title: Bisphosphonates inhibit stellate cell activity and enhance antitumor effects of nanoparticle albumin-bound paclitaxel in pancreatic ductal adenocarcinoma.
abstract: Pancreatic stellate cells (PSC) have been recognized as the principal cells responsible for the production of fibrosis in pancreatic ductal adenocarcinoma (PDAC). Recently, PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBP; pamidronate or zoledronic acid), which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro, we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover, NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1), and type I collagen expression. NBPs also induced PSCs apoptosis and cell-cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine. Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC.
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 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 Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Thiruvengadam
authors.initials: T
authors.lastname: Arumugam
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zobeida
authors.initials: Z
authors.lastname: Cruz-Monserrate
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: Defeng
authors.initials: D
authors.lastname: Deng
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Hwang
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 Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Raul Joshua
authors.initials: RJ
authors.lastname: Garza
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Evan
authors.initials: E
authors.lastname: Cohen
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
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: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
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-Bosque
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bincy
authors.initials: B
authors.lastname: Philip
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. Al-Azhar University, Cairo, Egypt.
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Rashed
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.
authors.forename: Mumin Alper
authors.initials: MA
authors.lastname: Erdogan
authors.affiliation: Universidad Autonoma de Nuevo Leon, San Nicolas de los Garza, Nuevo Leon, Mexico.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gutierrez-Puente
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 Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: James M
authors.initials: JM
authors.lastname: Reuben
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 Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Craig
authors.initials: C
authors.lastname: Logsdon
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. glopez@mdanderson.org.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
mesh_terms: D000328:Adult; D000418:Albumins / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D017239:Paclitaxel / Q000008:administration & dosage*; D000077268:Pamidronate; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000418:Albumins; D004164:Diphosphonates; D000077268:Pamidronate; D017239:Paclitaxel