Selective killing of G2 decatenation checkpoint defective colon cancer cells by catalytic topoisomerase II inhibitor.
Cancer cells with defective DNA decatenation checkpoint can be selectively targeted by the catalytic inhibitors of DNA topoisomerase IIα (topo IIα) enzyme. Upon treatment with catalytic topo IIα inhibitors, cells with defective decatenation checkpoint fail to arrest their cell cycle in G2 phase and enter into M phase with catenated and under-condensed chromosomes resulting into impaired mitosis and eventually cell death. In the present work we analyzed decatenation checkpoint in five different colon cancer cell lines (HCT116, HT-29, Caco2, COLO 205 and SW480) and in one non-cancerous cell line (HEK293T). Four out of the five colon cancer cell lines i.e. HCT116, HT-29, Caco2, and COLO 205 were found to be compromised for the decatenation checkpoint function at different extents, whereas SW480 and HEK293T cell lines were found to be proficient for the checkpoint function. Upon treatment with ICRF193, decatenation checkpoint defective cell lines failed to arrest the cell cycle in G2 phase and entered into M phase without proper chromosomal decatenation, resulting into the formation of tangled mass of catenated and under-condensed chromosomes. Such cells underwent mitotic catastrophe and rapid apoptosis like cell death and showed higher sensitivity for ICRF193. Our study suggests that catalytic inhibitors of topoisomerase IIα are promising therapeutic agents for the treatment of colon cancers with defective DNA decatenation checkpoint.
Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India; Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
Chetan Kumar
CK
Jain
Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India. Electronic address: susanta@iicb.res.in.
Susanta
S
Roychoudhury
Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India. Electronic address: hkmajumder@iicb.res.in.
Hemanta Kumar
HK
Majumder
D055162:Biocatalysis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002877:Chromosomes, Human / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology*; D054659:Diketopiperazines; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D008940:Mitotic Index; D010879:Piperazines / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D054659:Diketopiperazines; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D005047:Etoposide
Colorectal cancer; G(2) DNA decatenation checkpoint; ICRF193; Mitotic catastrophe; Topoisomerase IIα