title: Bisphosphonamidate clodronate prodrug exhibits selective cytotoxic activity against melanoma cell lines.
abstract: Bisphosphonates are used clinically to treat disorders of calcium metabolism and malignant bone disease and are known to inhibit cancer cell growth, adhesion, and invasion. However, clinical use of these agents for the treatment of extraskeletal disease is limited because of low cell permeability. We recently described a bisphosphonamidate prodrug strategy for efficient intracellular release of bisphosphonates, including clodronate (CLO), in non-small cell lung cancer cells. To evaluate anticancer activity of this prodrug class across many cancer cell types, the bisphosphonamidate clodronate prodrug (CLO prodrug) was screened against the NCI-60 cell line panel, and was found to exhibit selectivity toward melanoma cell lines. Here, we confirm efficient cellular uptake and intracellular activation of this prodrug class in melanoma cells. We further demonstrate inhibition of melanoma cell proliferation, induction of apoptosis, and an antitumor effect of CLO prodrug in a xenograft model. These data suggest a novel therapeutic application for the CLO prodrug and potential to selectively target melanoma cells.
authors: Corresponding Authors: Caren L. Freel Meyers, WBSB 307B, 725 N. Wolfe St., Baltimore, MD 21205. cmeyers@jhmi.edu.
authors: Marie R
authors: MR
authors: Webster
authors: Chandrashekhar
authors: C
authors: Kamat
authors: Nick
authors: N
authors: Connis
authors: Ming
authors: M
authors: Zhao
authors: Ashani T
authors: AT
authors: Weeraratna
authors: Michelle A
authors: MA
authors: Rudek
authors: Christine L
authors: CL
authors: Hann
authors: Caren L
authors: CL
authors: Freel Meyers
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004002:Clodronic Acid / Q000494:pharmacology*; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008819:Mice, Nude; D011355:Prodrugs / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004164:Diphosphonates; D011355:Prodrugs; D004002:Clodronic Acid