Cellular Regulation of Mammalian DNA Topoisomerases

Background: Acute myeloid leukemia (AML) represents the largest number of annual deaths from hematologic malignancy. In the United States, it was estimated that 21.380 individuals would be diagnosed with AML and 49.5% of patients would die in 2017. Therefore, the search for novel compounds capable of increasing the overall survival rate to the treatment of AML cells is urgent. Objectives: To investigate the cytotoxicity effect of the natural compound pomolic acid (PA) and to explore the mechanism of action of PA in AML cell lines with different phenotypes. Methods: Three different AML cell lines, HL60, U937 and Kasumi-1 cells with different mechanisms of resistance were used to analyze the effect of PA on the cell cycle progression, on DNA intercalation and on human DNA topoisomerases (hTopo I and IIα) in vitro studies. Theoretical experiments of the inhibition of hTopo I and IIα were done to explore the binding modes of PA. Results: PA reduced cell viability, induced cell death, increased sub-G0/G1 accumulation and activated caspases pathway in all cell lines, altered the cell cycle distribution and inhibited the catalytic activity of both human DNA topoisomerases. Conclusion: Finally, this study showed that PA has powerful antitumor activity against AML cells, suggesting that this natural compound might be a potent antineoplastic agent to improve the treatment scheme of this neoplasm.

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B. L. HORECKER and E. R. STADTMAN (Editors), Current Topics in Cellular Regulation, Vol. 9. XIX, 241 S., 46 Abb., 22 Tab. New York–San Francisco–London 1975: Academic Press. $ 24.50

Zeitschrift für allgemeine Mikrobiologie ◽

10.1002/jobm.3630170317 ◽

1977 ◽

Vol 17 (3) ◽

pp. 256-256

Author(s):

F. Zickler

Keyword(s):

New York ◽

San Francisco ◽

Academic Press ◽

Cellular Regulation

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Centrosome Structure And Function Is Altered By Experimental Manipulations With Formamide: Implications For Abnormal Cell Divisions During Cancer

Microscopy and Microanalysis ◽

10.1017/s1431927600019759 ◽

1999 ◽

Vol 5 (S2) ◽

pp. 1286-1287

Author(s):

Heide Schatten ◽

Christopher N. Hueser ◽

Amitabha Chakrabarti

Keyword(s):

Cell Cycle ◽

Genomic Stability ◽

Cellular Regulation ◽

Mitotic Apparatus ◽

Abnormal Cell ◽

Chemical Agents ◽

Abnormal Mitosis ◽

And Function ◽

Normal Mitosis ◽

Abnormal Cell Proliferation

The formation of abnormal mitosis associated with cancer has been intriguing for many decades. While microtubules had been the focus of previous studies, recent research has focused on centrosomes, microtubule organizing centers which organize the mitotic apparatus during cell division. During normal mitosis centrosomes form two poles but in cancer, centrosomes can form three, four, or more poles, and organize tripolar, quadripolar, and multipolar mitoses, respectively. This has severe consequences for genomic stability because chromosomes are separated unequally to three, four, or more poles. This can result in aneuploidy and gene amplifications with multiple defects in cellular regulation. It can result in malignancy that is accompanied by cell cycle imbalances and abnormal cell proliferation. While radiation and chemical agents are known to damage DNA and can lead to cell cycle abnormalities, the damage of centrosome structure leading to abnormal mitosis deserves also consideration.

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