Transcriptomics,Genomics

Dataset Information

42

Enhancement by Aneustat (OMN54) of docetaxel anticancer activity in a patient-derived prostate cancer tissue xenograft model


ABSTRACT: Purpose: To determine whether docetaxel therapy of advanced prostate cancer can be improved by using docetaxel in combination with Aneustat (OMN54), a multivalent botanical drug candidate undergoing a Phase-I Clinical Trial, and to identify the molecular action of this drug combination. Experimental Design: Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, either alone or in combination. Culture growth (at 48 hours) and xenograft size (at 3 weeks) were determined and animal health monitored. Xenografts were gene expression profiled using gene expression microarrays. Androgen receptor (AR) expression and AKT phosphorylation were examined. Results: Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner in vitro, reducing AR expression and AKT phosphorylation. Aneustat was not as effective as docetaxel in inhibiting LTL-313H xenograft growth. When combined, Aneustat and docetaxel markedly and synergistically enhanced anti-tumor activity without inducing major host toxicity, even leading to complete growth inhibition and tumor shrinkage not obtained with the single drugs. AR expression and AKT signalling in the xenografts were inhibited by docetaxel+Aneustat, but not by the single agents. Expression microarray analysis indicated that docetaxel+Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the drugs on their own. Conclusion: Our findings, obtained with a clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat. Overall design: NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, either alone or in combination. Eight xenograft samples, comprising two untreated controls, two treated with OMN54 alone, two treated with Docetaxel alone, and two treated with OMN54 + Docetaxel in combination, were gene expression profiled using microarrays.

REANALYSED by: GSE113533

INSTRUMENT(S): Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Probe Name version)

SUBMITTER: Shawn Anderson  

PROVIDER: GSE48667 | GEO | 2014-10-23

SECONDARY ACCESSION(S): PRJNA210977

REPOSITORIES: GEO

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