Novel quinone antiproliferative inhibitors of phosphatidylinositol-3-kinase.
The inhibition of phosphatidylinositol-3-kinase (PtdIns-3-kinase), protein kinase C and c-Src protein tyrosine kinase by a series of halogenated naphthoquinones and quinoline quinones related to the plant-derived naphthoquinones juglone and methyljuglone, which inhibit protein kinase C, has been investigated. Some of the compounds inhibited PtdIns-3-kinase at micromolar concentrations and below. PtdIns-3-kinase inhibition was time dependent and could be prevented by endogenous thiol. The compounds were only weak inhibitors of PtdIns-4-kinase. Some of the compounds inhibited protein kinase C, but c-Src protein tyrosine kinase was only weakly inhibited. In intact cells, PtdIns-3-kinase was only partly inhibited by concentrations of the halogenated quinones that inhibited cell growth. Some halogenated quinones showed in vivo antitumor activity without accompanying toxicity, while methyljuglone was without in vivo antitumor activity. Halogenated quinones may have multiple biochemical effects in the cell that could contribute to their cytotoxic and antitumor effects. Inhibition of PtdIns-3-kinase by the halogenated quinones may provide a lead for the development of more potent and specific inhibitors.
Frew
T
T
Arizona Cancer Center, University of Arizona, Tucson 85724, USA.
Powis
G
G
Berggren
M
M
Gallegos
A
A
Abraham
R T
RT
Ashendel
C L
CL
Zalkow
L H
LH
Hudson
C
C
Gruszecka-Kowalik
E
E
Burgess
E M
EM
D001943:Breast Neoplasms / Q000201:enzymology; D000081247:CSK Tyrosine-Protein Kinase; D003110:Colonic Neoplasms; D005260:Female; D006801:Humans; D009285:Naphthoquinones / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D009285:Naphthoquinones; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human