TY - JOUR
T1 - Rac1/Pak1/p38/MMP-2 axis regulates angiogenesis in ovarian cancer
AU - Gonzalez-Villasana, Vianey
AU - Fuentes-Mattei, Enrique
AU - Ivan, Cristina
AU - Dalton, Heather J.
AU - Rodriguez-Aguayo, Cristian
AU - Fernandez-De Thomas, Ricardo J.
AU - Aslan, Burcu
AU - Monroig, Paloma Del C.
AU - Velazquez-Torres, Guermarie
AU - Previs, Rebecca A.
AU - Pradeep, Sunila
AU - Kahraman, Nermin
AU - Wang, Huamin
AU - Kanlikilicer, Pinar
AU - Ozpolat, Bulent
AU - Calin, George
AU - Sood, Anil K.
AU - Lopez-Berestein, Gabriel
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Purpose: 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. Experimental Design: 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.
AB - Purpose: 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. Experimental Design: 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.
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U2 - 10.1158/1078-0432.CCR-14-2279
DO - 10.1158/1078-0432.CCR-14-2279
M3 - Article
C2 - 25595279
AN - SCOPUS:84930651943
SN - 1078-0432
VL - 21
SP - 2127
EP - 2137
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -