Antimitotic actions of a novel analog of the fungal metabolite palmarumycin CP1.
The pentacyclic palmarumycins are structurally unique natural products with both antifungal and antibacterial activities but their antineoplastic effects are not well established. We have examined their antiproliferative actions against tumor cells using a temperature-sensitive tsFT210 mouse mammary carcinoma cell line and found that a novel palmarumycin analog, [8-(furan-3-ylmethoxy)-1-oxo-1,4-dihydronaphthalene-4-spiro-2'-naphtho[1",8"-de][1',3'][dioxin] or SR-7, prominently blocked mammalian cell cycle transition in G2/M but not in G1 phase. We found no evidence for inhibition of the critical mitosis-controlling cyclin-dependent kinase Cdk1, or its regulator, the dual specificity phosphatase Cdc25. Moreover, Cdk1 was hypophosphorylated and not directly inhibited by SR-7. SR-7 also failed in vitro to hypernucleate bovine tubulin, did not compete with colchicine for tubulin binding, and only modestly blocked GTP-induced assembly. In addition, SR-7 caused almost equal inhibition of paclitaxel-sensitive and -resistant cell growth. Moreover, unlike benchmark tubulin-disrupting agents, SR-7 did not cause hyperphosphorylation of the antiapoptotic protein Bcl-2. Thus, SR-7 represents a novel chemical structure that can inhibit G2/M transition by a mechanism that appears to be independent of marked tubulin disruption.
Lazo
J S
JS
Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. lazo@pitt.edu
Tamura
K
K
Vogt
A
A
Jung
J K
JK
Rodriguez
S
S
Balachandran
R
R
Day
B W
BW
Wipf
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D009281:Naphthalenes; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D004146:Dioxanes; D009281:Naphthalenes; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D013141:Spiro Compounds; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C422643:palmarumycin CP(1); D018844:Cyclin-Dependent Kinases; D010744:Phosphoric Monoester Hydrolases; D003078:Colchicine