title: Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor.
abstract: A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compound's efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch-migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt-Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin.
authors.affiliation: Department of Biology, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Calderon
authors.affiliation: Department of Chemistry, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Keeling
authors.affiliation: Department of Biology, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rollins
authors.affiliation: Department of Chemistry, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Black
authors.affiliation: Department of Biology, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Kendall
authors.initials: K
authors.lastname: Collins
authors.affiliation: Department of Biology, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Nova
authors.initials: N
authors.lastname: Arnold
authors.affiliation: Department of Chemistry, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Vance
authors.affiliation: Department of Chemistry, Eastern Kentucky University , Richmond, Kentucky 40475, United States.
authors.forename: Margaret W
authors.identifier: http://orcid.org/0000-0002-1773-9368
authors.initials: MW
authors.lastname: Ndinguri
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D011966:Receptors, LHRH / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D002945:Cisplatin