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Rich66 · 05-24-2009, 10:18 PM

Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation

Supporting Info

Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, Center for Biophysics and Computational Biology, University of Illinois at Urbana−Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan, Department of Biology, Brookhaven National Laboratory, Upton, New York 11973, Department of Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands, and Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
J. Am. Chem. Soc., 2009, 131 (14), pp 5153–5162
DOI: 10.1021/ja808285e
Publication Date (Web): March 23, 2009
Copyright © 2009 American Chemical Society
† Department of Chemistry, University of Illinois at Urbana−Champaign.

, ‡ Center for Biophysics and Computational Biology, University of Illinois at Urbana−Champaign.

, § Institute of Biological Chemistry, Academia Sinica.

,

Department of Biology, Brookhaven National Laboratory.

,

Department of Endocrinology, and Metabolic Diseases, Leiden University Medical Center.

, # Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University.

, eo@chad.scs.uiuc.edu

Abstract

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links

Br J Cancer. 2007 May 21;96(10):1526-31. Epub 2007 Apr 17.
Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer.

FULL TEXT (free)

Duivenvoorden WC, Vukmirović-Popović S, Kalina M, Seidlitz E, Singh G.
Juravinski Cancer Centre, Hamilton, Ontario, Canada L8V 5C2.
Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.

PMID: 17437017 [PubMed - indexed for MEDLINE]

05-24-2009, 10:18 PM	#5
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Lipophilic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation Abstract Full Text HTML Hi-Res PDF[1992 KB] PDF w/ Links[448 KB] Supporting Info Department of Chemistry, University of Illinois at Urbana−Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, Center for Biophysics and Computational Biology, University of Illinois at Urbana−Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, Institute of Biological Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan, Department of Biology, Brookhaven National Laboratory, Upton, New York 11973, Department of Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands, and Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan J. Am. Chem. Soc., 2009, 131 (14), pp 5153–5162 DOI: 10.1021/ja808285e Publication Date (Web): March 23, 2009 Copyright © 2009 American Chemical Society † Department of Chemistry, University of Illinois at Urbana−Champaign. , ‡ Center for Biophysics and Computational Biology, University of Illinois at Urbana−Champaign. , § Institute of Biological Chemistry, Academia Sinica. , Department of Biology, Brookhaven National Laboratory. , Department of Endocrinology, and Metabolic Diseases, Leiden University Medical Center. , # Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University. , eo@chad.scs.uiuc.edu Abstract Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS. View: Full Text HTML \| Hi-Res PDF \| PDF w/ Links Br J Cancer. 2007 May 21;96(10):1526-31. Epub 2007 Apr 17. Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer. FULL TEXT (free) Duivenvoorden WC, Vukmirović-Popović S, Kalina M, Seidlitz E, Singh G. Juravinski Cancer Centre, Hamilton, Ontario, Canada L8V 5C2. Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis. PMID: 17437017 [PubMed - indexed for MEDLINE]