Cytotoxicity and mode of action of vanada- and niobatricarbadecaboranyl monohalide complexes in human HL-60 promyelocytic leukemia cells.
Vanada- and niobatricarbadecaboranyl monohalide complexes proved to be potent cytotoxic agents against murine and human leukemia and lymphoma growth as well as HeLa suspended uterine carcinoma. The vanada complex reduced the growth of KB nasopharynx, Hepe liver, HCT-8 ileum and 1-A9 ovary solid carcinomas. A mode of action study in human HL-60 promyelocytic leukemia cells showed that DNA and purine de novo syntheses were significantly inhibited with suppression of the regulatory enzymes activities of DNA polymerase alpha and PRPP-amido transferase. There was moderate inhibition of RNA synthesis and m-RNA polymerase activity. These complexes did not inhibit human topoisomerase I or II activity, although the niobium complex nicked the DNA. The complexes did activate caspases 3, 6 and 9 which are linked to apoptosis programmed cell death. These vanada- and niobatricarbadecaboranyl monohalide complexes appear to be more specific in their effects on leukemia cell metabolism than other sandwich complexes which have broad effects on multiple enzymes.
Hall
Iris H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA. iris_hall@unc.edu
Durham
Richard W
RW
Tram
Min
M
Mueller
Stephanie
S
Ramachandran
Bhaskar M
BM
Sneddon
Larry G
LG
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000473:pathology*; D009556:Niobium / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D014639:Vanadium / Q000737:chemistry*
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D059004:Topoisomerase I Inhibitors; C013108:metallocene; D014639:Vanadium; D009556:Niobium