In this current study, we suggest that ASNase combined with vitamin C could be as a cost-effective strategy to manage mCRPC.18F-FDG PET/CT imaging could indicate the therapeutic response of treatment for mCRPC.

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S100A3 Suppression Inhibits In Vitro and In Vivo Tumor Growth and Invasion of Human Castration-resistant Prostate Cancer Cells

Urology ◽

10.1016/j.urology.2014.09.018 ◽

2015 ◽

Vol 85 (1) ◽

pp. 273.e9-273.e15 ◽

Cited By ~ 13

Author(s):

Minyong Kang ◽

Hye Sun Lee ◽

Young Ju Lee ◽

Woo Suk Choi ◽

Yong Hyun Park ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Castration Resistant ◽

Tumor Growth And Invasion

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Targeting RET Kinase in Neuroendocrine Prostate Cancer

10.1101/622415 ◽

2019 ◽

Cited By ~ 1

Author(s):

Halena VanDeusen ◽

Johnny R. Ramroop ◽

Katherine L. Morel ◽

Anjali V Sheahan ◽

Zoi Sychev ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Cell Lines ◽

Treatment Options ◽

Kinase Signaling ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Novel Approach ◽

Neuroendocrine Prostate Cancer ◽

Aggressive Variant

AbstractIncreased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression and may be a novel treatment option.Statement of SignificanceThere are limited treatment options for patients with metastatic aggressive variant prostate cancer and none are curative. Here we identified aberrantly activated RET kinase signaling in multiple models of NEPC. Inhibiting RET restricted tumor growth, providing a novel approach for treating NEPC.

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Castration-resistant Prostate Cancer: The Targeting of Bone Microenvironment-related Survival Factors For Prostate Cancer Cells

Clinical Cancer Drugs ◽

10.2174/2212697x03666151203202934 ◽

2016 ◽

Vol 3 (1) ◽

pp. 16-22 ◽

Cited By ~ 1

Author(s):

Dimitrios Karamanolakis ◽

Athanasios Armakolas ◽

Michael Koutsilieris

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Bone Microenvironment ◽

Prostate Cancer Cells ◽

Survival Factors ◽

Castration Resistant ◽

Related Survival

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Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03369-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ding-fang Zhang ◽

Zhi-chun Yang ◽

Jian-qiang Chen ◽

Xiang-xiang Jin ◽

Yin-da Qiu ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Dna Damage ◽

Cell Adhesion ◽

Anticancer Activity ◽

Cancer Cells ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Dna Damage And Repair ◽

Castration Resistant

Abstract Background Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. Methods The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. Results The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. Conclusion Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

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