Colchicine induces autophagy and senescence in lung cancer cells at clinically admissible concentration: potential use of colchicine in combination with autophagy inhibitor in cancer therapy
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Colchicine is a well-known and potent microtubule targeting agent, but the therapeutic value of colchicine against cancer is limited by its toxicity against normal cells. But, there is no report of its cytotoxic potential against lung cancer cell, at clinically permissible or lower concentrations, minimally toxic to non-cancerous cells. Hence, in the present study, we investigated the possible mechanism by which the efficacy of colchicine against lung cancer cells at less toxic dose could be enhanced. Colchicine at clinically admissible concentration of 2.5 nM had no cytotoxic effect and caused no G2/M arrest in A549 cells. However, at this concentration, colchicine strongly hindered the reformation of cold depolymerised interphase and spindle microtubule. Colchicine induced senescence and reactive oxygen species mediated autophagy in A549 cells at this concentration. Autophagy inhibitor 3-methyladenine (3-MA) sensitised the cytotoxicity of colchicine in A549 cells by switching senescence to apoptotic death, and this combination had reduced cytotoxicity to normal lung fibroblast cells (WI38). Together, these findings indicated the possible use of colchicine at clinically relevant dose along with autophagy inhibitor in cancer therapy.
KeywordsColchicine ROS Autophagy Microtubule Lung cancer
The work was supported by grants from DST, Govt. of India (No. SR/SO/BB-14/2008) and DBT, Government of India (No. BT/ PR12889/AGR/36/624/2009) to GC. Confocal Microscope facility is from University-DBT-IPLS programme, Government of India (No. BT/PR14552/INF/22/123/2010), and FACS instrument facility is developed by grants from National Common Minimum Project, Government of India. SB was a senior research fellow of University Grant Commission. SD is a Senior Research Fellow of CSIR, Government of India. AG was a fellow of DBT-CU-IPLS programmne, Government of India (No. BT/PR14552/INF/22/123/2010).
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