Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer.
OBJECTIVE
Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations.


METHODS
Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis.


RESULTS
Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density.


CONCLUSIONS
Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer.
Department of Nanomedicine and Bioengineering; The University of Texas Health Science Center at Houston; Houston, TX USA; Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Nicole M
NM
Reusser
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Heather J
HJ
Dalton
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Sunila
S
Pradeep
Department of Experimental Therapeutics; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Vianey
V
Gonzalez-Villasana
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Nicholas B
NB
Jennings
Department of Internal Medicine; The University of Texas Health Science Center at Houston; Houston, TX USA.
Hernan G
HG
Vasquez
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Yunfei
Y
Wen
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Rajesh
R
Rupaimoole
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Archana S
AS
Nagaraja
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Kshipra
K
Gharpure
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Takahito
T
Miyake
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Jie
J
Huang
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Wei
W
Hu
Department of Nanomedicine and Bioengineering; The University of Texas Health Science Center at Houston; Houston, TX USA; Department of Experimental Therapeutics; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Cancer Biology; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Center for RNA Interference and Non-Coding RNA; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Gabriel
G
Lopez-Berestein
Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Cancer Biology; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Center for RNA Interference and Non-Coding RNA; The University of Texas MD Anderson Cancer Center; Houston, TX USA.
Anil K
AK
Sood
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004002:Clodronic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology
D020533:Angiogenesis Inhibitors; D050071:Bone Density Conservation Agents; D016207:Cytokines; D004002:Clodronic Acid
anti-angiogenesis; bisphosphonate; clodronate; ovarian cancer; tumor angiogenesis; tumor microenvironment; tumor-associated macrophages