Bisphosphonamidate clodronate prodrug exhibits selective cytotoxic activity against melanoma cell lines

Marie R. Webster, Chandrashekhar Kamat, Nick Connis, Ming Zhao, Ashani T. Weeraratna, Michelle A. Rudek, Christine L. Hann, Caren L.Freel Meyers

Research output: Contribution to journalArticlepeer-review

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. Mol Cancer Ther; 13(2); 297-306.

Original languageEnglish (US)
Pages (from-to)297-306
Number of pages10
JournalMolecular cancer therapeutics
Volume13
Issue number2
DOIs
StatePublished - Feb 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Bisphosphonamidate clodronate prodrug exhibits selective cytotoxic activity against melanoma cell lines'. Together they form a unique fingerprint.

Cite this