Complete metabolic response of metastatic castration‐resistant neuroendocrine carcinoma of the prostate after treatment with RRx‐001 and reintroduced platinum doublets

Ojemuyiwa, Michelle A.; Zeman, Karen; Spira, Alexander I.; Oronsky, Bryan; Ray, Carolyn; Trepel, Jane B.; Lee, Min Jung; Onyiuke, Ifeyinwa; Brzezniak, Christina

doi:10.1002/ccr3.1880

Cited by 2 publications

(2 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Even though 81% of prostate cancers are pathologically organ-confined at time of diagnosis. 10 After diagnosis prostate cancer can metastasized to other organs of the body if the treatment is not effective. 3-BPA is a known chemotherapeutic drug by itself.…”

Section: Increased Incidence Of Prostate Cancermentioning

confidence: 99%

Untitled

2020

JCPCR

View full text Add to dashboard Cite

Background:The number of deaths from prostate cancer is still high due to ATP Binding Cassette (ABC)-Mediated Multidrug Resistance (MDR). Overexpression of ABC transporters causes multidrug resistance in most prostate cancer chemotherapies. P-glycoprotein (P-gp) is one of the common drug transporters associated with MDR. There are no drugs approved by FDA to reverse MDR (inhibiting P-gp) in prostate cancer. This study utilized drug combination to reduce MDR expression by using 3-Bromopyruvate (3-BPA) to potentiate the therapeutic effect of SC-514. SC-514 is a relatively new hydrophobic dug, which has been shown to have anti-cancer effects via inhibition of NF-KB-dependent gene expression in cancer cells. 3-BPA is an alkylating agent, glycolytic inhibitor, and an anticancer drug that has a great potential to enhance the effects of anticancer drugs. Aim of study: This study aimed to reduce acquired and intrinsic ABC-mediated multidrug resistance (MDR) by increasing the drug efficiency of SC-514 via drug combination with 3-BPA. Method: Cell titer glow assay, multidrug resistance efflux assay, immunofluorescence assay and ELISA assay were utilized to investigate the drug efficiency of SC-514 in combination with 3-BPA and the number of drug resistance GR-PC-3 cells and PC-3 cells after treatment. Results:Combination of SC-514 and 3-BPA significantly decreased intracellular ATP and the number of MDR cells in GR-PC-3 and PC-3 prostate cancer cells. SC-514 and/3-BPA treatments reduce NF-KB activation, IL-6 expression, and BCL2 expression. However, SC-514 and/3-BPA treatments increase the expression of Bax. Conclusion: Combination of SC-514 and 3-BPA increased the therapeutic effect of SC-514 in prostate cancer treatment. The anticancer activities of SC-514 and 3-BPA in combination is promising for future drug development and drug combinations to completely reverse MDR in prostate cancer treatments.

show abstract

Section: Increased Incidence Of Prostate Cancermentioning

confidence: 99%

Untitled

2020

JCPCR

View full text Add to dashboard Cite

show abstract

“…In clinical trials RRx-001 has been shown to be biologically active at safe doses in target populations (those with advanced metastatic solid organ tumours), and to be a potent generator of reactive nitrogen and oxygen species in vivo 244,245 . A number of case reports and Phase I trials against metastatic or end-stage Non-Small and Small Cell Lung Cancers, squamous tumours, prostate cancers, and melanomas have indicated that RRx-001 may have beneficial effects when combined with previously exhausted chemo-or radio-therapeutic strategies [246][247][248][249][250][251] .…”

Section: Rrx-001mentioning

confidence: 99%

A Mechanistic Investigation of the Relationship Between Extramural Vascular Invasion (EMVI) and CpG Island Methylator Phenotype (CIMP) in Rectal Cancer

Rory¹

View full text Add to dashboard Cite

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer death worldwide. Each year, one million people will develop CRC, and 40-50% will die within five years. Furthermore, rectal and distal sigmoid cancers are known to present at a later stage and have a poorer prognosis than other colonic cancers. Rectal cancers that demonstrate pathological extramural vascular invasion (EMVI-positive) are known to have a poorer prognosis than those that do not (EMIV-negative), and EMVI has is acknowledged as an important risk factor for systemic recurrence, local recurrence and death. Additionally, EMVI status influences the need for pre- and post-operative chemoradiation (CRT); which may influence survival outcomes. Aberrant DNA methylation is emerging as a carcinogenic mechanism and potential biomarker in colorectal cancer. This study investigates the association between hypermethylation and EMVI in vivo and in vitro. Firstly, the in vivo associations between hypermethylation, EMVI, and clinical and histopathological outcomes are examined. Secondly, an investigation of the effects of demethylation on invasive colorectal cell lines in vitro aims to illuminate the genetic and cellular mechanisms that underlie methylation-dependent pathological cellular behaviour. Finally, highlighted biologic mechanisms are investigated in vivo to discover if there is an association with EMVI and survival outcomes. By these means the axis of association between hypermethylation, EMVI, and clinical outcomes is investigated. The investigation is conducted within the framework of consensus molecular subtyping in colorectal cancer, and in concordance with current methodologies of assessing DNA methylation status. The primary findings demonstrate that EMVI is associated with hypermethylation in vivo, but that there is no direct correlation between hypermethylation and disease-free (DFS) or overall survival (OS). In vitro, demethylation of hypermethylated colorectal cancer cells, by means of established demethylating agent 5-azacytidine and putative demethylator RRx-001, reduces their propensity to migrate and invade. Demethylation in vitro is also associated with changes in the expression of the metalloproteinases involved in the metabolism of the basement membrane and the epithelial-to-mesenchymal transition and tumour metastasis, notably MMP2 and TIMP2. Changes in expression were confirmed at transcriptomal and proteomic levels in response to demethylation. In vivo, MMP2 expression was shown to be statistically significantly associated with EMVI, DFS, and OS, and was also independently predictive of EMVI, raising the possibility that it could act as a diagnostic and predictive biomarker in rectal cancers. These findings indicate a mechanistic association between hypermethylation and EMVI, mediated by methylation-dependent expression of metalloproteinases. Metalloproteinase expression, specifically MMP2, may act as a potential biomarker for EMVI and correlates to survival outcomes in rectal cancer.

show abstract

Complete metabolic response of metastatic castration‐resistant neuroendocrine carcinoma of the prostate after treatment with RRx‐001 and reintroduced platinum doublets

Cited by 2 publications

References 17 publications

Untitled

Untitled

A Mechanistic Investigation of the Relationship Between Extramural Vascular Invasion (EMVI) and CpG Island Methylator Phenotype (CIMP) in Rectal Cancer

Contact Info

Product

Resources

About