Resistance to Bleomycin in Cancer Cell Lines Is Characterized by Prolonged Doubling Time, Reduced DNA Damage and Evasion of G2/M Arrest and Apoptosis

被引：34

作者：

Wang, Qi ^{[1
]}

Cui, Kangping ^{[2
]}

Espin-Garcia, Osvaldo ^{[3
,4
]}

Cheng, Dangxiao ^{[1
]}

Qiu, Xiaoping ^{[5
]}

Chen, Zhuo ^{[1
]}

Moore, Malcolm ^{[6
,7
]}

Bristow, Robert G. ^{[1
,8
,9
]}

Xu, Wei ^{[4
,10
]}

Der, Sandy ^{[1
]}

Liu, Geoffrey ^{[7
,10
]}

机构：

[1] Princess Margaret Hosp, Ontario Canc Inst, Dept Appl Mol Oncol, Toronto, ON M4X 1K9, Canada

[2] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada

[3] Univ Waterloo, Dept Stat & Actuarial Sci, Waterloo, ON N2L 3G1, Canada

[4] Princess Margaret Hosp, Dept Biostat, Toronto, ON M4X 1K9, Canada

[5] Wuhan Univ, Sch Med, Inst Virol, Wuhan 430072, Hubei, Peoples R China

[6] Univ Toronto, Dept Med & Pharmacol, Toronto, ON, Canada

[7] Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada

[8] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[9] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada

[10] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada

来源：

PLOS ONE | 2013年 / 8卷 / 12期

关键词：

ANTIOXIDANT ENZYMES; CHECKPOINT; GAMMA-H2AX; ACTIVATION; REPAIR; ASSAY;

D O I：

10.1371/journal.pone.0082363

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM) resistance using human cancer cell lines. Seven BLM-resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and gamma-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell lines. Results: Compared with parental cell lines, real time cytotoxicity assays revealed 7 to 49 fold increases in IC50 and a mean doubling time increase of 147 % (range 64 %-352%) in BLM-resistant sub-clones (p<0.05 for both). Higher maintenance BLM concentrations were associated with higher IC50 and increased doubling times (p<0.05). Significantly reduced DNA damage (COMET and gamma-H2AX assays), G2/M arrest, and apoptosis (p<0.05 for each set of comparison) following high-dose acute BLM exposure was observed in resistant sub-clones, compared with their BLM-sensitive parental counterparts. Three weeks of BLM-free culturing resulted in a partial return to BLM sensitivity in 3/7 BLM-resistant sub-clones (p<0.05). Conclusion: Bleomycin resistance may be associated with reduced DNA damage after bleomycin exposure, resulting in reduced G2/M arrest, and reduced apoptosis.

引用

页数：13

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