Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models

Yong Luo, Abul Kalam Azad, Styliani Karanika, Spyridon P. Basourakos, Xuemei Zuo, Jianxiang Wang, Luan Yang, Guang Yang, Dimitrios Korentzelos, Jianhua Yin, Sanghee Park, Penglie Zhang, James J. Campbell, Thomas J. Schall, Guangwen Cao, Likun Li, Timothy C. Thompson

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4-2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub-G1) in VCaP and C4-2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p-EGFR (Y1068), p-AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133-4 patient-derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 μm2) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control-treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors.

Original languageEnglish (US)
Pages (from-to)2163-2174
Number of pages12
JournalInternational Journal of Cancer
Volume142
Issue number10
DOIs
StatePublished - May 15 2018
Externally publishedYes

Keywords

  • CCX771
  • CXCR7
  • drug resistance
  • enzalutamide
  • mCRPC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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