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CXCR2 Inhibition Combined with Sorafenib Improved Antitumor and Antiangiogenic Response in Preclinical Models of Ovarian Cancer.

Devapatla B, Sharma A, Woo S - PLoS ONE (2015)

Bottom Line: However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance.We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits.The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.

ABSTRACT
Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy.

No MeSH data available.


Related in: MedlinePlus

CXCR2 expression in SKOV-3 ovarian xenograft tumors.A) Representative immunostaining for CXCR2 in control, sorafenib-sensitive (SS), and sorafenib—resistant (SR) tumors. B) CXCR2 expression was elevated in sorafenib-resistant tumors (P < 0.05) compared with sorafenib-sensitive tumors.
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pone.0139237.g003: CXCR2 expression in SKOV-3 ovarian xenograft tumors.A) Representative immunostaining for CXCR2 in control, sorafenib-sensitive (SS), and sorafenib—resistant (SR) tumors. B) CXCR2 expression was elevated in sorafenib-resistant tumors (P < 0.05) compared with sorafenib-sensitive tumors.

Mentions: We performed CXCR2 staining in xenograft tumors of sorafenib treatments to compare its expression (Fig 3A) in sensitive and resistant groups. CXCR2 expression was elevated in resistant tumors compared with sensitive and control tumors. We observed a threefold increase in resistant tumors compared with sensitive tumors (P < 0.05, Fig 3B) in the sorafenib treatment group.


CXCR2 Inhibition Combined with Sorafenib Improved Antitumor and Antiangiogenic Response in Preclinical Models of Ovarian Cancer.

Devapatla B, Sharma A, Woo S - PLoS ONE (2015)

CXCR2 expression in SKOV-3 ovarian xenograft tumors.A) Representative immunostaining for CXCR2 in control, sorafenib-sensitive (SS), and sorafenib—resistant (SR) tumors. B) CXCR2 expression was elevated in sorafenib-resistant tumors (P < 0.05) compared with sorafenib-sensitive tumors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4587670&req=5

pone.0139237.g003: CXCR2 expression in SKOV-3 ovarian xenograft tumors.A) Representative immunostaining for CXCR2 in control, sorafenib-sensitive (SS), and sorafenib—resistant (SR) tumors. B) CXCR2 expression was elevated in sorafenib-resistant tumors (P < 0.05) compared with sorafenib-sensitive tumors.
Mentions: We performed CXCR2 staining in xenograft tumors of sorafenib treatments to compare its expression (Fig 3A) in sensitive and resistant groups. CXCR2 expression was elevated in resistant tumors compared with sensitive and control tumors. We observed a threefold increase in resistant tumors compared with sensitive tumors (P < 0.05, Fig 3B) in the sorafenib treatment group.

Bottom Line: However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance.We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits.The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.

ABSTRACT
Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy.

No MeSH data available.


Related in: MedlinePlus