title: Small molecule inhibition of polo-like kinase 1 by volasertib (BI 6727) causes significant melanoma growth delay and regression in vivo.
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.
authors: Department of Dermatology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
authors: Brian D
authors: BD
authors: Cholewa
authors: Department of Dermatology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
authors: Mary A
authors: MA
authors: Ndiaye
authors: Department of Pathology and Laboratory Medicine, University of Wisconsin, 1685 Highland Avenue, Madison, WI 53705, USA.
authors: Wei
authors: W
authors: Huang
authors: Department of Biochemistry, Purdue University, 175 S. University Street, West Lafayette, IN 47907, USA.
authors: Xiaoqi
authors: X
authors: Liu
authors: Department of Dermatology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA; William S. Middleton VA Medical Center, 2500 Overlook Terrace, Madison, WI 53705, USA. Electronic address: nahmad@wisc.edu.
authors: Nihal
authors: N
authors: Ahmad
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011621:Pteridines / Q000494:pharmacology*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D053148:Caspase 3; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D011621:Pteridines; D016159:Tumor Suppressor Protein p53; D000097869:Polo-Like Kinase 1; C541363:BI 6727; C493956:CDKN1A protein, human; C495901:TP53 protein, human; C482119:BRAF protein, human; C505407:CASP3 protein, human
keywords: BI 6727; Melanoma; Plk1; Volasertib