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DOI: 10.1055/s-0042-109390
The Effect of Caffeine and chk2 Inhibitor on Doxorubicin-Induced Cellular Senescence in MCF-7 Cells
Publikationsverlauf
received 06. Januar 2016
accepted 24. Mai 2016
Publikationsdatum:
12. Juli 2016 (online)
![](https://www.thieme-connect.de/media/drugres/201609/lookinside/thumbnails/2016-01-1122_10-1055-s-0042-109390-1.jpg)
Abstract
Senescence is cellular growth arrest. Induction of senescence can be considered as an alternative approach for treating cancer cells being resistance to anti-cancer drugs. We investigated the effect of caffeine and chk2 inhibitor on doxorubicin induced senescence in MCF-7 cells. Caffeine and chk2 inhibitor were used in combination with doxorubicin. Cellular senescence was assessed by β-galactosidase assay. P21 expression was determined using immunoblotting. Cell proliferation was evaluated using prestoblue assay. Results revealed that doxorubicin induced senescence and increased p21 expression in MCF-7 cells. However, co-treatment of chk2 inhibitor and caffeine with doxorubicin could not augment doxorubicin-induced senescence. Moreover, p21 expression was decreased in combination studies compared to doxorubicin group. Our results indicate that caffeine, chk2 inhibitor and combination of chk2 inhibitor, caffeine and doxorubicin could not increase sensitivity of the cells to doxorubicin-induced senescence. Our findings demonstrate that low-dose doxorubicin induced senescence via the activation of ATM, -chk2, and -p21 pathways, while inhibition of ATM and chk2 cannot consider as a new target for sensitization of MCF-7 cells to doxorubicin. Thus, chk2 inhibitor and caffeine might not serve as desirable agents being capable to restore chemo sensitivity in doxorubicin-resistant breast tumors.
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References
- 1 Kim J, Freeman MR. JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells. Breast cancer research and treatment 2003; 79: 321-328
- 2 Munoz-Gamez J, Martín-Oliva D, Canuelo A et al. PARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis. Biochem J 2005; 386: 119-125
- 3 Zhang Y, Gao Y, Zhang G et al. DNMT3a plays a role in switches between doxorubicin-induced senescence and apoptosis of colorectal cancer cells. International Journal of Cancer 2011; 128: 551-561
- 4 Yang M-Y, Lin P-M, Liu Y-C et al. Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells. PloS one 2012; 7: e37205
- 5 Yu Y-C, Yang P-M, Chuah Q-Y et al. Radiation-induced senescence in securin-deficient cancer cells promotes cell invasion involving the IL-6/STAT3 and PDGF-BB/PDGFR pathways. Scientific reports 2013; 3
- 6 Kong Y, Cui H, Ramkumar C et al. Regulation of senescence in cancer and aging. Journal of aging research 2011; 2011: 963172-
- 7 Taylor JR, Lehmann BD, Chappell WH et al. Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget 2011; 2: 610
- 8 McGlynn LM, Kirkegaard T, Edwards J et al. Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients. Clinical Cancer Research 2009; 15: 1487-1495
- 9 Zhu J, Woods D, McMahon M et al. Senescence of human fibroblasts induced by oncogenic Raf. Genes & development 1998; 12: 2997-3007
- 10 Singh R, George J, Shukla Y. Role of senescence and mitotic catastrophe in cancer therapy. Cell Div 2010; 5: 4-
- 11 Zhou B-BS, Chaturvedi P, Spring K et al. Caffeine abolishes the mammalian G2/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity. Journal of Biological Chemistry 2000; 275: 10342-10348
- 12 Ashwell S, Zabludoff S. DNA damage detection and repair pathways – recent advances with inhibitors of checkpoint kinases in cancer therapy. Clinical Cancer Research 2008; 14: 4032-4037
- 13 Gewirtz DA, Holt SE, Elmore LW. Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochemical pharmacology 2008; 76: 947-957
- 14 Chen C-R, Wang W, Rogoff HA et al. Dual induction of apoptosis and senescence in cancer cells by Chk2 activation: checkpoint activation as a strategy against cancer. Cancer research 2005; 65: 6017-6021
- 15 Manna SK, Gangadharan C, Edupalli D et al. Ras puts the brake on doxorubicin-mediated cell death in p53-expressing cells. Journal of Biological Chemistry 2011; 286: 7339-7347
- 16 Jobson AG, Lountos GT, Lorenzi PL et al. Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]. Journal of Pharmacology and Experimental Therapeutics 2009; 331: 816-826
- 17 Rodriguez-Bravo V, Guaita-Esteruelas S, Salvador N et al. Different S/M checkpoint responses of tumor and non-tumor cell lines to DNA replication inhibition. Cancer research 2007; 67: 11648-11656
- 18 Zemskova M, Lilly MB, Lin Y-W et al. p53-dependent induction of prostate cancer cell senescence by the PIM1 protein kinase. Molecular Cancer Research 2010; 8: 1126-1141
- 19 Hirose Y, Katayama M, Mirzoeva OK et al. Akt activation suppresses Chk2-mediated, methylating agent – induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. Cancer research 2005; 65: 4861-4869
- 20 Ku BM, Lee YK, Jeong JY et al. Caffeine inhibits cell proliferation and regulates PKA/GSK3β pathways in U87MG human glioma cells. Molecules and cells 2011; 31: 275-279
- 21 Crescenzi E, Palumbo G, de Boer J et al. Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy. Clinical Cancer Research 2008; 14: 1877-1887
- 22 Goehe RW, Di X, Sharma K et al. The autophagy-senescence connection in chemotherapy: must tumor cells (self) eat before they sleep?. Journal of Pharmacology and Experimental Therapeutics 2012; 343: 763-778
- 23 Elmore LW, Di X, Dumur C et al. Evasion of a single-step, chemotherapy-induced senescence in breast cancer cells: implications for treatment response. Clinical cancer research 2005; 11: 2637-2643
- 24 Wansleben S, Davis E, Peres J et al. A novel role for the anti-senescence factor TBX2 in DNA repair and cisplatin resistance. Cell death & disease 2013; 4: e846
- 25 Vigneron A, Vousden KH. p53, ROS and senescence in the control of aging. Aging (Albany NY) 2010; 2: 471
- 26 Mosieniak G, Sliwinska MA, Alster O et al. Polyploidy formation in doxorubicin-treated cancer cells can favor escape from senescence. Neoplasia 2015; 17: 882-893
- 27 Sliwinska MA, Mosieniak G, Wolanin K et al. Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells. Mechanisms of ageing and development 2009; 130: 24-32
- 28 Luo Y, Zou P, Zou J et al. Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKα dependent manner. Experimental gerontology 2011; 46: 860-867
- 29 Demidenko ZN, Korotchkina LG, Gudkov AV et al. Paradoxical suppression of cellular senescence by p53. Proceedings of the National Academy of Sciences 2010; 107: 9660-9664
- 30 Fitzgerald AL, Osman AA, Xie TX et al. Reactive oxygen species and p21Waf1/Cip1 are both essential for p53-mediated senescence of head and neck cancer cells. Cell death & disease 2015; 6: e1678
- 31 Leontieva OV, Blagosklonny MV. CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle 2013; 12: 3063-3069