Enhanced inhibition of tumor growth using TRAIL-overexpressing adipose-derived stem cells in combination with the chemotherapeutic agent CPT-11 in castration-resistant prostate cancer

340 Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC.

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Dependence of Castration-Resistant Prostate Cancer (CRPC) Stem Cells on CRPC-Associated Fibroblasts

Journal of Cellular Physiology ◽

10.1002/jcp.24546 ◽

2014 ◽

Vol 229 (9) ◽

pp. 1170-1176 ◽

Cited By ~ 12

Author(s):

Helty Adisetiyo ◽

Mengmeng Liang ◽

Chun-Peng Liao ◽

Joseph H. Jeong ◽

Michael B. Cohen ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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

Frontiers in Oncology ◽

10.3389/fonc.2021.660320 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhoulei Li ◽

Peng He ◽

Yali Long ◽

Gang Yuan ◽

Wanqing Shen ◽

...

Keyword(s):

Prostate Cancer ◽

Vitamin C ◽

Tumor Growth ◽

Cancer Cells ◽

Cell Lines ◽

Combined Treatment ◽

Drug Repurposing ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

18F Fdg

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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Mesenchymal Stem Cells Desensitize Castration-resistant Prostate Cancer to Docetaxel Chemotherapy via Inducing TGF-β1-mediated Cell Autophagy

10.21203/rs.3.rs-33894/v1 ◽

2020 ◽

Author(s):

Yang Yu ◽

Wen-tao Zhang ◽

Fu-han Yang ◽

Ya-dong Guo ◽

Lin Ye ◽

...

Keyword(s):

Prostate Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Docetaxel Chemotherapy ◽

Tgf Β1

Abstract Background: Mesenchymal stem cells (MSCs) have been proved to accelerate prostate cancer (PCa) castration resistance progression. The purpose of this study is to investigate the contribution of MSCs to the development of docetaxel resistance in castration-resistant prostate cancer (CRPC) cells and its potential mechanisms.Methods: The effect of MSCs on CRPC cells resistance to docetaxel was determined using in-vivo and in-vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses.Results: MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel.Conclusions: These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.

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The emerging role of noncoding RNA in prostate cancer progression and its implication on diagnosis and treatment

10.31234/osf.io/4u2sd ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Cancer Progression ◽

Noncoding Rna ◽

Castration Resistant Prostate Cancer ◽

Systematic Analysis ◽

Castration Resistant ◽

Insight Into ◽

Generation Sequencing

Recent transcriptome studies using next-generation sequencing have detected aberrant changes in the expression of noncodingRNAs (ncRNAs) associated with cancer. For prostate cancer, the expression levels of ncRNAs including microRNAsand long noncoding RNAs are strongly associated with diagnosis, carcinogenesis and tumor growth. Moreover, androgenand its cognate receptor, androgen receptor (AR), regulate various signaling pathways for prostate tumor growth. In addition,progression to lethal castration-resistant prostate cancer (CRPC) is also owing to AR function. Systematic analysis ofAR-binding sites and their regulated transcripts revealed that many ncRNAs are widely regulated at the transcriptionallevel. Thus, recent studies provide new insight into the complicated molecular mechanism of prostate cancer progression.This review focused on the role of various ncRNAs in prostate cancer and the association between their expression andCRPC.

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