Abstract
Repetitive, low-dose (metronomic; METRO) drug administration of some anticancer agents can overcome drug resistance and increase drug efficacy in many cancers, but the mechanisms are not understood fully. Previously, we showed that METRO dosing of topotecan (TOPO) is more effective than conventional (CONV) dosing in aggressive human prostate cancer (PCa) cell lines and in mouse tumor xenograft models. To gain mechanistic insights into METRO-TOPO activity, in this study we determined the effect of METRO- and CONV-TOPO treatment in a panel of human PCa cell lines representing castration-sensitive/resistant, androgen receptor (+/−), and those of different ethnicity on cell growth and gene expression. Differentially expressed genes (DEGs) were identified for METRO-TOPO therapy and compared to a PCa patient cohort and The Cancer Genome Atlas (TCGA) database. The top five DEGs were SERPINB5, CDKN1A, TNF, FOS, and ANGPT1. Ingenuity Pathway Analysis predicted several upstream regulators and identified top molecular networks associated with METRO dosing, including tumor suppression, anti-proliferation, angiogenesis, invasion, metastasis, and inflammation. Further, the top DEGs were associated with increase survival of PCa patients (TCGA database), as well as ethnic differences in gene expression patterns in patients and cell lines representing African Americans (AA) and European Americans (EA). Thus, we have identified candidate pharmacogenomic biomarkers and novel pathways associated with METRO-TOPO therapy that will serve as a foundation for further investigation and validation of METRO-TOPO as a novel treatment option for prostate cancers.
Highlights
Prostate cancer (PCa) is the second leading cause of noncutaneous cancer related deaths in men in the United States
The effect of TOPO administration as CONV and METRO on prostate cancer cells were assessed by measurement of mitochondrial enzyme activity (MTT) (Figures 1A,B) and SRB (Supplementary Figure S1A) absorbance after 48 h and 72 h treatments
METRO exposure to TOPO in metastatic, androgen-insensitive, neuroendocrine prostate cancer (NEPC) (EA: PC-3M, DU145 and DUTXR) and metastatic, androgen-sensitive (EA: C4-2B, 22RV1and AA: MDA-Pca-2b) cells resulted in significant (p ≤ 0.05) time-dependent decreases in the IC50 value, which reflects increased sensitivity after 48 and 72 h compared to CONV treatment (Table 1)
Summary
Prostate cancer (PCa) is the second leading cause of noncutaneous cancer related deaths in men in the United States (www.cancer.org). PCa in individuals with precancerous, indolent, or slow growing malignant disease can evolve over many years. For those with advancing localized disease the standard treatment includes radical prostatectomy and radiation therapy with or without hormonal manipulation (Magnan et al, 2015; Hamdy et al, 2016). The use of enzalutamide, a 2nd generation antiandrogen therapy, in men with castration-resistant prostate cancer after chemotherapy showed clinical activity, PSA levels increased in majority patients whose disease had progressed again (Scher et al, 2012). Cabazitaxel, AA/ P, enzalutamide, and radium-223 are available for second-line treatment of CRPC following docetaxel (Heidenreich et al, 2014; Cornford et al, 2017) and increases median overall survival (OS) by less than a year (De Bono et al, 2010; Oudard et al, 2017; van den Bergh et al, 2016)
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