Low Doses of CPS49 and Flavopiridol Combination as Potential Treatment for Advanced Prostate Cancer.

Due to some inconsistencies in the figures provided by the first author that have come to light, and after a thorough investigation we would like to retract our paper: "Low doses of CPS49 and flavopiridol combination as potential treatment for advanced prostate cancer. By: Zalazar F, De Luca P, Gardner K, Figg WD, Meiss R, Spallanzani RG, Vallecorsa P, Elguero B, Cotignola J, Vazquez E, De Siervi A. Curr. Pharm. Biotechnol., 2015, 16(6), 553-63. Submission of a manuscript to the respective journals implies that all authors have read and agreed to the content of the Copyright Letter or the Terms and Conditions. As such this article represents a severe abuse of the scientific publishing system. Bentham Science Publishers takes a very strong view on this matter and apologizes to the readers of the journal for any inconvenience this may cause.

CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs.

Metabolic syndrome (MeS) has been identified as a risk factor for breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. High fat diet (HFD) increases intracellular NADH. We investigated the effect of CtBP1 hyperactivation by HFD intake on mouse breast carcinogenesis. We generated a MeS-like disease in female mice by chronically feeding animals with HFD. MeS increased postnatal mammary gland development and generated prominent duct patterns with markedly increased CtBP1 and Cyclin D1 expression. CtBP1 induced breast cancer cells proliferation. Serum from animals with MeS enriched the stem-like/progenitor cell population from breast cancer cells. CtBP1 increased breast tumor growth in MeS mice modulating multiple genes and miRNA expression implicated in cell proliferation, progenitor cells phenotype, epithelial to mesenchymal transition, mammary development and cell communication in the xenografts. These results define a novel function for CtBP1 in breast carcinogenesis.

Association of HO-1 and BRCA1 Is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer.

UNLABELLED: Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to cancer development. The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) is responsible for the maintenance of the cellular homeostasis, playing a critical role in the oxidative stress and the regulation of prostate cancer development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in prostate cancer. Interestingly, the tumor suppressor BRCA1 binds to the HO-1 promoter and modulates HO-1, inducing its protein levels through both the increment of its promoter activity and the induction of its transcriptional activation. In addition, in vitro and in vivo analyses show that BRCA1 also controls HO-1-negative targets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulation is also modulated by oxidative and genotoxic agents. Induction of DNA damage by mitoxantrone and etoposide repressed HO-1 transcription, whereas hydrogen peroxide and doxorubicin induced its expression. Xenograft studies showed that HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescence analysis revealed that BRCA1 overexpression and/or doxorubicin exposure induced the cytoplasmic retention of HO-1. Finally, the transcription factor NRF2 cooperates with BRCA1 protein to activate HO-1 promoter activity. In summary, these results show that the activation of BRCA1-NRF2/HO-1 axis defines a new mechanism for the maintenance of the cellular homeostasis in prostate cancer. IMPLICATIONS: Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2.

Low doses of CPS49 and flavopiridol combination as potential treatment for advanced prostate cancer.

Prostate cancer (PCa) still ranks as the second most frequently diagnosed cancer and metastatic castration resistant prostate cancer (CRPC) is a foremost cause of men cancer death around the world. The aim of this work was to investigate the selectivity and efficacy of new drug combinations for CRPC. We combined three compounds: paclitaxel (PTX: taxane that inhibits microtubule polymerization); 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole- 1,3(2H)-dione (CPS49; redox-reactive thalidomide analog with anti-angiogenic properties) and flavopiridol (flavo: semisynthetic flavonoid that inhibits cyclin dependent kinases). We assessed CPS49-flavo or -PTX combinations cytotoxicity in a panel of PCa cell lines and PC3 xenografts. We found that CPS49 enhanced flavo or PTX cytotoxicity in human PCa cell lines while showed resistance in a non-tumor cell line. Furthermore, xenografts generated by inoculation of human prostate carcinoma PC3 cells in nu/nu mice showed that CPS49/flavo administration reduced tumor growth both after 2 weeks of co-treatment and after 1 week of pretreatment with a low dose of flavo followed by 2 weeks of co-treatment. PTX and CPS49 combination did not significantly reduce tumor growth in PC3 xenografts. Histological analysis of xenograft PC3 tumor samples from CPS49/flavo combination showed extensive areas of necrosis induced by the treatment. RT-qPCR array containing 23 genes from PC3 cells or PC3 xenografts exposed to CPS49/flavo combination showed that this treatment shut down the expression of several genes involved in adhesion, migration or invasion. In summary, the antitumor activity of CPS49 or flavopiridol was improved by the combination of these compounds and using half dose of that previously reported. Hence, CPS49-flavo combination is a promising new alternative for PCa therapy.

Prostate tumor growth is impaired by CtBP1 depletion in high-fat diet-fed mice.

PURPOSE: Clinical and epidemiologic data suggest that obesity is associated with more aggressive forms of prostate cancer, poor prognosis, and increased mortality. C-terminal-binding protein 1 (CtBP1) is a transcription repressor of tumor suppressor genes and is activated by NADH binding. High calorie intake decreases intracellular NAD(+)/NADH ratio. The aim of this work was to assess the effect of high-fat diet (HFD) and CtBP1 expression modulation over prostate xenograft growth. EXPERIMENTAL DESIGN: We developed a metabolic syndrome-like disease in vivo model by feeding male nude mice with HFD during 16 weeks. Control diet (CD)-fed animals were maintained at the same conditions. Mice were inoculated with PC3 cells stable transfected with shCtBP1 or control plasmids. Genome-wide expression profiles and Gene Set Enrichment Analysis (GSEA) were performed from PC3.shCtBP1 versus PC3.pGIPZ HFD-fed mice tumors. RESULTS: No significant differences were observed in tumor growth on CD-fed mice; however, we found that only 60% of HFD-fed mice inoculated with CtBP1-depleted cells developed a tumor. Moreover these tumors were significantly smaller than those generated by PC3.pGIPZ control xenografts. We found 823 genes differentially expressed in shCtBP1 tumors from HFD-fed mice. GSEA from expression dataset showed that most of these genes correspond to cell adhesion, metabolic process, and cell cycle. CONCLUSIONS: Metabolic syndrome-like diseases and CtBP1 expression cooperate to induce prostate tumor growth. Hence, targeting of CtBP1 expression might be considered for prostate cancer management and therapy in the subset of patients with metabolic syndromes.

Unveiling the association of STAT3 and HO-1 in prostate cancer: role beyond heme degradation.

Activation of the androgen receptor (AR) is a key step in the development of prostate cancer (PCa). Several mechanisms have been identified in AR activation, among them signal transducer and activator of transcription 3 (STAT3) signaling. Disruption of STAT3 activity has been associated to cancer progression. Recent studies suggest that heme oxygenase 1 (HO-1) may play a key role in PCa that may be independent of its catalytic function. We sought to explore whether HO-1 operates on AR transcriptional activity through the STAT3 axis. Our results display that HO-1 induction in PCa cells represses AR activation by decreasing the prostate-specific antigen (PSA) promoter activity and mRNA levels. Strikingly, this is the first report to show by chromatin immunoprecipitation analysis that HO-1 associates to gene promoters, revealing a novel function for HO-1 in the nucleus. Furthermore, HO-1 and STAT3 directly interact as determined by co-immunoprecipitation studies. Forced expression of HO-1 increases STAT3 cytoplasmic retention. When PCa cells were transfected with a constitutively active STAT3 mutant, PSA and STAT3 downstream target genes were abrogated under hemin treatment. Additionally, a significant decrease in pSTAT3 protein levels was detected in the nuclear fraction of these cells. Confocal microscopy images exhibit a decreased rate of AR/STAT3 nuclear co-localization under hemin treatment. In vivo studies confirmed that STAT3 nuclear delimitation was significantly decreased in PC3 tumors overexpressing HO-1 grown as xenografts in nude mice. These results provide a novel function for HO-1 down-modulating AR transcriptional activity in PCa, interfering with STAT3 signaling, evidencing its role beyond heme degradation.

BRCA1 loss induces GADD153-mediated doxorubicin resistance in prostate cancer.

BRCA1 plays numerous roles in the regulation of genome integrity and chemoresistance. Although BRCA1 interaction with key proteins involved in DNA repair is well known, its role as a coregulator in the transcriptional response to DNA damage remains poorly understood. In this study, we show that BRCA1 plays a central role in the transcriptional response to genotoxic stress in prostate cancer. BRCA1 expression mediates apoptosis, cell-cycle arrest, and decreased viability in response to doxorubicin treatment. Xenograft studies using human prostate carcinoma PC3 cells show that BRCA1 depletion results in increased tumor growth. A focused survey of BRCA1-regulated genes in prostate carcinoma reveals that multiple regulators of genome stability and cell-cycle control, including BLM, FEN1, DDB2, H3F3B, BRCA2, CCNB2, MAD2L1, and GADD153, are direct transcriptional targets of BRCA1. Furthermore, we show that BRCA1 targets GADD153 promoter to increase its transcription in response to DNA damage. Finally, GADD153 depletion significantly abrogates BRCA1 influence on cell-cycle progression and cell death in response to doxorubicin treatment. These findings define a novel transcriptional pathway through which BRCA1 orchestrates cell fate decisions in response to genotoxic insults, and suggest that BRCA1 status should be considered for new chemotherapeutic treatment strategies in prostate cancer.