C12, a combretastatin-A4 analog, exerts anticancer activity by targeting microtubules.

Abstract

Combretastatin A4 and its analogs are undergoing various clinical trials for the treatment of different cancers. This study illustrated the molecular mechanism and antitumor activity of C12, (5-Quinolin-3-yl and 4-(3,4,5-trimethoxyphenyl) substituted imidazol-2-amine), a synthetic analog of CA-4. C12 reduced the tumor volume of MCF-7 xenograft in NOD-SCID mice without affecting the bodyweight of the mice. Further, C12 inhibited the proliferation of several types of cancer cells more efficiently than their noncancerous counterparts. Using GFP-EB1 imaging, the effects of C12 on the interphase microtubule dynamics were determined in live HeLa cells. C12 (10 nM, half-maximal proliferation inhibitory concentration) reduced the growth rate of microtubules by 52% and increased the pause time of microtubules by 68%. In addition, fluorescence recovery after photobleaching analysis demonstrated that 10 nM C12 strongly suppressed spindle microtubule dynamics in HeLa cells. C12 treatment reduced the interpolar distance between the two spindle poles, increased the chromosome congression index, inhibited chromosome movement, and increased the level of mitotic checkpoint complex proteins BubR1 and Mad2. The evidence presented here indicated that C12 could induce different modes of cell death, depending on the extent of microtubule depolymerization. Since C12 targets both the mitotic and non-mitotic cells and showed a stronger activity against cancerous cells than non-cancerous cells, it may have an advantage in cancer chemotherapy. The results significantly enhance our understanding of the antitumor mechanism of the microtubule-depolymerizing agents.

• Authors: Anuradha Kumari, Shalini Srivastava, Rajesh K Manne, Shailendra Sisodiya, Manas K Santra, Sankar K Guchhait, Dulal Panda
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 170 Pg. 113663 (12 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 31606408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Bibenzyls
• combretastatin

Topics

• A549 Cells
• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, metabolism)
• Bibenzyls (administration & dosage, metabolism)
• Cell Proliferation (drug effects, physiology)
• Drug Delivery Systems (methods)
• HeLa Cells
• Humans
• MCF-7 Cells
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Microtubules (drug effects, metabolism, pathology)