Inhibition of melanoma tumor growth by a pharmacological inhibitor of MetAP-2, PPI-2458.
Over the past few decades, melanoma has shown the fastest growing incidence rate of all cancers. This malignancy is clinically defined by its potential to rapidly metastasize, and advanced metastatic melanomas are highly resistant to existing therapeutic regimens. Here, we report that PPI-2458, a novel, orally active agent of the fumagillin class of irreversible methionine aminopeptidase-2 (MetAP-2) inhibitors, potently inhibited the proliferation of B16F10 melanoma cells in vitro, with a growth inhibitory concentration 50% (GI50) of 0.2 nM. B16F10 growth inhibition was correlated with the inhibition of MetAP-2 enzyme, in a dose-dependent fashion, as determined by a pharmacodynamic assay, which measures the amount of uninhibited MetAP-2 following PPI-2458 treatment. Prolonged exposure of B16F10 cells to PPI-2458 at concentrations of up to 1 microM, 5,000-fold above the GI50, did not alter their sensitivity to PPI-2458 growth inhibition and no drug resistance was observed. Moreover, prolonged exposure to this agent induced melanogenesis, concomitant with the elevated expression of the melanocyte-specific enzymes tyrosinase and tyrosinase-related proteins (TRP) 1 and 2, a morphological feature associated with differentiated melanocytes. PPI-2458, when administered orally (p.o.), significantly inhibited B16F10 tumor growth in mice in a dose-dependent fashion, with a maximum inhibition of 62% at 100 mg/kg. This growth inhibition was directly correlated to the amount of irreversibly inhibited MetAP-2 (80% at 100 mg/kg PPI-2458) in tumor tissue. These data demonstrate that PPI-2458 has potent antiproliferative activity against B16F10 cells in vitro and in vivo, and that both activities are directly correlated with levels of MetAP-2 enzyme inhibition. This antiproliferative activity, coupled with additional observations from studies in vitro (absence of detectable resistance to PPI-2458 and induction of morphological features consistent with differentiated melanocytes), provides a rationale for assessing the therapeutic potential of PPI-2458 in the treatment of melanoma.
Hannig
Gerhard
G
PRAECIS Pharmaceuticals, Incorporated, Department of Preclinical Research, Waltham, MA 02451, USA. gerhard.hannig@praecis.com
Lazarus
Douglas D
DD
Bernier
Sylvie G
SG
Karp
Russell M
RM
Lorusso
Jeanine
J
Qiu
Daniel
D
Labenski
Matthew T
MT
Wakefield
Jim D
JD
Thompson
Charles D
CD
Westlin
William F
WF
D000284:Administration, Oral; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D008543:Melanins / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D063208:Methionyl Aminopeptidases; D051379:Mice; D008810:Mice, Inbred C57BL; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004852:Epoxy Compounds; D006023:Glycoproteins; D008543:Melanins; C488724:PPI 2458; D000626:Aminopeptidases; C489894:Metap2 protein, mouse; D063208:Methionyl Aminopeptidases; D014633:Valine