title: Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer.
abstract: OBJECTIVE
  Zoledronic acid is being increasingly recognized for its antitumor properties, but the underlying functions are not well understood. In this study, we hypothesized that zoledronic acid inhibits ovarian cancer angiogenesis preventing Rac1 activation.
  
  
  METHODS
  The biologic effects of zoledronic acid were examined using a series of in vitro [cell invasion, cytokine production, Rac1 activation, reverse-phase protein array, and in vivo (orthotopic mouse models)] experiments.
  
  
  RESULTS
  There was significant inhibition of ovarian cancer (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of proangiogenic cytokines in response to zoledronic acid treatment. Furthermore, zoledronic acid inactivated Rac1 and decreased the levels of Pak1/p38/matrix metalloproteinase-2 in ovarian cancer cells. In vivo, zoledronic acid reduced tumor growth, angiogenesis, and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when zoledronic acid was combined with nab-paclitaxel.
  
  
  CONCLUSIONS
  Zoledronic acid has robust antitumor and antiangiogenic activity and merits further clinical development as ovarian cancer treatment.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vianey
authors.initials: V
authors.lastname: Gonzalez-Villasana
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Enrique
authors.initials: E
authors.lastname: Fuentes-Mattei
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Fernandez-de Thomas
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Burcu
authors.initials: B
authors.lastname: Aslan
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
authors.forename: Paloma
authors.initials: P
authors.lastname: Del C Monroig
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guermarie
authors.initials: G
authors.lastname: Velazquez-Torres
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Previs
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nermin
authors.initials: N
authors.lastname: Kahraman
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pinar
authors.initials: P
authors.lastname: Kanlikilicer
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bulent
authors.initials: B
authors.lastname: Ozpolat
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNAi and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: George
authors.initials: G
authors.lastname: Calin
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNAi and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNAi and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas. glopez@mdanderson.org.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
mesh_terms: D000418:Albumins / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid; D054462:p21-Activated Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; C107953:RAC1 protein, human; D000077211:Zoledronic Acid; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020830:rac1 GTP-Binding Protein; D017239:Paclitaxel