Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo

Brian D. Cholewa, Mary A. Ndiaye, Wei Huang, Xiaoqi Liu, Nihal Ahmad

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The objective of this study was to determine the therapeutic potential of polo-like kinase 1 (Plk1) inhibition in melanoma, in vivo. Employing Vectra technology, we assessed the Plk1 expression profile in benign nevi, malignant (stages I–IV) and metastatic melanomas. We found a significant elevation of Plk1 immunostaining in melanoma tissues. Further, a second generation small molecule Plk1 inhibitor, BI 6727, resulted in reductions in growth, viability and clonogenic survival, as well as an increase in apoptosis of A375 and Hs 294T melanoma cells. BI 6727 treatment also resulted in a G2/M-as well as S-phase cell cycle arrest in melanoma cells. Importantly, BI 6727 (intravenous injection; 10 and 25 mg/kg body weight) treatment resulted in significant tumor growth delay and regression in vivo in A375-and Hs 294T-implanted xenografts in athymic nude mice. These anti-melanoma effects were accompanied with a decreased cellular proliferation (Ki-67 staining) and induction of apoptosis (caspase 3 activation). In addition, BI 6727 treatment caused a marked induction of p53 and p21 in vitro as well as in vivo. Overall, we suggest that Plk1 inhibition may be a useful approach as a monotherapy as well as in combination with other existing therapeutics, for melanoma management.

Original languageEnglish
Pages (from-to)179-187
Number of pages9
JournalCancer Letters
Volume385
DOIs
StatePublished - Jan 28 2017

Bibliographical note

Funding Information:
This work was partially supported by funding from the National Institutes of Health (grant numbers R01AR059130 and R01CA176748 to N.A.; T32 ES007015-35 to B.D.C.); The Department of Veterans Affairs (VA Merit Review Award, grant number 1I01BX001008 ); as well as by the University of Wisconsin Carbone Cancer Center (UWCCC) Support Grant (NIH; grant number P30 CA014520 ). The authors also thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory, in part supported by the UW Department of Pathology and Laboratory Medicine and the UWCCC, for use of its facilities and services.

Publisher Copyright:
© 2016

Keywords

  • BI 6727
  • Melanoma
  • Plk1
  • Volasertib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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