Antiproliferative activity of colchicine analogues on MDR-positive and MDR-negative human cancer cell lines.

Abstract

In this study the in vitro antitumor activity of a series of 20 colchicine analogues was tested and compared with colchicine and thiocolchicine on three different human cancer cell lines, two of which express the multidrug-resistance (MDR) phenotype. At concentrations from 1 nM to 100 microM, all compounds tested inhibited cancer cell proliferation. The IC50 values indicate that the three fluorinated analogues were the most active compounds, with a similar decreasing order of potency (IDN 5005 > IDN 5079 > IDN 5080) on the two MDR-expressing cell lines, whereas thiocolchicine was the most effective compound on the MDR-negative MDA-MB 231 cells. A strong correlation (r = 0.94; P = 0.004) was found between IC50 values obtained using the two MDR-positive cell lines. Conversely, IC50 values obtained in MDA-MB 231 cells did not show a significant correlation with MDR-positive cell lines, thereby suggesting some difference in the antiproliferative mechanism(s) of colchicine analogues. Cell cycle analysis of the most active analogues in breast cancer cells showed a relationship between cell cycle blocking activity and growth inhibition. The most active agents on the MDR-positive MCF7 ADRr cell line, after 24 h of culture, in terms of cell cycle blocking activity were the three fluorinated analogues. Interestingly, after 72 h, when the cell cycle block subsided, a consistent amount of DNA fragmentation was evident. The extent of cell cycle block, measured as the G2/G1 ratio, was significantly correlated with the apoptosis rate expressed as a percentage of DNA fragmentation on both cell lines, thereby suggesting that a large number of blocked cells underwent the apoptotic pathway.

• Authors: R De Vincenzo, G Scambia, C Ferlini, M Distefano, P Filippini, A Riva, E Bombardelli, D Pocar, M L Gelmi, P Benedetti Panici, S Mancuso
• Journal: Anti-cancer drug design (Anticancer Drug Des) Vol. 13 Issue 1 Pg. 19-33 (Jan 1998) ISSN: 0266-9536 [Print] United States
• PMID: 9474240 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Growth Inhibitors
• Fluorine
• thiocholchicine
• Colchicine

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Cycle (drug effects)
• Colchicine (analogs & derivatives, chemistry, pharmacology)
• Drug Resistance, Multiple
• Fluorine
• Growth Inhibitors (pharmacology)
• Humans
• Structure-Activity Relationship
• Tumor Cells, Cultured