Kinamycins A and C, bacterial metabolites that contain an unusual diazo group, as potential new anticancer agents: antiproliferative and cell cycle effects.
The cell growth and cell cycle inhibitory properties of the bacterial metabolites kinamycin A and kinamycin C were investigated in an attempt to determine their mechanism of action and to develop these or their analogs as anticancer agents. Both kinamycin A and kinamycin C have a highly unusual and potentially reactive diazo group. Even with short incubations, both the kinamycins were shown to have very potent cell growth inhibitory effects on either Chinese hamster ovary or K562 cells. Kinamycin C induced a rapid apoptotic response in K562 cells. The cell cycle analysis results in synchronized Chinese hamster ovary cells treated with kinamycin A revealed that they only displayed a G1/S phase block upon entry to the second cycle. Both kinamycins inhibited the catalytic decatenation activity of DNA topoisomerase IIalpha, but neither kinamycin acted as a topoisomerase II poison. Their inhibition of catalytic activity was not correlated with cell growth inhibitory effects. Pretreatment of the kinamycins with dithiothreitol protected the topoisomerase IIalpha activity, which suggested that they may be targeting critical protein sulfhydryl groups, either through reaction with the quinone or with an activated electrophilic diazo group. Neither kinamycin A nor kinamycin C intercalated into DNA, nor were they able to cross-link DNA. Although the cellular target(s) of the kinamycins has yet to be identified, the cluster map analysis, and the cell cycle and proapoptotic effects suggest that kinamycin C has a target different than other established anticancer compounds.
Hasinoff
Brian B
BB
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada. B_Hasinoff@UManitoba.ca
Wu
Xing
X
Yalowich
Jack C
JC
Goodfellow
Valerie
V
Laufer
Radoslaw S
RS
Adedayo
Otunola
O
Dmitrienko
Gary I
GI
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000378:metabolism; D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D006224:Cricetinae; D003432:Cross-Linking Reagents; D027081:DNA Gyrase / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D004278:DNA, Superhelical / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D020014:K562 Cells; D009243:NAD / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D000095602:Angucyclines and Angucyclinones
D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate; D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D001391:Azo Compounds; D003432:Cross-Linking Reagents; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II; D004273:DNA, Neoplasm; D004278:DNA, Superhelical; D004268:DNA-Binding Proteins; D009243:NAD; D009285:Naphthoquinones; D011809:Quinones; D059005:Topoisomerase II Inhibitors; C515381:kinamycin C; D000095602:Angucyclines and Angucyclinones; C001507:kinamycin A