Besides various side effects caused by platinum anticancer drugs, they are not efficiently absorbed by the tumor cells. Two Pt-peptide conjugates; cyclic mPeg-CNGRC-Pt (7) and cyclic mPeg-CNGRC-Pten (8) bearing the Asn-Gly-Arg (NGR) targeting sequence, a malonoyl linker and low molecular weight miniPEG groups have been synthesized. The platinum ligand was attached to the peptide via the carboxylic end of the malonate group at the end of the peptide. The pegylated peptide is non toxic and highly soluble in water. Platinum conjugates synthesized using the pegylated peptides are also water soluble with reduced or eliminated peptide immunogenicity. The choice of carboplatin as our untargeted platinum complex was due to the fact that malonate linker chelates platinum in a manner similar to carboplatin. Cell toxicity assay and competition assay on the PC-3 cells (CD13 positive receptors) revealed selective delivery and destruction of PC-3 cells using targeted Pt-peptide conjugates 7 and 8 significantly more than untargeted carboplatin. Platinum uptake on PC-3 cells was 12-fold more for conjugate 7 and 3-fold more for conjugate 8 compared to the untargeted carboplatin indicating selectively activation of the CD13 receptors and delivery of the conjugates to CD13 positive cells. Further analysis on effects of conjugates 7 and 8 on PC-3 cells using caspase-3/7, fluorescence microscopy and DNA fragmentation confirmed that the cells were dying by apoptosis.
Pancreatic ductal adenocarcinomas are invariably lethal, and developing effective treatments that have minimal side effects is a challenge. Previous studies from our laboratory have shown that conjugates of cell membrane disrupting lytic peptides and luteinizing hormone releasing hormone (LHRH) target and destroy human prostate and breast cancer cells in xenografts in the nude mouse model (Hansel et al., Mol Cell Endocrinol 2007;260-262:183-9; Hansel et al., Mol Cell Endocrinol 2007;269:26-33), which express LHRH receptors. The objectives of our study were to synthesize a bioconjugate of LHRH analog ([DLys 6 ]-LHRH) and a dietary microchemical (curcumin) and test the hypothesis that [DLys 6 ]-LHRH-curcumin targets and inhibits pancreatic cancer cell growth in vitro and in vivo. In in vitro studies, we determined by confocal microscopy, flow cytometry analysis and reverse transcriptase-polymerase chain reaction that MIAPaCa-2, Panc-1 and BxPC-3 pancreatic cancer cell lines express LHRH receptors. [DLys 6 ]-LHRH-curcumin inhibited cell proliferation of pancreatic cancer cell lines and induced apoptotic cell death (p < 0.05). Apoptosis was induced by cleavage of polyadenosine-5 0 -diphosphate-ribose-polymerase and caspase-3. The activity of [DLys 6 ]-LHRH-curcumin was equal to free curcumin at equimolar concentrations in vitro. Unlike curcumin itself, the [DLys 6 ]-LHRH-curcumin conjugate is water soluble which allows its intravenous administration. In two in vivo studies, [DLys 6 ]-LHRH-curcumin given intravenously caused a significant (p < 0.01) reduction in tumor weights and volumes, and free curcumin given by gavage at an equal dose failed to cause a significant reduction in tumor weights and volumes in the nude mouse pancreatic cancer model. [DLys 6 ]-LHRH-curcumin treatment enhanced apoptosis compared to [DLys 6 ]-LHRH and vehicle-treated controls in tumor tissue. In conclusion, [DLys 6 ]-LHRH-curcumin may be useful in treating pancreatic cancer.Pancreatic cancer is a highly lethal disease with extremely poor prognosis. It has been estimated that 42,470 new cases and 35,240 deaths in United States were due to pancreatic cancer in 2009. 1 The 5-year relative survival rate for all stages is approximately 4%. Current treatments, such as radiation, surgery, chemotherapy or a combination of these modalities have had little impact on survival rate in pancreatic cancer patients. One of the major problems in cancer chemotherapy is the severe toxic side effects of anticancer drugs designed to destroy rapidly dividing cells, including those found in healthy tissues. These severe side effects often result in dose reduction, treatment delay or discontinuance of therapy. To overcome these limitations, various systems have been developed to deliver anticancer drugs used in chemotherapy to increase solubility, decrease adverse side effects and limit nonspecific activity. 2,3 Targeted anticancer drug delivery systems are an advanced approach for delivering the anticancer drugs. Cancer cell targeting can be achieved by...
The low incidence of prostate cancer in Asians has been attributed to chemopreventative properties of certain chemicals found in their diet. This study characterized the androgenic and chemopreventative properties of the Jamaican bush tea “Bizzy,” using androgen receptor positive and negative cell lines. Exposure of prostate cells to Biz-2 resulted in a growth inhibition (GI50) of 15 ppm in LNCaP cells and 3.6 ppm in DU145 cells. Biz-2 elicited a 2-fold increase in the mRNA of the anti-apoptotic gene Bcl2, with a 10-fold increase in that of the proapoptotic gene Bax. We observed a 2.4- to 7.5-fold change in apoptotic cells in both cell lines. Biz-2 at 10 ppm elicited a time- and dose-dependent stimulation of both the protein and mRNA levels of several androgen-regulated genes. Biz-2 caused a 36% decrease in PSA secretion and a significant increase in PSA mRNA. The relative binding affinity (IC50) of Biz-2 for AR was 2- to 5-fold lower than that of the synthetic androgen R1881. Biz-2 was found to be a specific ligand for the AR in that the natural ligand, DHT, and the anti-androgen, flutamide, displaced Biz-2 bound to AR and inhibited Biz-2-induced transcription and PSA secretion. This study provided evidence that Biz-2 extract possesses the ability to modulate prostate cancer cell biology in an AR-dependent manner.
The expression of luteinizing hormone releasing hormone (LHRH) receptors by pancreatic cancer cells has been clearly established. We observed that pancreatic cancer cell lines contain different numbers of LHRH receptors (BxPC3>MIAPaCa-2>PANC-1) using relative quantitation of RNA by real time PCR. In an in vitro study, we found that treatment of PANC-1 cells in culture with small amounts (10 or 30 ng/ml) of follicle stimulating hormone (FSH) caused a 3-fold increase in LHRH receptor gene expression. Therefore, we hypothesized that pre-treatment of nude mice bearing PANC-1 tumor xenografts with FSH will increase the number of LHRH receptors which will enhance the ability of the EP-100 (LHRH conjugated lytic peptide) to target and destroy PANC-1 pancreatic cancer cells. Our main objective was to determine in vitro and in vivo if FSH enhances the efficacy of EP-100 in targeting and destroying PANC-1 cells. PANC-1 cells (5000/well) were pretreated with FSH (10 and 30 ng/mL) for 24 h followed by EP-100 (4 and 6 µM) for 24 h in a medium containing 0.2% Dextran charcoal treated serum. MTT cell viability assay results showed that pre-treatment of PANC-1 cells with FSH significantly (P<0.001) enhanced the cytotoxicity of EP-100. PANC-1 tumor xenograft bearing Athymic Balb/C nude mice (n=11) were treated with EP-100 (0.2 and 0.02 mg/kg), iv, once a week for three weeks with or without FSH pre-treatment, sc, (3 mg/kg for three days prior to administering the conjugate). The treatment groups included were baseline (sacrificed at the beginning of treatment), vehicle, FSH alone, EP-100 (0.02 mg/kg) alone, EP-100 (0.02mg/kg) with FSH, EP-100 (0.2 mg/kg) alone, EP-100 (0.2 mg/kg) with FSH. FSH pre-treatment significantly enhanced the ability of EP-100 (0.02 mg/kg – P<0.05 and 0.2 mg/kg – P<0.001 compared to baseline) to regress the growth of PANC-1 tumor xenografts in vivo. Histopathological evaluation revealed an increase in tumor necrosis in FSH pre-treated mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3522. doi:10.1158/1538-7445.AM2011-3522
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