Project description:Bufalin is a major cardiotonic compound in the traditional Chinese medicine Chanshu preparations of toad skin secretions. Cell culture studies have suggested anti-cancer potential involving multiple cellular processes including differentiation, apoptosis, senescence and angiogenesis. In prostate cancer (PCa) cell models, P53-dependent and independent caspase-mediated apoptosis and androgen receptor (AR) antagonism have been described for bufalin at micromolar concentrations. Since pharmacokinetic study in humans indicated single nanomolar bufalin was safely achievable in the peripheral circulation, we evaluated its cellular activity within range with the AR-positive, P53-wild type and PTEN-negative human LNCaP PCa cells in vitro. Our data show that bufalin induced caspase-mediated apoptosis at 10 nanomolar or higher exposure concentration with concomitant suppression of AR protein and its best known target prostate specific antigen (PSA) and steroid receptor co-activator 1 and 3 (SRC-1, SRC-3). Bufalin exposure induced protein abundance of P53 (not mRNA) and P21Cip1, G2 arrest and increased senescence-like phenotype (SA-galactosidase). Small interference RNA knocking down of P53 attenuated bufalin-induced senescence, whereas knocking down of P21Cip1 exacerbated bufalin-induced caspase-mediated apoptosis. In vivo, daily i.p. injection of bufalin (1.5 mg/kg body weight) for 9 weeks delayed LNCaP subcutaneous xenograft tumor growth in NSG SCID mice with a 67% decrease of final weight without affecting body weight. Tumors from bufalin-treated mice exhibited increased phospho-P53 and SA-galactosidase without detectable caspase-mediated apoptosis or suppression of AR and PSA. Our data suggest potential applications of bufalin in adjuvant therapy of PCa recurrence in patients or chemoprevention of prostate carcinogenesis, engaging a selective activation of P53-senescence.
Project description:The p160 Steroid Receptor Coactivators SRC-1, SRC-2, and SRC-3 are critical components of the AR transcriptional complex and are frequently upregulated in prostate cancer (PC). We showed that inhibition of the SRCs via a small molecule inhibitor significantly diminishes AR signaling output, expression of CRPC-associated transcripts and proliferation of CRPC cells both in vitro and in vivo.
Project description:The p160 Steroid Receptor Coactivators SRC-1, SRC-2, and SRC-3 are critical components of the AR transcriptional complex and are frequently upregulated in prostate cancer (PC). We showed that inhibition of the SRCs via a small molecule inhibitor significantly diminishes AR signaling output, expression of CRPC-associated transcripts and proliferation of CRPC cells both in vitro and in vivo.
Project description:Bufalin, a natural toxin isolated from the Chinese toad venom preparation Chan ’su, has been used in leukemia therapy in the mainland China by inducing human leukemia cells to differentiation and apoptosis. In the present study, oligonucleotide microarrays were used to assess profiles of target gene regulation at several points at a 48h period by bufalin at an appropriate concentration in the human promyelocytic leukemia cell line HL60. Data from the gene expression profiles indicated that bufalin altered the expression of 1206 genes which are distributed in multiple profiles of regulation. Results are consistent with bufalin regulating HL60 cells proliferation and differentiation as well as apoptosis. Keywords: time course
Project description:SChLAP1 is a novel long non-coding RNA expressed in prostate cancer. Here we performed transcriptional profiling of the prostate cancer cell lines LNCaP and 22Rv1 comparing non-targeting siRNA treatment versus SChLAP1-siRNA treatment. Goal was to determine the effect of SChLAP1 knockdown on gene expression in prostate cancer. Two-condition experiment: non-targeting siRNA versus SChLAP1 siRNA treated cells. Biological replicates: 1 control replicate, 2 treatment replicates. Technical replicates: 3 replicates per SChLAP1 siRNA. Cell lines: 22Rv1 and LNCaP.