The high affinity of highly charged polynuclear platinum complexes for glycans such as heparan su... more The high affinity of highly charged polynuclear platinum complexes for glycans such as heparan sulfate results in modulation of the biomolecule signaling functions leading to inhibition of angiogenesis.
Over half of all cancer patients will receive a platinum drug during their treatment. Recent inte... more Over half of all cancer patients will receive a platinum drug during their treatment. Recent interest in our labs involve exploiting the high affinity of a discrete class of platinum-based anticancer agents, polynuclear platinum complexes (PPCs), for sulfated glycosaminoglycans (sGAGs). sGAGs are increasingly seen as potential biomarkers and molecular targets in many forms of cancer. sGAG expression levels were quantified in patient derived xenograft (PDX) and cellular models of triple negative breast cancer (TNBC) and ovarian cancer. PPCs, but not carboplatin, show increased levels of tumor uptake and efficacy in models expressing high levels of sGAGs. sGAGs may provide a viable target for PPCs, producing a significant advantage over clinical platinum agents in this setting. Citation Format: Jennifer E Koblinski, Erica J Peterson, James D. Hampton, J Chuck Harrell, Nicholas P Farrell. Toward precision medicine for platinums [abstract]. In: Proceedings of the AACR-NCI-EORTC Internat...
Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG... more Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG island methylation has been implicated in tumor suppressor gene silencing. Here we demonstrate a mechanistic link between the p53 tumor suppressor gene and control of epigenetic regulation by genomic methylation. Deletion of p53in HCT116 human colon carcinoma cells and primary mouse astrocytes resulted in a 6-fold increase of DNA cytosine methyltransferase 1 (Dnmt1) mRNA and protein, suggesting relief of p53-mediated Dnmt1repression. A p53 consensus binding site in exon 1 of the human Dnmt1gene bound recombinant p53 in vitro and endogenous p53 in vivo in the absence of stimuli that activate p53, implying that p53 controls Dnmt1transcription through direct DNA binding. Interestingly, ionizing radiation or etoposide, both of which stabilize and activate p53, diminished p53 binding in chromatin immunoprecipitation assays, concomitant with a 5-fold increase in Dnmt1 levels. Our findings sug...
Triple negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers.... more Triple negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive, and when metastatic is often drug resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for TNBC patients. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models to the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor...
The leaving group L in [(R3P)AuL]n+ regulates the cytotoxic mechanism against CEM leukemia cells ... more The leaving group L in [(R3P)AuL]n+ regulates the cytotoxic mechanism against CEM leukemia cells and the reactivity towards Sp1 ZnF3.
Ru(ii)/lapachol complex shows significant selectivity for triple negative breast cancer (TNBC) co... more Ru(ii)/lapachol complex shows significant selectivity for triple negative breast cancer (TNBC) compared to the non-tumor human breast epithelial cell line.
Investigations are reported on the biological activity of an oxindolimine-oxidovanadium(IV) compl... more Investigations are reported on the biological activity of an oxindolimine-oxidovanadium(IV) complex, compared to that of analogous copper(II) or zinc(II) compounds with significant antiproliferative action against different tumor cells. This vanadyl...
Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate... more Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate molecules that bind to a wide variety of proteins and exercise important physiological and pathological processes. This chapter focuses on the concept of metalloglycomics and reviews the structure and conformation of GAGs and the role of various metal ions during the interaction of GAGs with their biological partners such as proteins and enzymes. The use of metal complexes in heparin analysis is discussed. Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumor-related events including angiogenesis, cell invasion, metastasis, and inflammation. HS is identified as a ligand receptor for polynuclear platinum complexes (PPCs) defining a new mechanism of cellular accumulation for platinum drugs with implications for tumor selectivity. The covalent and noncovalent interaction of PPCs with GAGs and the functional consequences of strong binding with HS are exp...
Chemical communications (Cambridge, England), Dec 20, 2016
The HIV nucleocapsid NCp7-SL2 RNA interaction is interrupted in the presence of a formally substi... more The HIV nucleocapsid NCp7-SL2 RNA interaction is interrupted in the presence of a formally substitution-inert gold(dien)-nucleobase/N-heterocycle AuN4 compound where the N-heterocycle serves the dual purposes of a template for "non-covalent" molecular recognition of the essential tryptophan of the protein, mimicking the natural reaction and subsequent "fixation" by Au-Cys bond formation providing a chemotype for a new distinct class of nucleocapsid-nucleic acid antagonist.
The high affinity of highly charged polynuclear platinum complexes for glycans such as heparan su... more The high affinity of highly charged polynuclear platinum complexes for glycans such as heparan sulfate results in modulation of the biomolecule signaling functions leading to inhibition of angiogenesis.
Over half of all cancer patients will receive a platinum drug during their treatment. Recent inte... more Over half of all cancer patients will receive a platinum drug during their treatment. Recent interest in our labs involve exploiting the high affinity of a discrete class of platinum-based anticancer agents, polynuclear platinum complexes (PPCs), for sulfated glycosaminoglycans (sGAGs). sGAGs are increasingly seen as potential biomarkers and molecular targets in many forms of cancer. sGAG expression levels were quantified in patient derived xenograft (PDX) and cellular models of triple negative breast cancer (TNBC) and ovarian cancer. PPCs, but not carboplatin, show increased levels of tumor uptake and efficacy in models expressing high levels of sGAGs. sGAGs may provide a viable target for PPCs, producing a significant advantage over clinical platinum agents in this setting. Citation Format: Jennifer E Koblinski, Erica J Peterson, James D. Hampton, J Chuck Harrell, Nicholas P Farrell. Toward precision medicine for platinums [abstract]. In: Proceedings of the AACR-NCI-EORTC Internat...
Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG... more Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG island methylation has been implicated in tumor suppressor gene silencing. Here we demonstrate a mechanistic link between the p53 tumor suppressor gene and control of epigenetic regulation by genomic methylation. Deletion of p53in HCT116 human colon carcinoma cells and primary mouse astrocytes resulted in a 6-fold increase of DNA cytosine methyltransferase 1 (Dnmt1) mRNA and protein, suggesting relief of p53-mediated Dnmt1repression. A p53 consensus binding site in exon 1 of the human Dnmt1gene bound recombinant p53 in vitro and endogenous p53 in vivo in the absence of stimuli that activate p53, implying that p53 controls Dnmt1transcription through direct DNA binding. Interestingly, ionizing radiation or etoposide, both of which stabilize and activate p53, diminished p53 binding in chromatin immunoprecipitation assays, concomitant with a 5-fold increase in Dnmt1 levels. Our findings sug...
Triple negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers.... more Triple negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive, and when metastatic is often drug resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for TNBC patients. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models to the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor...
The leaving group L in [(R3P)AuL]n+ regulates the cytotoxic mechanism against CEM leukemia cells ... more The leaving group L in [(R3P)AuL]n+ regulates the cytotoxic mechanism against CEM leukemia cells and the reactivity towards Sp1 ZnF3.
Ru(ii)/lapachol complex shows significant selectivity for triple negative breast cancer (TNBC) co... more Ru(ii)/lapachol complex shows significant selectivity for triple negative breast cancer (TNBC) compared to the non-tumor human breast epithelial cell line.
Investigations are reported on the biological activity of an oxindolimine-oxidovanadium(IV) compl... more Investigations are reported on the biological activity of an oxindolimine-oxidovanadium(IV) complex, compared to that of analogous copper(II) or zinc(II) compounds with significant antiproliferative action against different tumor cells. This vanadyl...
Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate... more Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate molecules that bind to a wide variety of proteins and exercise important physiological and pathological processes. This chapter focuses on the concept of metalloglycomics and reviews the structure and conformation of GAGs and the role of various metal ions during the interaction of GAGs with their biological partners such as proteins and enzymes. The use of metal complexes in heparin analysis is discussed. Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumor-related events including angiogenesis, cell invasion, metastasis, and inflammation. HS is identified as a ligand receptor for polynuclear platinum complexes (PPCs) defining a new mechanism of cellular accumulation for platinum drugs with implications for tumor selectivity. The covalent and noncovalent interaction of PPCs with GAGs and the functional consequences of strong binding with HS are exp...
Chemical communications (Cambridge, England), Dec 20, 2016
The HIV nucleocapsid NCp7-SL2 RNA interaction is interrupted in the presence of a formally substi... more The HIV nucleocapsid NCp7-SL2 RNA interaction is interrupted in the presence of a formally substitution-inert gold(dien)-nucleobase/N-heterocycle AuN4 compound where the N-heterocycle serves the dual purposes of a template for "non-covalent" molecular recognition of the essential tryptophan of the protein, mimicking the natural reaction and subsequent "fixation" by Au-Cys bond formation providing a chemotype for a new distinct class of nucleocapsid-nucleic acid antagonist.
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Papers by Erica J Peterson